Download Case 1: Polyuria at the Magic Kingdom Case 2: Seizures as a clue

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CLINICIAN’S CORNER
Case 1: Polyuria at the Magic
Kingdom
Case 2: Seizures as a clue
to…
three-year-old boy presented to the endocrinology
clinic at the Children’s Hospital of Western Ontario
(London, Ontario) with an eight-month history of progressive polydipsia and polyuria. His symptoms became obvious
to his family during a recent summer vacation at Disney
World (Orlando, USA), where he drank 6 L of water per
day and voided every 20 min. He frequently woke up
overnight to ask for water and soaked multiple diapers.
There was no history of headache, fever, weight loss,
fatigue, fractures or extremity pain.
He had a history of seborrheic scalp dermatitis since
birth, which was unresponsive to treatment with topical
steroids. He also had recurrent otitis media requiring
myringotomy tubes, and recurrent otitis externa. His family
history was unremarkable.
On physical examination, his height and weight were
measured at the 40th and 5th percentiles, respectively. His
vital signs were normal. His head and neck examinations
revealed multiple discrete, superficial, yellow scaly lesions
with surrounding erythema on his scalp and left-sided ptosis; fundoscopy was normal. There was mild, shotty lymphadenopathy of the cervical and inguinal regions with no
associated hepatosplenomegaly.
Before his referral to the clinic, the patient had blood
work on several occasions revealing normal blood glucose
levels. His urinalysis, serum electrolytes and complete
blood count were also normal. Further testing revealed the
diagnosis.
A
A
four-month-old girl with a history of right leg hemihypertrophy and hypopigmented skin patches presented
to the emergency room with irritability and a four-day history of jerky movements. These were described as symmetrical flexion of both upper extremities, occurring in clusters
lasting 5 min to 10 min.
She was afebrile with stable vital signs and no obvious
dysmorphic features. Her weight was 6.7 kg (75th percentile). Several white spots were noted on her right cheek
and both legs. She had right thigh hemihypertrophy. There
was mildly decreased central tone with head lag and normal peripheral tone. There were no abdominal masses.
She was born to a 33-year-old G3P1A1 mother at
40 weeks’ gestation by vaginal delivery. Her birth weight
was 3.46 kg (between the 50th and 75th percentiles). The
pregnancy was uncomplicated and her prenatal ultrasound
was normal. On the first day of life, she was noted to have
right leg hemihypertrophy and was seen by the genetics
department. Her family history was negative for overgrowth syndromes. Her mother had one hypopigmented
skin lesion on her left leg. There was no consanguinity.
Her hemoglobin, blood gas and glucose levels were normal. Her calcium level was mildly elevated at 2.95 mmol/L
(normal 2.17 mmol/L to 2.44 mmol/L). The remainder of
her electrolyte levels, including phosphate and magnesium,
were normal. Further investigations revealed her diagnosis.
Correspondence: Dr Jeremy Friedman, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario M5G 1X8.
Telephone 416-813-7368, fax 416-813-5663, e-mail [email protected]
Case 1 accepted for publication March 5, 2008. Case 2 accepted April 22, 2008
Paediatr Child Health Vol 13 No 7 September 2008
©2008 Pulsus Group Inc. All rights reserved
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TABLE 1
Differential diagnosis of polyuria and polydipsia
Diabetes mellitus
Type 1 diabetes mellitus
Type 2 diabetes mellitus
Central diabetes insipidus
Acquired
Trauma (eg, neurosurgery, head injury)
Hypoxic/ischemic brain injury
Neoplasms (eg, craniopharyngioma, optic glioma)
Infections (eg, encephalitis)
Infiltrative diseases (eg, Langerhans cell histiocytosis)
Drugs (eg, ethanol, phenytoin, alpha-adrenergic agents)
Congenital cerebral malformations
Familial (eg, autosomal dominant, DIDMOAD syndrome)
Nephrogenic diabetes insipidus
Acquired
Metabolic disturbances (eg, hypercalcemia, hypokalemia)
Chronic renal disease
Postobstructive uropathy
Drugs (eg, lithium, rifampin, clozapine)
Familial (eg, X-linked recessive, autosomal recessive)
Primary polydipsia
Compulsive or habitual
Drugs (eg, lithium, carbamazepine)
Psychological disturbance
Figure 1) Frontal skull x-ray taken shortly after presentation showing
multiple poorly marginated, lucent destructive lesions involving the
anterior frontal bone (arrows) and the anterolateral aspect of the left
orbit
CASE 1 DIAGNOSIS:
LANGERHANS CELL HISTIOCYTOSIS
Central diabetes insipidus (DI) was confirmed by a water
deprivation test with vasopressin. A skeletal survey
revealed lytic lesions in the left anterior frontal bone and
orbital roof (Figure 1). On magnetic resonance imaging of
the head, these lesions displayed features characteristic of
eosinophilic granulomas. There was diffuse thickening of
the pituitary stalk; the physiological hyperintense signal in
the posterior pituitary was absent. Biopsy of the patient’s
scalp lesions confirmed the diagnosis of Langerhans cell
histiocytosis (LCH).
The patient was started on desamino d-arginine vasopressin (DDAVP) with near complete resolution of his urinary symptoms. He underwent chemotherapy, resulting in
resolution of his dermatitis, bony lesions and recurrent ear
infections. There has been no evidence of other pituitary
dysfunction.
