SELF-ASSESSMENT

PAE

Self-assessment

Questions

Case 1

round facies. As a result of these observations, hand X-rays

are later requested (Figure 2).

C) What is the radiological abnormality demonstrated?

A 7-year-old boy presents to the Paediatric Emergency

Department with an ongoing generalized tonic-clonic

seizure already lasting 45 minutes. He was afebrile on

arrival of the ambulance crew to the home and is still fitting

on arrival to the Emergency Department, despite adminis-

tration of rectal diazepam en route. He continues to display

clinical seizure activity despite intravenous lorazepam and

rectal paraldehyde administration. A phenytoin infusion

with cardiac monitoring is commenced.

Initial investigations reveal serum sodium 140 mmol/l,

potassium 3.9 mmol/l, corrected calcium 1.06 mmol/l, al-

bumin 40 g/l, phosphate 1.93 mmol/l, magnesium 0.72

mmol/l. Liver function tests and full blood count are

normal. CRP is mildly elevated at 17 mg/l. Venous blood

gas on arrival showed pH 7.16, pCO2 11.5 kPa, base excess

�2.0 mEq/l and a blood glucose level of 4.8 mmol/l. Blood

pressure is recorded as 126/72 mmHg.

A) What is the single most appropriate therapy to correct

the biochemical abnormality observed? (Choose ONE

ONLY)

a) Intravenous calcium bicarbonate

b) Intravenous calcium gluconate

c) Intravenous magnesium sulphate

d) Intravenous sodium bicarbonate

e) Oral phosphate binders

Despite the intervention above, the seizure continues,

requiring rapid sequence induction with thiopentone, intu-

bation and ventilation. Prior to transfer to the Paediatric

Intensive Care Unit a CT head scan is performed given the

prolonged and refractory nature of the seizure (Figure 1).

B) What abnormality is demonstrated on the CT head scan?

(Choose ONE ONLY)

a) Bilateral demyelinating disease

b) Early bilateral cerebral ischaemic changes

c) Fronto-temporal cerebral haemorrhages

d) Lesions within the basal ganglia

e) Post-chiasmal optic nerve gliomata

Once stable and transferred to the Paediatric Intensive

Care Unit, detailed history reveals below average school

performance and a history of frequent muscle cramps.

Further examination reveals that his weight is 27.1 kg (75th

centile) and height is 115 cm (2nd centile) and that he has

Richard AL Breene BM BCh BA MRCPCH is a Paediatric Registrar at

Addenbrooke’s Hospital, Cambridge, UK.

Matthew J Murray MB BChir MA FRCPCH DCH PGCME FHEA PhD is a Consultant

Paediatrician at the Department of Paediatric Haematology and

Oncology, Addenbrooke’s Hospital, Cambridge, UK.

DIATRICS AND CHILD HEALTH 24:2 92

(Choose ONE ONLY)

a) Chronic osteomyelitis

b) Fibrodysplasia ossificans progressiva

c) Generalized osteopenia

d) Non-accidental injury

e) Short fourth metacarpal bones

D) Given the clinical picture and radiological findings

which of the following diagnoses is most likely? (Choose

ONE ONLY)

a) DiGeorge syndrome

b) McCune Albright syndrome

c) Neurofibromatosis Type I

d) PradereWilli syndrome

e) Pseudohypoparathyroidism

Case 2

A 5-month-old boy presents to the rapid-referral clinic with

a history of abnormal movements increasing in frequency

and severity over the last 2 weeks. He had a brief coryzal

illness 3 weeks earlier. Over the last few days he has had

clusters of abnormal jerky spasms and drawing up his legs

to his abdomen, mostly occurring shortly after waking. His

mother has captured some of the movements on her mobile

communication device, which she shows you. As a result,

you are sufficiently concerned to perform baseline blood

tests which reveal normal electrolytes (including calcium

and magnesium) and glucose. EEG and neuroimaging is

also arranged (Figure 3).

A) What abnormality is demonstrated on the CT scan?

