September
Question: 1
You are asked to see a 6-week-old female infant. The pregnancy was uncomplicated but notable for prenatal
ultrasonography that revealed holoprosencephaly. Her birth weight was 2.6 kg. She had a blood glucose level
taken shortly after her birth that was 32 mg/dL (1.8 mmol/L) by glucometer. Her physical examination
demonstrated slightly widened sutures, a small umbilical hernia, and polydactyly.
She presents now with jaundice. Her total bilirubin is 15.1 mg/dL (258 µmol/L), with a direct bilirubin of 2.2 mg/dL
(37.6 µmol/L). As part of the evaluation for her jaundice, she has thyroid function tests sent that return with a
free thyroxine concentration of 0.8 ng/dL and a thyroid-stimulating hormone level of 0.8 µU/mL.
Of the following, the MOST likely explanation for the girl’s diagnosis is a mutation in
A. GLI2
B. LHX3
C.
LHX4
D. SOX2
E.
SOX3
Correct Answer: A
This infant has a low free thyroxine (T4) level and a low normal thyroid-stimulating hormone (TSH) level consistent
with central hypothyroidism. Her history of hypoglycemia and direct hyperbilirubinemia suggest growth hormone
(GH) or adrenocorticotropic hormone (ACTH) deficiency. Thus, she appears to have multiple pituitary hormone
deficiencies. Of the choices listed, mutations in GLI2 are associated with holoprosencephaly (HPE).
Mutations in several genes in the sonic hedgehog (SHH) signaling pathway have been implicated in HPE. These
include SHH itself, a protein that influences patterning in the early embryo; patched 1 (PTCH1), a receptor for
SHH; GLI2, a transcription factor that mediates SHH signaling; and dispatched homolog 1 (DISP1), a protein that
may play an essential role in hedgehog patterning activities. Of these, mutations in GLI2 have been found in
patients with HPE or HPE-like phenotype with and without pituitary hormone deficiencies and in patients with
pituitary hormone deficiencies with and without HPE craniofacial features. Pituitary hormone deficiencies range
from isolated GH deficiency to GH deficiency plus one, more, or all anterior pituitary hormone deficiencies. One
mutation has also been associated with antidiuretic hormone deficiency. Some patients with GLI2 mutations also
have polydactyly. Pituitary findings include anterior pituitary aplasia or hypoplasia +/- ectopic posterior pituitary.
Fibroblast growth factor 8 (FGF8) mutations may also cause HPE and hypopituitarism.
Mutations in the other transcription factors in the response choices are also associated with syndromic
hypopituitarism. The major findings are as follows: LHX3 with neck abnormalities, LHX4 with cerebellar
abnormalities, SOX2 with anophthalmia and esophageal atresia, and SOX3 with developmental delay. See the
Table for all findings.
PREP Pearls:

Mutations in GLI2 are associated with hypopituitarism, holoprosencephaly, and polydactyly.

Mutations in pituitary early developmental genes are associated with hypopituitarism and other
developmental anomalies

