Q 1:
You are evaluating a 13-year-old girl who complains of malaise, fatigue, and occasional
abdominal discomfort. You diagnosed hypothyroidism due to chronic lymphocytic thyroiditis
(Hashimoto thyroiditis) 6 years ago. She has normal serum immunoglobulin A concentrations. A
tissue transglutaminase antibody study was negative 1 month before this visit, and free
thyroxine and thyroid-stimulating hormone (TSH) values were normal at that time. She reports that she has been eatinAg poorly and has lost 5 lb since you saw her at the beginning of the summer.
Of the following, the MOST important laboratory studies to obtain at this time are
A. complete blood count and erythrocyte sedimentation rate
B. duodenal biopsy for cryptic celiac disease
C. measurement of cortisol and adrenocorticotropic hormone
D. measurement of free thyroxine and TSH
E. mononucleosis spot test and liver function study
Answer
C
The malaise, fatigue, weight loss, abdominal discomfort, and tanned skin reported
for the girl in the vignette are signs of Addison disease. Adrenal insufficiency causes an
elevation in serum potassium concentrations, decrease in serum sodium concentrations, and
shifts in muscle electrolyte concentrations that result in weakness, myalgias, and
gastrointestinal symptoms. Skin pigmentation is increased by high concentrations of
adrenocorticotropic hormone. The presence of both autoimmune hypothyroidism and suspected
adrenal insufficiency in this girl suggests the diagnosis of autoimmune polyglandular syndrome
type 2. The genetic defect in this disorder is not yet known, but the girl is at risk for other
endocrine autoimmunities, including ovarian failure and diabetes.
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Q 2-3
A 12-year-old girl with a past medical history of brittle asthma presents with a history of loss of weight, dizziness and palpitations over the past few weeks. Her maternal grandmother had ‘thyroid problems’. On examination she looks flushed with warm peripheries, pulse rate 110 bpm. She has a smooth goitre 5 6 cm with an audible bruit.
2. What ONE investigation would be MOST useful in establishing a diagnosis?
a- Thyroid stimulating antibodies
b- Ultrasound scan of the neck
c- Thyroid function tests (TSH & Free T4)
d- Fine needle biopsy of the goitre
e- Antithyroid peroxisomal antibodies
3- As part of your management plan which ONE of the following would you recommend:
a- Radioactive iodine treatment
b- Surgical removal of the thyroid gland
c- Pharmacotherapy with carbimazole
d- Beta blockade with propanolol
e- Lugol’s iodine
Answer
C
The malaise, fatigue, weight loss, abdominal discomfort, and tanned skin reported
for the girl in the vignette are signs of Addison disease. Adrenal insufficiency causes an
elevation in serum potassium concentrations, decrease in serum sodium concentrations, and
shifts in muscle electrolyte concentrations that result in weakness, myalgias, and
gastrointestinal symptoms. Skin pigmentation is increased by high concentrations of
adrenocorticotropic hormone. The presence of both autoimmune hypothyroidism and suspected
adrenal insufficiency in this girl suggests the diagnosis of autoimmune polyglandular syndrome
type 2. The genetic defect in this disorder is not yet known, but the girl is at risk for other
endocrine autoimmunities, including ovarian failure and diabetes.
-------------
Q 2-3
A 12-year-old girl with a past medical history of brittle asthma presents with a history of loss of weight, dizziness and palpitations over the past few weeks. Her maternal grandmother had ‘thyroid problems’. On examination she looks flushed with warm peripheries, pulse rate 110 bpm. She has a smooth goitre 5 6 cm with an audible bruit.
2. What ONE investigation would be MOST useful in establishing a diagnosis?
a- Thyroid stimulating antibodies
b- Ultrasound scan of the neck
c- Thyroid function tests (TSH & Free T4)
d- Fine needle biopsy of the goitre
e- Antithyroid peroxisomal antibodies
3- As part of your management plan which ONE of the following would you recommend:
a- Radioactive iodine treatment
b- Surgical removal of the thyroid gland
c- Pharmacotherapy with carbimazole
d- Beta blockade with propanolol
e- Lugol’s iodine
Answers
2. c. Thyroid function tests
3. c. Pharmacotherapy with carbimazole
Graves’ disease: Graves’ disease describes a form of thyrotoxicosis caused by the presence of thyroid stimulating antibodies resulting in excess thyroid hormone secretion.