(Choose ONE ONLY)

a) Cerebral abscess

b) Cortical hamartoma

c) Medulloblastoma

d) Neuronal migration defect

e) Subdural haemorrhage

On further questioning you elicit more of the past med-

ical history. The infant was found to have a soft systolic

cardiac murmur postnatally, loudest at the upper right

sternal edge, and was referred for an outpatient echocar-

diogram. This demonstrated a hyperechoic lesion in the left

ventricle near the outflow tract. The murmur is no longer

audible and further cardiac follow-up is awaited. In addi-

tion, he became jaundiced in the newborn period and

required phototherapy for 36 hours. The infant’s weight,

length and occipito-frontal circumference (OFC) are plotted:

weight 7.4 kg (50th centile), length 66 cm (50th centile),

OFC 44 cm (91st centile).

B) Select the most likely diagnosis from the following list

(Choose ONE ONLY)

a) Alagille syndrome

� 2013 Elsevier Ltd. All rights reserved.

Figure 3 Representative axial section of a CT head scan of the 5-month-

old male infant.Figure 1 Representative axial section of a CT head scan of the 7-year-old

male.

SELF-ASSESSMENT

b) Early infantile epileptic encephalopathy (EIEE; Ohta-

hara syndrome)

c) Li-Fraumeni syndrome

d) Tuberous sclerosis

e) Williams syndrome

Case 3

Select the most likely diagnosis for each question (Choose

ONE ONLY)

Note: Each answer may be used more than once

a) Ataxia telangiectasia

b) Congenital myasthenia

c) Congenital myotonic dystrophy

d) Friedrich ataxia

e) Hereditary sensorimotor neuropathy

f) Lead poisoning

g) Mitochondrial myopathy

h) PradereWilli syndrome

Figure 2 Plain X-ray of hands of the 7-year-old male.

PAEDIATRICS AND CHILD HEALTH 24:2 93

i) Spinal muscular atrophy Type 1

j) Vitamin B12 deficiency

A) A 20 month-old girl from a Pakistani family presents

with symptoms of abdominal pain, confusion and irri-

tability. She has been falling over more frequently and

on examination you note she has an ataxic gait and

appears pale. Urine dipstick reveals glycosuria.

B) A term infant on the postnatal ward is undergoing

routine newborn examination. You gather from the

midwives that she has been struggling with breast

feeding. The delivery notes mention an antenatal history

of polyhydramnios and reduced fetal movements. The

baby’s mother appears to have a flat affect. On exami-

nation you identify generalized hypotonia with weak

suck, normal reflexes and bilateral talipes equinovarus.

Answers

Case 1

A b) Intravenous calcium gluconate

B d) Lesions within the basal ganglia

C e) Short fourth metacarpal bones

D e) Pseudohypoparathyroidism

A

Hypocalcaemia is the major biochemical abnormality in this

case. There is also mild hyperphosphataemia. Hypo-

calcaemia can lead to symptoms of muscle weakness,

tetany and cramps with onset of seizures in severe cases.

Acute treatment of the hypocalcaemia involves an intrave-

nous infusion of 10% calcium gluconate over 5 minutes

with ECG monitoring. In severe cases further infusions may

be required. Causes of hypocalcaemia include hypo-

albuminaemia (however, the corrected calcium will remain

in the normal range), chronic renal failure, vitamin D

deficiency, hypomagnesaemia, hypoparathyroidism (auto-

immune, DiGeorge syndrome or post-thyroidectomy) and

pseudohypoparathyroidism. The magnesium in this case is

� 2013 Elsevier Ltd. All rights reserved.

SELF-ASSESSMENT

within the normal range. Respiratory acidosis as seen here

is typical following a prolonged seizure. In this case it

corrected with ventilatory support; there is no significant

metabolic component to the acidosis warranting correction.

It should be noted that fluids containing calcium and those

containing bicarbonate should not be administered at the

same time, as the resultant calcium carbonate that forms is

insoluble and precipitates within the bloodstream.

B

The CT scan shown in Figure 1 demonstrates ectopic

bilateral calcification of the basal ganglia. Early ischaemic

changes are difficult to assess in CT but would include loss

of grey-white discrimination and/or focal oedema or

hypoattenuation. Similarly white matter changes such as in

demyelinating diseases would appear as hypoattenuated

areas on CT scan, although magnetic resonance imaging

would be the imaging modality of choice. Demyelinating

disease can be primary, as seen in multiple sclerosis for

example, or secondary due to e.g. ischaemia, infection or

metabolic conditions e.g. adrenoleukodystrophy.