Mutations in pituitary-specific differentiation genes are associated with only pituitary hormone deficiencies.
Question: 2
A 15-year-old girl has been treated for the pulmonary and gastrointestinal manifestations of cystic fibrosis (CF)
since age 2 years, when she presented with impaired weight gain and linear growth and a history of multiple
episodes of pneumonia and less severe respiratory infections. Now she is losing weight even though she is
adherent to pancreatic enzyme replacement, has stable pulmonary function, and does not have clinical or
laboratory evidence of an underlying infection.
Of the following, the BEST test to order to determine if this young lady has cystic fibrosis–related diabetes is
A. fasting plasma glucose level
B. 2-hour post–oral glucose challenge glucose level
C.
plasma glycated hemoglobin level (HbA1c)
D. random urine analysis
E.
serum fructosamine level
Correct Answer: B
The 2-hour post–oral glucose challenge glucose level result is currently considered the best test for the diagnosis
of cystic fibrosis–related diabetes (CFRD) because it is more sensitive in detecting early CFRD than the other
options. Fasting plasma glucose, glycated hemoglobin (HbA1c), and fructosamine levels and urine analyses do not
have proven efficacy for the detection of all stages of CFRD.
Cystic fibrosis (CF) shortens the half-life of red blood cells, reducing the time- and glucose-dependent
accumulation of hemoglobin glycosylation. Thus, HbA1c levels underestimate the average blood glucose levels in
individuals with cystic fibrosis and cannot be used to screen for diabetes mellitus in individuals with CFRD. Levels
of another glycosylated protein, fructosamine, have also been found to underestimate average past blood glucose
levels in individuals with cystic fibrosis.
There are 4 stages of glucose control in individuals with CF; CFRD includes the third and fourth phases. During the
first stage, or the glucose tolerant (GT) stage, oral glucose tolerance test results are normal, even though firstphase insulin release is decreasing, because there is a sufficient compensatory increase in insulin sensitivity to
maintain euglycemia. The second stage, the indeterminate glucose tolerance (INDET) stage, occurs when
increased insulin sensitivity can no longer compensate for the loss of first-phase insulin release, thereby leading to
a progressive delay in peak insulin secretion that results in worsening control of glucose homeostasis after intake
of carbohydrates. During the INDET stage, glucose levels rise above 200 mg/dL from 30 minutes after the
challenge, remain there until just over 1 hour after the carbohydrate challenge, and return to normal by 2 hours
after the challenge. The third stage, diabetes mellitus without fasting hyperglycemia (CFRD FH-) occurs when
blood glucose levels no longer drop below 200 mg/dL (11.1 mmol/L) by 2 hours after the challenge and CFRD has
started. During this stage, fasting blood glucose levels are not elevated. Compared to other types of diabetes,
there is actually an increased risk of fasting hypoglycemia during this stage. The fourth stage, diabetes mellitus
with fasting hyperglycemia (CFRD FH+), occurs when fasting hyperglycemia (blood glucose levels greater than or
equal to 126 mg/dL [7 mmol/L]) occurs. Since the blood glucose levels are not consistently elevated enough to
cause glycosuria throughout the day during the CFRD FH- stage of CFRD, lack of glycosuria cannot be used to
exclude CFRD in a patient with CF.
In CFRD FH-, postprandial, but not fasting, blood glucose levels are elevated, and treatment focuses on the use of
a mealtime rapid-acting insulin analog.
The value of basal insulin therapy alone or basal–bolus therapy has yet to be determined. CFRD FH+ is usually
treated with standard basal–bolus insulin regimens, including basal and rapid-acting insulin by multiple daily
injections or continuous subcutaneous infusion.
The definition of CFRD, like the definition of other type of diabetes mellitus, is currently based on identifying when
the blood glucose levels are high enough to increase the risk for the development of microvascular complications
such as nephropathy and retinopathy. While HbA1c levels may be spuriously low in CFRD, the American Diabetes
Association and the Cystic Fibrosis Foundation still recommend that for most patients with CFRD, the HbA 1c
treatment goal should be less than or equal to 7% to reduce the risk of microvascular complications. In addition,
multiple daily self–glucose monitoring is recommended, with glucose targets the same as those for other forms of
diabetes mellitus. In addition, there is a growing body of evidence suggesting that individuals with INDET are at
increased risk for worsening nutritional status and pulmonary function even if they are not at increased risk for
microvascular complications. Trials of early initiation of insulin therapy are underway.
Oral antidiabetic agents are not recommended in patients with CFRD. Insulin sensitizers are not recommended,
since insulin insufficiency, rather than insulin resistance, is the key component of pancreatic diabetes.
Sulfonylureas do not have long-term benefit and may accelerate loss of islet β-cell function by causing islet β-cell
apoptosis.
Cystic fibrosis is one of several causes of diabetes mellitus related to primary pancreatic disease (ie, type 3c
diabetes mellitus). Other causes include acute and chronic pancreatitis, hereditary hemochromatosis, pancreatic
cancer, pancreatic surgery, and pancreatic aplasia. Patients with pancreatic aplasia may present with neonatal
diabetes mellitus if little or none of the pancreas is present. If a greater amount of the pancreas is present,
diabetes mellitus may present at an older age.
Transient diabetes mellitus is not uncommon in patients with acute pancreatitis. Patients with chronic pancreatitis
accompanied by pancreatic calcifications are more likely to have diabetes mellitus than those without pancreatic
calcifications. Persistent diabetes mellitus is likely to appear only during the advanced stages of chronic
pancreatitis. Thus, these patients are not likely to manifest persistent diabetes mellitus until a decade after onset
of the chronic pancreatitis. Patients with chronic pancreatitis may have glucagon deficiency and, thus, increased
risk for hypoglycemia.
Risk of diabetes mellitus following pancreatic surgery—when the surgery involves removal of the distal pancreas
because of its concentration of islets of Langerhans—is greater in the tail than elsewhere in the pancreas. The risk
for development of diabetes mellitus after pancreatic surgery is also greater in patients with chronic pancreatitis
than in those without chronic pancreatitis. Counterintuitively, many patients with both pancreatic cancer and
impaired glucose tolerance or diabetes mellitus will have improvement in their glucose tolerance following surgical
treatment of the cancer, while those undergoing pancreatic surgery for nonmalignant issues have increased risk
for worsening glucose tolerance after surgery.
Autoimmune pancreatitis, rare in pediatric age ranges, may cause chronic pancreatitis that is strongly associated
with diabetes mellitus. Glucocorticoid therapy improves glucose tolerance and other aspects of pancreatitis in
about half of patients with autoimmune pancreatitis.
PREP Pearls:

Cystic fibrosis (CF) shortens the half-life of red blood cells, reducing the time- and glucose-dependent
accumulation of hemoglobin glycosylation.