Graves’ disease is much more common in females (between 5:1 and 10:1 F:M ratio) and is associated with a strong family history of thyroid disease.
Typically Graves’ disease presents with weight loss, heat intolerance, sweatiness, palpitations, diarrhoea, anxiety and psychosis e all signs of a hyper-metabolic state. The initial investigation is a thyroid profile to include free thyroxine (FT4) and thyroid stimulating hormone (TSH) levels.
The FT4 will typically be elevated with suppressed TSH levels confirming thyrotoxicosis.
Other routine investigations include an USS of the neck (to rule out any “hot” nodules), and TSI (thyroid stimulating immunoglobulins).
Radio-iodine scans or fine needle biopsies should only be requested in the light of unusual clinical findings such as a nodule.
Free triiodothyronine (FT3) may be useful in diagnosing rare ‘T3 toxicosis’. Antithyroid antibodies
may be strongly positive (often seen in Down syndrome), and lead to eventual spontaneous resolution of
the disease to the hypothyroid state e “Hashitoxicosis”.
First line treatment is pharmacotherapy with a thionamide drug e.g. carbimazole/methimazole or propylthiouracil (PTU).
PTU is recommended as a second-line treatment if side effects prevent the use of carbimazole.
The two treatment options are :
(1) ‘block and replace’ to reduce the hormone production with large doses of carbimazole until the patient is rendered ‘hypothyroid’ followed by added thyroxine tablets versus
(2) the ‘titration’ method which effectively titrates the amount of thionamide given to maintain euthyroidism.
There is currently a national trial to establish the relative benefit of these two regimens. In any case close attention to the full blood count during treatment is required, to detect agranulocytosis, and all families are
given instructions to attend urgently if unexplained fever and sore throat occurs on treatment.
Beta-blockade in the first 6 weeks reduces the symptoms of thyrotoxicosis but is contraindicated in the presence of asthma.
Lugol’s iodine can produce rapid reduction in thyroxine levels in thyrotoxiccrisis. It is important to discuss all later definitive treatment options (radio-iodine/surgery) with the patient.
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Q : 4-6
A 5-year-old Asian boy is referred to the paediatric endocrinology. He has previously been well however 10 months earlier he was noticed to have developed pubic hair, which has been increasing steadily. He has an adult type body odour, and he has developed acne on his face. On examination you note pubic hair and penis Tanner stage 3, testicular volumes of 5 ml bilaterally. Abdominal and neurological examinations are normal.
Q6. How would you proceed with this patient? Select ONE answer only please.
a Perform a gonadotrophin-releasing hormone (GnRH) test and measure testosterone levels
b Reassure parents that this is likely to be a variant of normal as some Asian children can be quite hirsute
and appear more virilized
c Arrange to see the family back in outpatients in 6 weeks to review the child and calculate his growth
velocity before requesting any tests
d Perform an HCG test with androgen levels before and after stimulation
e Perform a short Synacthen test with measurement of adrenal androgens and 17 alpha hydroxyprogesterone
5. Which TWO of the radiological tests below would you perform? Select TWO answers only please.
a X-ray head
b Testicular ultrasound scan
c MRI hypothalamus and pituitary
d CT chest
e X-ray of the hand and wrist for bone age
f Ultrasound scan of the adrenal glands
6. All the following are possible causes of precocious puberty EXCEPT: Select ONE answer only please.
a McCuneeAlbright syndrome
b Anorexia nervosa
c Hypothyroidism
d Hyperthyroidism
e Neurofibromatosis type 1
Answers:
4 a. Perform a GnRH test and measure testosterone levels
5. c. MRI Head, f. Ultrasound scan (USS) of the adrenal
glands
6. b. Anorexia nervosa
Precocious puberty in males: precocious puberty refers to the onset of puberty outside of the lower limit of the normal age range. For boys this is considered as puberty at an age less than 9 years.