C

Figure 2 shows short fourth metacarpal bones bilaterally.

Additional ectopic calcification of the right radial artery is

present. Fibrodysplasia ossificans progressiva is an extremely

rare connective tissuedisorder. Fibrous tissue is spontaneously

ossified following injury which leads to joint deformation.

Typically symptoms start in the neck and shoulders before

progressing downwards. Plain X-rays can be helpful in diag-

nosis of chronic osteomyelitis with evidence of patchy osteo-

penia or evidence of bone destruction, but MRI is the imaging

modality of choice. There is no evidence of fracture or callus

formation to suggest injury, non-accidental or otherwise.

D

These findings together with the clinical picture make a

diagnosis of pseudohypoparathyroidism likely. Pseudohy-

poparathyroidism is a rare condition, more common in

males, associated with end-organ resistance to parathyroid

hormone (PTH), hence development of hypocalcaemia.

Whilst patients have a low serum calcium and high phos-

phate the PTH level is appropriately high. The classical

phenotype of Type 1a pseudohypoparathyroidism includes

short stature, round facies, reduced IQ, calcified basal

ganglia and shortened fourth and fifth metacarpal bones

(Type 1b pseudohypoparathyroidism patients lack the

physical appearance of Type 1a, but have similar

biochemical abnormalities). There is also an association

with resistance to thyroid-stimulating hormone (TSH) with

concomitant raised levels. The constellation was first

described by Albright and is hence sometimes known as

Albright’s hereditary osteodystrophy. This is not to be

confused with McCune Albright syndrome which is the

constellation of precocious puberty, polyostotic fibrous

dysplasia and unilateral cafe-au-lait spots.

Pseudohypoparathyroidism due to end-organ resistance

from receptor or post-receptor abnormalities is more com-

mon than true hypoparathyroidism. In normal physiology,

PAEDIATRICS AND CHILD HEALTH 24:2 94

PTH acts on renal tubules to excrete phosphate in the urine.

Resistance to the action of PTH leads to retention of phos-

phate, and secondary hypocalcaemia. In Type 1 pseudo-

hypoparathyroidism following administration of PTH, there

is no phosphaturic response and a blunted increase in uri-

nary cyclic AMP. In Type 2 pseudohypoparathyroidism the

urinary cyclic AMP response is normal. Type 2 is rarer and

lacks the classical phenotypic appearance described above.

Pseudopseudohypoparathyroidism is a term used to

describe a condition with a similar phenotype to pseudo-

hypoparathyroidism but with normal biochemistry. Patients

diagnosed with pseudohypoparathyroidism will require

long-term calcium and Vitamin D supplementation, and

thyroid function should be assessed in view of association

with TSH resistance. DiGeorge syndrome is associated with

hypocalcaemia, but involves a very different phenotype to

pseudohypoparathyroidisim. The DiGeorge phenotype may

be remembered by the mnemonic CATCH-22: Cardiac ab-

normalities, Abnormal facies, Thymic aplasia, Cleft palate,

Hypocalcaemia/hypoparathyroidism, 22q11 deletion.

Case 2

A b) Cortical hamartoma

B d) Tuberous sclerosis

A

The age of onset and history are suggestive of the onset of

infantile spasms. Peak age of onset for infantile spasms is be-

tween 4 and 7months of age. There is often a history of several

weeks or months of subtler abnormal movements prior to

presentation, often leading to a delay in diagnosis. Infantile

spasms are strongly associatedwithmental retardation, severe

developmental delay and loss of acquired motor skills. Often

infantswill have a variable encephalopathic picture.Theymay

frequently be irritable and appear distressed by the spasms.

Causes of infantile spasms include tuberous sclerosis (25%),

birth asphyxia, meningoencephalitis, head trauma, severe

hypoglycaemia, and idiopathic (30%). Treatments include

steroids [or adreno-cortical trophic hormone (ACTH)] and the

anti-epileptic medication vigabatrin.