In early stages of cystic fibrosis related diabetes mellitus, fasting glucose concentrations are normal.
Question: 3
A 4-year-old boy presents to the endocrine clinic for evaluation of precocious puberty. He is growing rapidly
(height, 90th percentile; midparental height, 50th percentile), has body odor and comedonal acne, and is Tanner
stage 2 for pubic hair and phallus. His testes are 4 mL in volume on the right and 4 to 5 mL in volume on the left,
but you palpate a mass at the inferior pole of his left testis. He had laboratory tests before his visit, the results of
which are as follows:

Sodium, 140 mEq/L (140 mmol/L)

Potassium, 3.9 mEq/L (3.9 mmol/L)

Bicarbonate, 22 mEq/L (22 mmol/L)

17-hydroxyprogesterone, 23,610 ng/dL

Testosterone, 32 ng/dL (1.11 nmol/L)

Dehydroepiandrosterone sulfate (DHEA-S), 109 µg/dL (2.9 µmol/L)

Chorionic gonadotropin (β-HCG), 1 mIU/mL (1 IU/L)
Of the following, the BEST next step in the evaluation of this patient’s testicular finding is
A. computed tomography of the abdomen
B. magnetic resonance imaging of the pelvis
C.
measurement of plasma renin
D. measurement of serum cortisol
E.
ultrasonography of the testes
Correct Answer: E
The patient in the vignette has congenital adrenal hyperplasia (CAH) and adrenal rest tumors of the testes, and
one such mass is at least palpable on the left side. Testicular ultrasonography will confirm this diagnosis and may
demonstrate the presence of a similar lesion (or lesions) on the right side as well, which may further explain why
the testicular size is greater than 3 mL. Measurement of serum cortisol or plasma renin would not help in
evaluating this patient’s testicular findings. Computed tomography of the abdomen or pelvic magnetic resonance
imaging is not needed to confirm the presence of the testicular lesions. Testicular adrenal rest tumors are most
often found in patients with CAH and can take up a large part of the testis volume. Patients with classic CAH are at
risk of developing these lesions, and such lesions will occur more frequently if a patient’s adrenals have been
inadequately suppressed (as will be the case with sustained nonadherence). Simple virilizers diagnosed late can
also develop adrenal rest tumors.
Patients with CAH as young as 3 years old have been found to have these lesions. Although in most patients there
is an established diagnosis of CAH, adrenal rest tumors occur in patients who were previously not diagnosed (in up
to 18% of cases). In the general population, adrenal rest tumors within the testes occur in 7.5% to 15% of
newborn infants. The rest tumors are small and regress during the first couple of months of life. From a
histological perspective, the adrenal rest tumors in the testes may appear similar to Leydig cell tumors—electron
microscopy will reveal characteristics associated with steroid-producing cell—but they do not have the Reinke
crystals typical of Leydig cells. The prevalence of adrenal rest tumors in boys with CAH due to 21-hydroxylase
enzyme deficiency ranges from 21% to 28%. Adrenal rest tumors are benign “tumors” and can be found anywhere
along the path of gonadal descent between the adrenal glands and the scrotum. They are dependent on
adrenocorticotropic hormone (ACTH) secretion and will manifest during periods of persistent elevation of the ACTH
concentration. On the other hand, with appropriate glucocorticoid therapy and suppression of the ACTH, the rest
tumors will regress in most patients. They can also occur in other disease states characterized by increased ACTH
production, such as Cushing disease, Nelson syndrome, and Addison disease. When present, adrenal rest tumors
often occur bilaterally and there may be multiple lesions present. When undiagnosed, they may impact testicular
function (obstruction of the seminiferous tubules) and lead to infertility.
PREP Pearls:

Adrenal rest tissue (adrenal rest “tumors”) is ectopic adrenal tissue.

Increased adrenocorticotropic hormone secretion can lead to enlargement of adrenal rest tissue in the
gonads.

Enlarged testis size in patients with poorly controlled congenital adrenal hyperplasia may be due to
enlarged adrenal rest tissue and may regress when appropriate adrenal suppression (with glucocorticoid
therapy) is achieved.


Question: 4
You are beginning a study of a new immunomodulatory drug for patients with type 1 diabetes mellitus.
The study is a blinded placebo-controlled design, with two-thirds of subjects receiving the drug and onethird receiving placebo. You have received grant funding and approval from both the institutional review
board and clinical research center. You have trained the staff and navigated all the steps necessary to
recruit your first patient. Only the pharmacist drawing up the study medication will know to which arm the
subject has been randomized before unblinding.

You have identified a 14-year-old girl whose parents are very eager to do anything to reverse her disease.
The child, however, is more skeptical given that the study involves multiple visits to the research center
along with blood draws and infusions of the study drug.

You have reviewed the informed consent forms with her parents and the assent form with her. Before
signing the forms, the child asks you which treatment group you think would be “best” for her. You answer
that the reason the study is being done is because the community of diabetes doctors is not yet sure
which therapy is best.

Of the following, the research tenet that would MOST likely be violated if the community of physicians
running the trial already had convincing evidence that one treatment was superior is