The first sign of progression into puberty is the enlargement of the testicles, and a volume of 4 ml heralds the onset of puberty.
It is important to consider premature adrenarche/pubarche which is considered a variation of normal but where testicular enlargement is not seen.
Clinicians should also be aware of virilizing conditions which result in gonadotrophin-independent
precocity such as non-salt-losing congenital adrenal hyperplasia, androgen producing tumours where testicles may be smaller than normal, familial testotoxicosis and McCuneeAlbright syndrome with polyostotic fibrous
dysplasia of bone and caf e au lait patches.
Precocious puberty is classified into gonadotrophindependent precocious puberty (GDPP) sometimes called
‘true’ or central precocious puberty, and gonadotrophinindependent precocious puberty (GIPP) pseudo-precocious puberty, In GDPP puberty progresses in a concordant manner and is driven by the activation of the hypothalamic-pituitary axis, while GIPP tends to progress in a discordant manner.
GDPP in boys is rarely idiopathic and as such all boys should be investigated appropriately by a qualified clinician to rule out an underlying cause. Investigations should
include:
Blood: testosterone, FSH/LH in response to GnRH stimulation
Radiology: Bone age, MRI Head.
It is important to determine the underlying cause and treat this as appropriate. Depending on the age of presentation it may be important to stop the progression of puberty to reduce psychological distress and to allow longer to grow before epiphyseal fusion.
Treatment may be given with long-acting GnRH analogues (in combination with cyproterone acetate initially) until the family and child are psychologically prepared for puberty and a reasonable final
height likely to be achieved.
Anorexia nervosa causes delayed puberty as the low body mass index (BMI) does not allow for a normal progression of puberty.
Patients with anorexia nervosa have multiple hormone disturbances including low levels of FSH and LH.
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Q 7, 8:
You review a 6-year-old girl in your clinic with delayed motor milestones and mild learning disability. She was born at term, weighing 3.3 kg, to a 29-year-old mother following an uncomplicated pregnancy. She reports that the child had problems with feeding for the first few years of life, and in particular
needed nasogastric tube feeds for the first 18 months of life.
This has now settled and she is feeding very well. On examination the child is overweight with a weight on the 91st centile and a height on the 9th centile. She has short stubby fingers, one caf e-au-lait birthmark on her abdomen and almond shaped eyes. You suspect the child has Pradere Willi Syndrome.
7. What is the likely underlying genetic cause of this condition?
a Triploidy on chromosome 21
b Maternal uniparental isodisomy of chromosome 7
c Deletion of paternal copies of genes on chromosome 15
d Monosomy X
e Duplication of the long arm of the X chromosome
8. Which ONE of the following would you NOT recommend as part of the therapy for this child?
a Dietician review
b Physiotherapy
c Speech and language therapy
d Growth hormone therapy
e Cardiology review
Answers:
7. c. Deletion of paternal copies of genes on chromosome 15
8. e. Cardiology review
PradereWilli Syndrome (PWS): PWS is a rare genetic disorder involving chromosome 15. The underlying genetic cause is loss of the paternal PWS region on chromosome 15 (15q11e13) either by deletions, maternal uniparental disomy (UPD) or translocations. The incidence of PWS is
approximately 1 in 20,000.
During pregnancy mothers may report decreased foetal movement and a breech presentation. Most babies have a good birth weight, but are noted to have the following features: hypotonia, difficulty establishing respiration, poor feeding, hypogonadism. Babies with PWS are classically described as having short stubby fingers, and almond shaped eyes. Problems relating to poor feeding persist through infancy, often manifesting as poor weight gain. In early childhood delayed milestones become evident. By the age of about 3 years children with PWS usually begin to display signs of hyperphagia and exaggerated food seeking behaviour.
If unchecked this results in an excessive weight gain.