The CT scan here shows a cortical tuber (or hamartoma)

suggestive of tuberous sclerosis (TS) as the underlying

cause of the onset of infantile spasms. There is no subdural

haemorrhage on the scan. The history alludes to a recent

coryzal illness, but the infant has not been unwell enough

to make an intracerebral abscess the likely underlying cause

of his symptoms. Furthermore, an intracerebral abscess is

characterized by the presence of a ring-enhancing lesion on

CT scan performed with contrast. This appearance occurs

due to the development of a capsule around necrotic tissue.

Contrast cannot pass through the capsule and appears as a

bright ring surrounding a relatively dark lesion. Medullo-

blastomas typically arise in the posterior fossa and present

with cerebellar signs and symptoms of raised intracranial

pressure such as headache and vomiting. In this case the

electroencephalogram (EEG) confirmed hypsarrhythmia

(high amplitude irregular spikes and waves on a disorga-

nized, chaotic background). Hypsarrhythmia is seen in two

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SELF-ASSESSMENT

thirds of cases of infantile spasms. West syndrome is the

name given to the combination of infantile spasms and

hypsarrhythmia on EEG.

B

Tuberous sclerosis (TS) is a rare (1 in 20,000) multi-system

genetic disease caused by mutations in the tuberous scle-

rosis complex genese TSC1 on chromosome 9q34 orTSC2 on

chromosome 16p13. It has an autosomal dominant pattern of

inheritance, with variable expression and incomplete pene-

trance, although two thirds of cases arise from spontaneous

mutations. The TSC1 andTSC2 genes code for the production

of hamartin and tuberin proteins and are tumour suppressor

genes.Mutations at these loci result in loss of control over cell

growth and cell division, leading to development of non-

malignant tumours. TS usually presents with seizures,

often as infantile spasms, with developmental delay and

learning difficulties present in over 60% of patients.

The 2012 International Tuberous Sclerosis Complex

Consensus Group have published current, updated guidelines

using best available evidence to diagnose tuberous sclerosis

complex in affected individuals. The identification of either a

TSC1 orTSC2 pathogenicmutation is now sufficient tomake a

diagnosis of tuberous sclerosis complex (TSC). A pathogenic

mutation is defined as amutation that clearly inactivates TSC1

or TSC2 protein function (e.g. nonsense mutation), prevents

protein synthesis (e.g. genomic deletion), or a missense mu-

tation whose effect on protein function has been demon-

strated. Other gene variants whose effect on function is not

known are insufficient to make a definite diagnosis. 10e25%

of TSC patients have nomutation identifiedwith conventional

testing. This does not exclude the diagnosis or have any

bearing on clinical diagnostic criteria. To confirm a definitive

diagnosis of TS, according to the revised clinical criteria, two

major features from the following list must be present, or one

major feature and �two minor features. A possible diagnosis

exists with either one major feature or �two minor features.

Ninety-six percent of patients will have at least one of the

dermatological manifestations listed:

Major features:

1) hypomelanotic macules (�3, at least 5 mm diameter):

‘ash leaf spots’ of depigmentation, best seen with a

Wood’s light);

2) facial angiofibroma (butterfly red rash on nose and

cheeks, previously known as adenoma sebaceum);

3) ungual fibromas (fleshy tumours around nail beds in

fingers and toes, onset occurs in adolescence);

4) Shagreen patch (thickened, leathery skin on lower back

or nape of neck);

5) multiple retinal nodular hamartomas;

6) cortical dysplasias (including tubers and cerebral white

matter radial migration lines);

7) subependymal nodules in the walls of the ventricles;

8) subependymal giant cell astrocytoma (SEGA). SEGAs

often present at the Foramen of Munro causing obstruc-

tion of cerebrospinal fluid flow and hydrocephalus;

PAEDIATRICS AND CHILD HEALTH 24:2 95

9) cardiac rhabdomyoma. These benign tumours grow

during pregnancy and regress after birth, many dis-

appearing entirely. Problems if present tend to arise in

the first year of life and can include ventricular outflow

obstruction, arrhythmia and heart murmurs. The pres-

ence of a rhabdomyoma is strongly suggestive of a

diagnosis of TS. The cardiac murmur heard in this case

postnatally was due to a cardiac rhabdomyoma. The

subsequent disappearance of the murmur is consistent

with spontaneous regression of the tumour.