A. clinical equipoise
B. cognitive bias
C.
randomization
D. therapeutic fallacy
E.
uncertainty principle
Correct Answer: A
The ethics and procedures performed when enrolling patients into research trials are complex and seem to be
perpetually molded and modified over time. Clinical equipoise, the current standard in the United States, holds
that the community of physicians establishes practice standards and that subjects can be enrolled into research
trials with multiple arms if there is a sense of collective uncertainty about the optimal treatment regimen.
However, the uncertainty principle holds that a particular patient should only be entered into a research trial with
multiple arms if the clinician responsible for that patient’s care is uncertain which treatment is most appropriate
for that patient. It is the standard principle applied to research studies conducted in the United Kingdom. The
difference between clinical equipoise and the uncertainty principle is that clinical equipoise exists when the overall
consensus (many people) is that one treatment is not preferred over another, whereas the uncertainty principle
applies if just the involved clinician (one person) holds such a view.
Many clinical research trials are designed as randomized trials. Many of these trials compare a placebo (sham
treatment) to an active form of therapy. This is done to avoid some possible biases, including selection biases that
lead to a mismatching of some key features of groups in each arm of the study. Cognitive biases occur when an
observer (subject or investigator) deviates systematically from a rational standard or good judgment. An example
of cognitive bias would be if an investigator implements a well-designed, appropriately powered blinded study for
a new therapy and finds out, at the end of the study, that there was no benefit (and perhaps a harm) to the
experimental treatment but feels at the end of the study that somehow the results might be flawed. An example of
this is diethylstilbestrol (DES) use during pregnancy to prevent low birth weight and preterm delivery. Dieckmann
and colleagues reported in their 1953 paper that “stilbestrol did not reduce the incidence of abortion, prematurity,
or postmaturity,” yet—possibly because the overwhelming sentiment in the obstetric community was that DES
must work—failed to notice that their data showed DES was associated with an increased risk of low birth weight
and preterm deliveries (ie, 7.5% of babies of primiparous mothers treated with DES had birth weights of <2,500
grams, versus 4.0% of controls).
Randomization violations can occur, but in the case outlined in the vignette, this is unlikely since the investigator
and subject are both blinded to which study medication is being administered.
Therapeutic fallacy is a false expectation on the part of the subjects or the providers that the research study will
also provide for the subject’s medical needs and welfare as patients. Many people and physicians participate in
research because of a desire to receive the “newest” treatment or “better care.”
The intervention in many studies has a potential for harm. These harms or risks can be “anticipated” or
“unanticipated.” Subjects consenting to be in research trials should be advised of the anticipated risks of each arm
of the study and counseled that they will be monitored for unanticipated risks. Anticipated risks are typically
outlined in an informed consent statement for adults and may be generally described in an assent statement for
older children.
Rarely, informed consent statements give an incomplete or misleading reason for the research study so that
investigators can engage in deception of subjects. This is done primarily in psychological studies. Despite the
contravening of the informed consent process, deception is generally considered ethically acceptable if the
following 4 conditions are present:
1. The research question cannot be answered without deception
2. The value of the potential research results justifies use of deception
3. Research subjects are not deceived about intervention risks
4. Subjects are told how and why they were deceived once they finish the research study
Trials should be designed so that, if successful, they will be convincing enough to resolve disputes about which
practice is preferred. It is therefore important to make sure that studies do not have flawed design or poor
implementation. Examples of flawed design include underpowering the study for the primary outcomes, including a
poor comparison group, or studying the wrong dose or regimen of a treatment.
PREP Pearls:

Therapeutic fallacy is a false expectation that a research study will provide for the subject’s medical needs.

Clinical equipoise holds that subjects can be enrolled into research trials if there is a collective sense of
uncertainty about optimal treatment in the medical community.

The uncertainty principle holds that a particular patient should only be entered into a research trial with
multiple arms if the clinician responsible for that patient’s care is uncertain which treatment is most
appropriate for that patient.
Question: 5
You are being consulted on a 15-year-old boy who has Duchenne muscular dystrophy (DMD). He presents with
multiple vertebral compression fractures that involve T4, T5, T6, T7, T8, T9, and L1 vertebrae. He was diagnosed
with DMD at age 3 years and has been in a wheelchair since age 9 years. He appears slightly cushingoid. His
height is at less than the 3rd percentile and weight is at the 50th percentile for age. His sexual maturity rating is
Tanner stage 2 for pubic hair, and he has a testicular volume of 4 to 6 mL bilaterally. He has taken prednisone 20
mg daily since age 5 years for treatment of DMD. He also takes vitamin D3 2,000 IU and calcium carbonate 500
mg daily. His dual energy X-ray absorptiometry demonstrates an L2–L4 bone mineral density z score of -4.0 for
lumbar spine, and a z score of -4.1 for total body bone mineral density.
Laboratory evaluation reveals the following:

Calcium, 9.6 mg/dL (2.4 mmol/L)

Phosphorous, 4.2 mg/dL (1.36 mmol/L)

Alkaline phosphatase, 79 U/L

25-hydroxyvitamin D, 55 nmol/L

Parathyroid hormone, 22 pg/mL (22 ng/L)