A significant number of patients go on to develop complications including obstructive sleep apnoea, poor sleep patterns, scoliosis, short stature, poor coordination, and delayed milestone with possible mild to moderate learning difficulties.
Management of PWS patients and their families involves a multi-disciplinary team involving: geneticists, endocrinologists, physiotherapists, occupational therapists, dieticians, community physicians, speech and language therapists. Endocrine management of patients with PWS focuses on preventing excessive weight gain, and optimizing body composition in childhood; and addressing
hypogonadism and infertility issues in adolescence and as
a young adult.
Growth hormone (GH) therapy is used primarily for the improvement of body composition. The increase in muscle mass improves body tone, and helps overcome the delay in developmental milestones, and this helps with weight control. Height velocity is also sometimes noted to improve, particularly in the first year of therapy. Some unexpected deaths have been reported in patients with PWS on GH. As part of the pre-treatment work-up it is advised to perform an antero-posterior (AP) spinal X-ray to assess for scoliosis
and a polysomnograph, however abnormal results would not be an absolute contraindication to treatment, though more stringent follow up may be prudent. The other genetic disorders listed above include Down
Syndrome (Trisomy 21) which can present like PWS in the neonatal period, with a floppy infant with poor feeding.
These children usually have other features characteristic of Down Syndrome, including a single palmer crease and upslanting palpebral fissures. They have a tendency to gain weight as they grow older, but not to the same degree as children with PWS.
Maternal uniparental disomy on chromosome 7 results in RusselleSilver Syndrome, which presents with a small baby with intra-uterine growth retardation. These babies usually have small triangular faces, and clinodactyly (incurving) of the 5th finger. They tend to remain small throughout their lives.
Monosomy X results in Turner Syndrome (karyotype X0), which presents phenotypically as a girl with short
stature, webbing of the neck and a wide carrying angle. Duplication of the long arm of the X chromosome will result in a phenotype quite similar to Turner Syndrome, with short stature, webbing of the neck, but in addition there are other associated features like development delay, microcephaly, and seizures.
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Q 9:
You are asked to see an 8-year-boy in whom medulloblastoma was diagnosed at age 3 years. Treatment at that time consisted of chemotherapy and craniospinal irradiation. During the past year, he grew 2 cm, although he is eating normally, and his weight is appropriate for height. Despite spinal irradiation, the upper-to-lower segment ratio is normal for his age.
Of the following, the MOST likely diagnosis is
A. acquired growth hormone deficiency
B. chemotherapy-induced renal failure
C. Cushing syndrome
D. irradiation-induced epiphyseal fusion
E. tumor recurrence
Answer:
A
Cranial irradiation has gradual deleterious effects on pituitary hormone secretion due to damage
to hypothalamic releasing factors. Growth hormone, thyroid-stimulating hormone (TSH), and the
gonadotropins tend to be affected most, with adrenocorticotropic hormone (ACTH) relatively
protected, although all neuroendocrine function can be disturbed by cranial irradiation. The boy
described in the vignette has a normal upper-to-lower segment ratio, indicating that his spine still
is growing despite radiation. This suggests that his growth attenuation is due to an acquired
endocrine deficiency of either growth hormone or thyroid hormone. Early in the deficiency
process, if this child were tested with standard stimuli to growth hormone release, he might be
able to release growth hormone, but if continuous nocturnal growth hormone sampling were
performed, diminished and disorderly spontaneous growth hormone release might be
documented. With time, secretory function to stimuli also would be lost.
Renal failure from chemotherapy would be expected to have manifested earlier and been
recognized by this time. Cushing syndrome is a possible but rare cause of growth attenuation
caused by adrenal or pituitary oversecretion of cortisol or ACTH, respectively, and is not
associated with cranial irradiation. Irradiation-induced epiphyseal fusion at the level of the spine
is common following spinal irradiation. The epiphyseal fusion of the spine results in an increased
lower segment (measured from the pubic symphysis to the heel) compared with the upper
segment because the legs continue to grow while the spine does not. This results in an
increased lower segment-to-upper segment ratio. Tumor recurrence has more obvious
manifestations than statural growth attenuation
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