10) lymphangioleiomyomatosis (predominantly occurs in

females, caused by replacement of lung parenchyma

with multiple cysts of disordered smooth muscle, leading

to risk of spontaneous pneumothorax or haemoptysis).

11) Renal angiomyolipomas (usually multiple and bilateral

in TS);

Minor features:

1) “confetti” skin lesions (1e2 mm hypopigmented lesions

with a reticulated appearance).

2) dental enamel pits (more than 3);

3) intraoral fibromas (�2);

4) retinal achromic patch;

5) non-renal hamartomas;

6) multiple renal cysts;

TS patients will require long-term follow-up. A multidis-

ciplinary approach must be taken to address neuro-

developmental problems. Anticonvulsant therapy will be

required for seizures. Neurosurgical resection of SEGA or a

tuber (if intractable seizures are felt to be originating fromone

tuber)may be performed.Monitoring of renal function, blood

pressure and regular ophthalmological review should be

performed. Genetic counselling should be offered for family

members. The prognosis for patients with TS varies with the

severity of the phenotype involved. Patients with milder

phenotypes can live long productive lives, whereas more

severely affected individuals may have severe developmental

delay, poor seizure outcomes, poor intellectual capabilities

and autistic behaviour. The leading causes of death in TS

include renal disease, brain tumours, pulmonary lym-

phangioleiomyomatosis, status epilepticus and pneumonia.

Early infantile epileptic encephalopathy (EIEE, Ohtahara

syndrome) typically presents in the first 10 days of life, with

tonic spasms which are more sustained than those seen in

infantile spasms. Cases are mostly associated with struc-

tural brain abnormalities and there is a poor developmental

prognosis with high early mortality. Williams syndrome is a

sporadic condition caused by a microdeletion on chromo-

some 7. Known cardiac associations include supravalvular

aortic stenosis, peripheral pulmonary artery stenosis and

pulmonary valve stenosis. It is not typically associated with

seizures, but is associated with microcephaly, reduced IQ,

and an outgoing personality. Other phenotypic features

include transient neonatal hypercalcaemia, hypoplastic

nails, medial eyebrow flare and short palpebral fissures.

Alagille syndrome is a very rare complex multisystem

� 2013 Elsevier Ltd. All rights reserved.

SELF-ASSESSMENT

condition requiring three of the following five criteria to

make the diagnosis: cholestasis, characteristic facies

(triangular face with broad forehead, pointed chin), heart

disease (most commonly peripheral pulmonary artery ste-

nosis), posterior embryotoxon (prominent ring at junction

of cornea and sclera requiring slit lamp examination) and

vertebral anomalies (butterfly vertebrae). Li-Fraumeni

syndrome is a rare autosomal-dominant condition greatly

increasing susceptibility to a range of cancers from a young

age.

Case 3

A f) Lead poisoning

B c) Congenital myotonic dystrophy

A

The most likely diagnosis accounting for the constellation of

symptoms described is lead poisoning. Lead is toxic to many

organs and systems in the body. Children are at increased risk

of lead poisoning due to their ongoing growth and develop-

ment, andmore rapid absorption in children than adults. Lead

interfereswith thedevelopment of thenervous systemand can

cause permanent learning and behavioural difficulties.

Symptoms include those seen in the described case e

abdominal pain, ataxia, anaemia, confusion and irritability.