Urine calcium-to-creatinine ratio, 0.25
Of the following, the MOST likely factor(s) contributing to his osteoporosis is/are
A. decreased bone formation and increased bone resorption due to poor weight bearing, chronic
glucocorticoids use, and altered GH–IGF-1 axis
B. decreased bone formation and increased resorption due to glucocorticoid induced suppression of GH–
IGF-1 axis as evidenced by the short stature
C.
increased bone resorption and reduced bone formation due to the delayed puberty and lower
concentration of sex hormones
D. increased bone resorption due to increased RANKL expression on osteoclasts and decreased
osteoprotegerin production by osteoblasts
E.
increased bone resorption due to nonambulation and poor weight bearing, resulting in poor mechanical
load and reduced influence of gravity
Correct Answer: A
Axial skeletal fractures, as reported in the boy in this vignette, and fractures after low biomechanical force are
suggestive of fragility fractures. Absence of weight bearing, chronic use of glucocorticoids, altered growth
hormone–insulin-like growth factor 1 (GH–IGF-1) axis, low skeletal muscle fat content, poor exposure to sunlight,
and inadequate intake of calcium and vitamin D all could contribute to the osteoporosis seen in the boy in the
vignette. Even though chronic hypogonadism and androgen insufficiency can result in osteoporosis, lower
concentrations of sex hormones from delayed puberty only lead to reduced bone mineral density for age in this
subject.
Osteoporosis is a metabolic bone disease in which osteoblastic bone formation lags behind the osteoclastic bone
resorption, which results in micro-architectural deterioration of bone tissue, increased bone fragility, and fracture.
Reduction in physical activity, insufficient vitamin D and calcium intake, reduced estrogens and androgens,
hyperparathyroidism, reduced renal production of 1,25(OH)2D, anorexia nervosa, hyperthyroidism,
hyperparathyroidism, hypercortisolism, and chronic inflammation can all contribute to osteoporosis. Mechanical
load and effect of gravity from regular routine weight bearing physical activities are essential to maintain bone
mass. Therefore, inactivity leads to rapid bone loss.
Bone is continuously remodeled (ie, resorbed and formed).This is mediated by the osteoblasts, which help with
bone formation, and osteoclasts, which resorb the bone. During childhood and adolescence, bone formation
slightly exceeds resorption. Adolescence is the critical time period for accumulation of bone mass, with maximal
rate of bone mineral content accrual around age 12.5 years in girls and 14 years in boys.
Communication between osteoblasts and osteoclasts is necessary for the regulatory balance between bone
formation and resorption. Communication between these cells is mediated by receptor activator of nuclear factor
κ-B (RANK) ligand (RANKL), expressed on the osteoblast cell surface, which binds to the cell membrane receptor
RANK on osteoclast progenitors and thus stimulates osteoclastogenesis (Figure).
Osteoblasts also secrete a protein, osteoprotegerin (OPG), that acts as a soluble receptor for RANKL (natural
RANKL neutralizing protein), thus blocking the effect of RANK. Transforming growth factor β1 is released from the
bone matrix during bone resorption and acts as a primary coupling factor for bone remodeling.
There are multiple factors that are important in bone formation and resorption. Parathyroid hormone (PTH), the
calciotropic hormone, activates osteoclasts, thereby leading to increased bone resorption and liberating calcium
and phosphate from bone. PTH also increases absorption of calcium from the distal renal tubule; lowers phosphate
levels by inhibiting phosphate reabsorption in the proximal and distal renal tubule; and stimulates 1 αhydroxylation of 25-hydroxyvitamin D (25[OH]D) to increase production of 1,25 dihydroxyvitamin D (1,25[OH] 2D).
1,25(OH)2D increases calcium absorption from the gut and distal renal tubule and suppresses the overactivity of
PTH, thus maintaining serum calcium concentration. Continuous oversecretion of PTH, as occurs in
hyperparathyroidism, stimulates osteoclast-induced bone resorption. Intermittent PTH exposure results in
osteoblast-dependent bone formation and prohibits bone resorption. Pulsatile PTH secretion, as seen in healthy
individuals, is important for the anabolic actions of PTH. Calcitonin, produced by parafollicular cells of the thyroid
gland, has modest inhibitory effects on osteoclastic activity.
Growth hormone (GH) is essential for longitudinal bone growth. GH stimulates hepatocytes to secrete IGF-1.
Chondrocytes, osteoblasts, and other cells also produce IGF-1 locally. IGF-1 stimulates chondrocytes and
osteoblasts in the epiphyseal plates, resulting in bone formation. Other hormones such as thyroid hormones and
sex steroids (ie, estrogens and androgens) also have roles in bone growth and maintenance of bone mass. Thyroid
hormone receptors are expressed on chondrocytes, bone marrow stromal cells, osteoblasts, and osteoclast
precursors. Thyroid hormone excess stimulates bone resorption. Estrogens reduce the number and activity of
osteoclasts and reduce bone resorption. Estrogen stimulates chondrogenesis in the epiphyseal growth plate and
stimulates OPG production by osteoblasts. Androgens are converted to estrogens by the adipocyte-derived
aromatase and may also have some antiresorptive effect independent of estrogen actions.
Glucocorticoids inhibit osteoblast function, reduce life span of osteoblasts, induce RANKL and induce osteoclastic
resorption, thereby inhibiting bone formation and increasing resorption. Glucocorticoids also reduce calcium
absorption from the gut, increase vitamin D catabolism, and directly inhibit actions of IGF-1, thereby decreasing
secretion of GH and altering the GH–IGF-1 axis.
PREP Pearls:

Factors which that stimulate bone formation are mechanical load, growth hormone–insulin-like growth
factor 1 (GH–IGF1), and intermittent parathyroid hormone (PTH).

Factors that stimulate bone resorption are thyroid hormone and continuous PTH.

Factors that inhibit bone resorption are estrogen, androgen, and calcitonin, and the factor that inhibits
bone formation is glucocorticoids.
Question: 6
A 7-year-old boy was admitted for failure to thrive with a history of polyuria and polydipsia. He also presented
with metabolic acidosis, elevated blood urea nitrogen, and elevated renin and aldosterone levels. He had normal
levels of creatinine and liver enzymes and a normal complete blood cell count. After admission, his overnight urine
volume was noted to be excessive and consistently dilute. His morning urinalysis had a low urine specific gravity
with 1+ glucose and proteinuria. Further evaluation found his urine to have hypercalciuria and a high fractional
excretion of sodium and potassium.
By report, this young boy had an uncomplicated full-term delivery with a normal birth weight and length. He met
all motor and development milestones with no health issues to explain his gradual fall from the 50th percentile for
height and weight to below the 5th percentile for both over the past five years. He had a normal lead level and
stool analysis findings at age 5 years, but he has not returned to his doctor for 2 years. He has had 2 overnight
hospital admissions for dehydration at another local hospital emergency department in the past year. His mother
recalls that there was a concern for diabetes mellitus based on the urinalysis results at his last admission, but the
blood glucose values were normal. He has a family history that includes parental consanguinity with 2 healthy
siblings. His father has type 2 diabetes mellitus, and two maternal uncles had short stature and both died
following end-stage renal disease before age 40 years.
On examination, the child is alert and interactive but appears tired. He has a weight and height at the first
percentile and normal head circumference. He has a normal blood pressure and pulse. He has blonde hair and fair
skin. He has no dysmorphic features. He complains of photophobia, but his examination is otherwise normal.
Magnetic resonance imaging, including neurohypophyseal bright signal on T1 sequence, is normal.
Of the following, the test that is MOST likely to establish his diagnosis is
A. leukocyte cystine levels
B. serum ceruloplasmin
C.
serum myoglobin
D. serum uric acid
E.
urinary homocysteine
Correct Answer: A
The differential diagnosis for this child’s findings of renal tubular Fanconi syndrome and poor growth includes
cystinosis, Wilson disease, galactosemia, glycogen storage disease, and tyrosinemia. Nephropathic cystinosis is
the most likely metabolic cause of renal tubular Fanconi syndrome and failure to thrive in this child. In particular,
cystinosis can mimic diabetes insipidus and diabetes mellitus when it first presents, with polyuria, glycosuria (with
normal serum glucose), and failure to thrive. Blonde hair, fair skin, and photophobia are also typical of cystinosis.
The diagnosis of this rare autosomal recessive disorder is made by observing the presence of typical corneal
crystals on slit-lamp examination and documenting elevated leukocyte cystine content. Intracellular lysosomal
crystal formation occurs throughout the body (including the thyroid and gonads) due to an inherited defect of
lysosomal membrane transport. The accumulated cystine crystals likely accelerate renal cell apoptosis with
development of eventual end-stage renal disease. Cysteamine therapy lowers cystine accumulation by cycling into
the cell lysosome, where it binds to cystine to form a complex that can exit to the cytoplasm using a lysine
transport mechanism. Cysteamine therapy can delay renal glomerular deterioration and improve linear growth and
vision.
Wilson disease is an autosomal-recessive genetic disorder caused by accumulation of copper in the liver and brain,
with progression over time to liver failure and neuropsychiatric disorder. Renal tubular acidosis can also occur.
Diagnostic findings of Wilson disease include slit-lamp evidence for Kayser–Fleischer rings and levels of
ceruloplasmin and copper that are paradoxically low in the serum but elevated in the urine. Galactosemia is an
autosomal recessive disorder of galactose metabolism that can cause eventual liver and kidney failure, cataracts,
and progressive disease. Luckily, most infants are diagnosed on newborn screening. Glycogen storage diseases
(GSDs) are a heterogeneous group of 11 disorders of glycogen synthesis or breakdown. GSD type I can cause
lactic acidosis and hyperuricemia, and type V can cause renal failure due to myoglobinuria. Tyrosinemia type 1 is a
rare autosomal-recessive defect that presents in the first year of life with severe liver dysfunction and growth
failure associated with neurologic crises. Homocysteinuria (elevated urinary homocysteine) is associated with tall
stature.
Metabolic and renal diseases that result in metabolic acidosis are associated with impaired linear growth due to a
variety of proposed mechanisms. Acidosis may inhibit growth hormone (GH) secretion and action on peripheral
tissues. Studies have demonstrated inhibited pulsatile secretion of growth hormone in vivo as well as
downregulation of hepatic insulin-like growth factor (IGF) 1 and GH receptor mRNA expression. End-organ growth
hormone resistance may also occur. Metabolic acidosis is often associated with increased bone resorption.
Underlying renal disease exacerbates these growth issues when poor nutrition, increased levels of inflammatory
cytokines, secondary hyperparathyroidism, and low vitamin D levels further impair bone mineralization.
The GH-releasing hormone (GHRH) receptor is down regulated in prolonged hypoxia. Patients with hypoxia often
also suffer from simultaneous inadequate caloric intake and elevated cytokines. All of these factors play a role in
decreasing the number of hepatic growth hormone receptors and contribute to decreased circulating levels of IGF3 and insulin-like growth factor binding protein (IGFBP) 3. Levels of IGFBPs that are not regulated by growth
hormone (IGFBP-1, 2, 4, and 6) are often elevated. The pathogeneses of growth failure in congenital heart disease
and hemoglobinopathies are likely multifactorial due to impaired oxygen delivery to tissues, increased work of the
cardiovascular system, energy demands of increased hematopoiesis, and impaired nutrition. Poor growth
associated with hypoxemia due to poorly controlled asthma is exacerbated by steroid use, and cystic fibrosis
patients have the additional stressors of pancreatic insufficiency, chronic infections, and cystic fibrosis –related
diabetes (CFRD).
PREP Pearls:

Nephropathic cystinosis can cause renal tubular Fanconi syndrome and failure to thrive. Treatment with
cysteamine can improve growth in these patients.