Other commonly seen symptoms in children includevomiting,

anorexia, andconstipation. Inmore severe casespoisoningcan

lead to peripheral neuropathy, raised intracranial pressure,

seizures, coma and death. Renal damage can occur with

exposure to lead, and can cause Fanconi syndrome, with

impaired proximal tubular function. This explains the findings

of glycosuria. Young children are more prone to accidental

ingestion of lead, typically in old houses with lead-containing

paint. Other exposures include kohl, an ancient cosmetic from

the Middle East, South Asia, and parts of Africa that has many

names. This was the cause in the described case. It has many

traditional uses and is applied in some cultures to faces and

umbilical stumps of infants and toddlers. Although legislation

restricts availability of lead-containing products in many

countries, cheaper home-made alternatives with high lead

levels are often imported. Lead poisoning is confirmed by an

elevated serum lead level. Typically, blood count will reveal a

microcytic anaemia with basophilic stippling. X-rays may

reveal the presence of ‘lead lines’, radiodense lines at the

metaphyses of the long bones of growing children, especially

around the knee joint. These appear due to increased calcifi-

cation due to disrupted metabolism in the growing bone and

their width can give an indication of the chronicity of lead

exposure. X-raysmayalso reveal lead-containingmaterial, e.g.

chips of paint, in the gastrointestinal tract. Treatment of lead

poisoning is by chelation therapy e either orally with dimer-

captosuccinic acid (DMSA) or parenterally with British anti-

Lewisite, also called dimercaprol.

B

This case describes a ‘floppy infant’. Causes of generalized

hypotonia in the neonatal period are numerous and include

non-neurological and neurological diagnoses. Non-

PAEDIATRICS AND CHILD HEALTH 24:2 96

neurological causes of a floppy infant which should be ruled

out include sepsis, birth asphyxia, chromosomal abnormal-

ities (most commonly Down syndrome and PradereWilli

syndrome), congenital hypothyroidism, cervical cord pa-

thology (including trauma) and metabolic causes. Neurolog-

ical causes includespinalmuscular atrophyType1,hereditary

sensorimotor neuropathies, congenital myasthenia, congen-

ital myopathy (including mitochondrial myopathies) and

congenital myotonic dystrophy.

Myotonic dystrophy of congenital onset is inherited as

an autosomal dominant condition. Myotonic dystrophy is a

trinucleotide repeat disorder with severity depending on the

length of CTG repeat sequence (normal is up to 37 repeats,

symptoms can occur with more than 50 repeats, and

congenital cases such as this typically have thousands of

repeats). The condition displays genetic anticipation with

severity increasing in each subsequent generation. The

mother tends to be the affected parent due to genetic

imprinting. In this case the mother’s flat affect is due to

facial weakness from the condition. There may often have

been reduced fetal movements in pregnancy and poly-

hydramnios secondary to reduced swallowing in utero.

Affected patients display hypotonia, facial weakness and

dysphagia, hence the feeding problems. Talipes and

arthrogryposis (multiple congenital joint contractures pre-

sent from birth) can occur. Myotonia itself develops later in

life. In congenital form there is often later respiratory

involvement (diaphragm and intercostal muscles) and car-

diac features (e.g. hypotension, syncope, arrhythmias).

Severe congenital forms may need ventilatory assistance

after birth, and likely nasogastric feeding support if swal-

lowing is sufficiently impaired. If suspected, the mother

should be examined for facial weakness, classical myotonic

handshake (slow release grip), and a diagnostic electro-

myogram (EMG) and muscle biopsy performed.

Further reading

1. Mantovani G. Clinical review: pseudohypoparathyroid-

ism: diagnosis and treatment. J Clin Endocrinol Metab

2011; 96: 3020e30.

2. Northrup H, Krueger DA. Tuberous sclerosis complex

diagnostic criteria update: recommendations of the 2012

International Tuberous Sclerosis Complex Consensus

Conference. Pediatr Neurol 2013; 49: 243e54.

3. Tuberous Sclerosis Association Information and Support

Resources, http://www.tuberous-sclerosis.org/Info-and-

support-resources.htm.

4. Karri SK, Saper RB, Kales SN. Lead encephalopathy due

to traditional medicines. Curr Drug Saf 2008; 3: 54e9.

5. Bellinger DC. Lead. Pediatrics 2004; 113(suppl 3):

1016e22.

6. Peredo DE, Hannibal MC. The floppy infant: evaluation

of hypotonia. Pediatr Rev 2007; 30: e66e76.

7. Forsyth R, Newton R. Oxford specialist handbook of

paediatric neurology, Oxford University Press 2007.

ISBN: 9780198569398.

� 2013 Elsevier Ltd. All rights reserved.