Metabolic acidosis is associated with inhibited pulsatile secretion of growth hormone in vivo as well as
downregulation of hepatic insulin-like growth factor 1 and growth hormone receptor mRNA expression.

Cystinosis can mimic diabetes insipidus and diabetes mellitus when it first presents, with polyuria,
glycosuria (with normal serum glucose level), and failure to thrive. Blonde hair, fair skin, and photophobia
are also typical of cystinosis.
Question: 7
As you review your charts for your endocrine clinic tomorrow morning, you note that your 8:00 am patient is a
return patient with poorly controlled congenital adrenal hyperplasia (CAH). He has not been adherent to his
hydrocortisone replacement in the past.
You note that your 8:30 am patient is a new patient to your practice, a 14-year-old boy with Fragile X syndrome
(FXS) and “maternal concerns.” You anticipate an abnormal testicular examination finding for this patient as well.
Of the following, the expected findings you are MOST likely to see in your patients would include
A. macroorchidism in the patient who has CAH
B. malignant intratesticular tumors in the patient who has CAH
C.
malignant intratesticular tumors in the patient who has FXS
D. normal testicular function in the patient who has FXS
E.
testicular pain with palpation in the patient who has FXS
Correct Answer: D
Both congenital adrenal hyperplasia and fragile X syndrome are associated with testicular abnormalities, including
testicular enlargement. Fragile X syndrome (FXS) is the leading cause of inherited intellectual disability and
autism, with estimated incidences of 1 per 5,000 boys and 1 per 2,500 girls. In most cases, FXS is caused by
hypermethylation and inactivation of FMR1 on the long arm of chromosome X resulting from trinucleotide (CGG)
repeat expansion of the 5’ untranslated region of FMR1. Fully affected boys usually have more than 200 CGG
repeats. Loss of FMR1 expression due to the expanded repeat leads to reduced synthesis of the fragile X mental
retardation protein (FMRP), an mRNA-binding protein that is highly expressed in neurons. FMRP negatively
regulates protein synthesis in the brain, and many clinical features of FXS are thought to result from increased
synaptic protein synthesis.
Clinical features of FXS in boys include autism and intellectual disabilities, attention deficit and hyperactivity,
increased risk of epilepsy, motor coordination problems, craniofacial abnormalities (long face and large prominent
ears), joint laxity, and macroorchidism in 80% of affected pubertal boys. The enlarged testes are caused by
increased interstitial volume and increased peritubular collagen fibers rather than by an increase in the
seminiferous tubules. Enlargement of the testes is usually most pronounced after onset of puberty, although some
prepubertal boys also have macroorchidism. The testes have normal function, are not tender to touch, and are not
at risk for malignancy.
A Prader–Willi syndrome (PWS)-like phenotype of FXS has also been described in boys. Patients have extreme
obesity, a round face, small and broad hands, and regional skin pigmentation. Unlike those with PWS, these
patients do not have neonatal hypotonia, extreme hyperphagia during toddlerhood, or methylation abnormalities
at chromosome 15q11-13.
Fragile X syndrome in girls has much more variable presentation. Approximately 50% with the FMR1 mutation will
have the spectrum of behavioral, intellectual, and physical findings often seen in boys, although they usually have
a milder presentation.
Individuals with premutation FXS have between 50 and 200 CGG repeats in FMR1. Males with the premutation
may have neurocognitive defects and are at risk for a tremor or ataxia syndrome (FXTAS). Females may also have
these symptoms, but they are less frequent and less severe. Females with premutation FXS are at an increased
risk for premature ovarian failure, which, in contrast, is not seen in females with full FXS.
Testing for FXS usually involves polymerase chain reaction (PCR) and Southern blot analysis. PCR is effective in
picking up FMR1 repeats in the normal and premutation range but is less sensitive with larger mutations. Southern
blot is effective in detection of all mutation sizes and in determining methylation status of the FMR1 promoter. As
PCR detection improves, Southern blot testing may no longer be necessary.
Testicular adrenal rest tumors (TARTs) are often found next to the hilum of the testis (ie, the paratesticular
region) and are rarely found within the testis. The most common location is the connective tissue adjacent to the
spermatic cord. They are usually bilateral and nonpalpable but may be painful to touch. They are often found on
ultrasonography. On gross examination, TARTs are circumscribed, well-delineated dark brown nodules.
Histologically, they have nuclear pleomorphism, low mitotic activity, extensive fibrosis, cord-like design, and high
concentration of lipochrome pigment. They may grow in size with high adrenocorticotropic hormone (ACTH) levels,
as can be seen in Nelson syndrome, Cushing disease, Addison disease, or poorly controlled congenital adrenal
hyperplasia. Usually, they will shrink with glucocorticoid therapy, but there have been cases of autonomous TARTs
with no response to steroid therapy. TARTs are benign tumors with no risk for malignant transformation. Surgical
excision is only required if they are causing obstructive damage to the testis.
PREP Pearls:

Testicular adrenal rest tumors are usually located in paratesticular regions. They are often bilateral and
nonpalpable but may be painful to touch. They are not at risk for malignant transformation.

Fragile X syndrome (FXS) results from trinucleotide (CGG) repeat expansion of the 5’ untranslated region
of FMR1 on the X chromosome.

Macroorchidism in FXS is most pronounced after onset of puberty and results from increased interstitial
volume and increased peritubular collagen fibers. Testicular function is normal in FXS.
Question: 8
A 3-year-old girl presents with a goiter. Her heart rate is 80 beats/min. She is attentive and has normal vision and
hearing. The remainder of her physical examination is unremarkable. Laboratory evaluation reveals a free
thyroxine level of 2.8 ng/dL (36 pmol/L) and a thyroid-stimulating hormone level of 6 mIU/mL.
Of the following, the MOST likely genetic abnormality in the thyroid-hormone receptor (TR) responsible for her
condition is a(an)
A. absent TRβ allele
B. heterozygous mutation in TRα, causing dominant-negative activity
C.
heterozygous mutation in TRα, causing haploinsufficiency
D. heterozygous mutation in TRβ, causing dominant-negative activity
E.
heterozygous mutation in TRβ, causing haploinsufficiency
Correct Answer: D
This patient has resistance to thyroid hormone (RTH). RTH is caused by mutations in the thyroid hormone receptor
(TR), a nuclear hormone receptor. When the ligand for the TR, triiodothyronine (T3), is not bound, TRs exist as
homodimers or as heterodimers with retinoid X receptors and are attached to DNA thyroid hormone response
elements (TRE) in association with corepressor proteins; transcription is repressed. When T 3 binds to the TR, the
corepressor is released; a coactivator, steroid receptor coactivator-1 (SRC-1), is able to bind to the TR, thereby
allowing transcriptional activation. The TR has two isoforms, TRα and TRβ, encoded on chromosomes 17 and 3,
respectively.
Resistance to thyroid hormone is caused by mutations in the TRβ isoform. TRβ mediates thyroid hormone (TH)
feedback to thyrotropin-releasing hormone (TRH) and thyroid-stimulating hormone (TSH), and a mutation blunts
this feedback so that more TH is produced. In RTH, there is an elevated serum level of free thyroxine (T 4) and, to
a lesser extent, T3; a normal or slightly increased TSH level; and a goiter.
Most cases of RTH are autosomal dominant. Mutant TRß interferes with the function of the wild-type TRß, which is
known as a dominant-negative effect. For a dominant-negative effect to occur, binding to TREs and the ability to
homodimerize or heterodimerize must be preserved.
In the past, RTH was classified as generalized (GRTH) or peripheral (PRTH). In GRTH, patients appeared
eumetabolic. In PRTH, patients appeared hypermetabolic with poor weight gain, as well as with other symptoms,
including hearing defects, attention-deficit disorder, learning disabilities, mental retardation, and delayed bone
formation. However, it is now known that GRTH and PRTH are part of the same spectrum, as identical mutations
have been found in patients classified as having GRTH or PRTH, many of whom are members of the same family.
Possible explanations include differences in the relative levels of mutant and wild-type TR expression and genetic
variability of factors (other than TR) altering the phenotype of RTH.
When both TRβ genes are mutant, RTH is severe with very high TH levels. There is hypothyroidism in bone and
brain due to interference of the double dose of mutant TRβ on the function of TRα and thyrotoxicosis in other
tissues, such as the heart, due to high TH levels in tissues that predominantly express TRα1.
When one TRß gene is absent, patients have no signs or symptoms because only one TRß allele is necessary for
thyroid function.
When both TRβ genes are absent, patients have severe deafness (TRß is necessary for cochlear maturation) and
monochromatic vision (TRß is necessary for cone photoreceptor development). Some of these patients have some
TH responsiveness, so it is thought that TRα1 can partially substitute for TRß.
More recently, dominant-negative TRα mutations have been identified. TRα does not mediate TH feedback to
TRH/TSH, so patients with TRα mutations do not have elevated TH levels. They have a peripheral hypothyroidism
that may respond to supraphysiologic doses of levothyroxine.
The distribution of the TR isoforms varies between different tissues. TRα has one T 3-binding splice product, TRα1,
which is predominantly expressed in the brain, heart, and skeletal muscle, and two non-T3-binding splice products,
TRα2 and TRα3. TRβ has three T3-binding splice products: TRβ1 is expressed widely; TRβ2 is expressed primarily
in the brain, retina, and inner ear; and TRβ3 is expressed in kidney, liver, and lung. The variation of TH resistance
in different tissues can be explained by the relative expression and distribution of the TR isoforms, as well as of
the nuclear receptor corepressors and coactivators. The selective actions of TR are also influenced by local ligand
binding availability, by transport of TH into the cell by monocarboxylate transporter (MCT8) or other related
transporters, and by the sequence and location of the TH response elements.
PREP Pearls:

Mutations in TRβ can cause resistance to thyroid hormone (RTH).

Most cases of RTH are autosomal dominant and reflect the dominant-negative activity of mutant thyroid
hormone receptor (TR) interfering with wild-type TRβ.

Variable expression of TR isoforms in different tissues can lead to variable clinical presentations.