Clinicians are generally quick to think of diabetes mellitus when a patient presents with polydipsia and polyuria,
but it is crucial to consider other causes (Table 1). Primary
polydipsia may occur in children with compulsive or habitual excessive water intake. Psychiatric and hypothalamic
causes of intense thirst are less common. Most cases of DI
are acquired and other, sometimes subtle, clinical features
may suggest the underlying diagnosis, as in our case. More
importantly, DI should be considered even when electrolyte
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Hypothalamic lesion
DIDMOAD – Central diabetes insipidus (DI), diabetes mellitus (DM), optic
atrophy (OA) and deafness (D). Adapted from reference 1
levels are normal because children with an intact thirst
mechanism and free access to fluids can consume enough
water to prevent hypernatremia.
A water deprivation test is required to differentiate
between central and nephrogenic DI. However, the community paediatrician should look for associated features to direct
a referral to the appropriate specialist. For example, a history
of hypercalcemia, chronic renal disease, obstructive uropathy
or use of medications such as lithium suggests nephrogenic DI.
This would prompt referral to a paediatric nephrologist. A
positive family history may point to a genetic cause of central
or nephrogenic DI. Trauma related to neurosurgery or accidental brain injury can cause central DI. Signs and symptoms
of increased intracranial pressure are consistent with primary
brain tumours that cause central DI. Tumours located near the
base of the hypothalamus may be associated with clinical evidence of other pituitary hormone dysfunction. Central DI
may rarely occur in viral encephalitis, bacterial meningitis,
congenital cytomegalovirus and toxoplasma infections.
Approximately 10% of cases are thought to be idiopathic.
LCH is a rare infiltrative disorder with diverse clinical
manifestations that simulate other common conditions. The
unifying feature of the disorder is the presence on histology
of Langerhans cells, which normally function as antigenpresenting cells in the immune system. In LCH, abnormal
immature Langerhans cells can accumulate in multiple
organ systems, making the diagnosis very challenging. The
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most common initial presentations in children include
lesions of the skin, isolated or multifocal bone lesions, lymphadenopathy and generalized symptoms such as fever and
weight loss. LCH typically presents in childhood with a
peak onset between one and four years of age. Incidence is
approximately two to five in one million children.
The dermatological manifestations of LCH often mimic
seborrheic dermatitis of infancy. Children tend to present
with erythema and scaling, particularly of the scalp and groin.
The presence of petechial hemorrhages within the lesions is
highly suggestive of LCH, and erosive intertrigo may be seen
in the groin and axillae. A variety of other skin lesions have
been described, including eczematous-like rashes. Given the
difficulty in distinguishing LCH from other benign dermatoses, it is important to maintain a high index of suspicion
for any dermatitis that does not respond to standard therapy.
The clinical hallmark of LCH is the presence of lytic bone
lesions. These eosinophilic granulomas may be identified
incidentally on imaging or may present with bony pain,
swelling or functional limitations. LCH can affect any bone;
however, the skull, mandible, spine and ribs are most
commonly involved. Lesions of the skull are typically round
and osteolytic with a ‘punched-out’ appearance, as in our
patient. Lesions of the mandible and maxilla may lead to gingival swelling and loosened teeth. Involvement of the inner
ear bones may cause recurrent otitis media and mastoiditis.
Patients presenting with skull lesions are at higher risk of
central nervous system involvement such as DI, which
develops in over 10% of patients. Typical features on
magnetic resonance imaging include thickening of the
pituitary stalk with prominent contrast enhancement and
loss of the normal hyperintense signal in the posterior
pituitary. Other endocrine abnormalities, such as growth
hormone deficiency, may arise later on.
Baseline investigations in a patient with suspected LCH
include a complete blood count, electrolytes, liver function
tests, urinalysis and a skeletal survey. Further investigations
will depend on the presenting features of LCH. Treatment
ranges from resection of local lesions to chemotherapy, and
is determined by the sites of disease, degree of organ involvement and age at diagnosis, all of which are also important
prognostic factors. All children with suspected or confirmed
LCH should be referred to a paediatric oncologist. The outcome of LCH varies, but recurrence is common, particularly
for patients like ours with multisystem disease.
CLINICAL PEARLS
• Although diabetes mellitus is a common cause of
polyuria and polydipsia, it is equally important to
consider other diagnoses, including DI.
• A normal electrolyte profile does not rule out a
diagnosis of central or nephrogenic DI.
• LCH can mimic common childhood diseases
including diaper rash, seborrheic dermatitis and
recurrent otitis media. When a common condition is
recalcitrant or persists beyond the expected age, this
Paediatr Child Health Vol 13 No 7 September 2008
may suggest a misdiagnosis and prompt consideration
of alternative explanations, such as LCH.
REFERENCE
1. Baylis PH, Cheetham T. Diabetes insipidus. Arch Dis Child
1998;79:84-9.
RECOMMENDED READING
1. Majzoub JA, Srivatsa A. Diabetes insipidus: Clinical and basic aspects.
Pediatr Endocrinol Rev 2006;4(Suppl 1):60-5.
2. Savasan S. An enigmatic disease: Childhood Langerhans cell
histiocytosis in 2005. Int J Dermatol 2006;45:182-8.
3. Kilborn TN, Teh J, Goodman TR. Paediatric manifestations of
Langerhans cell histiocytosis: A review of the clinical and radiological
findings. Clin Radiol 2003;58:269-78.
Tania Cellucci MD
Shayna Zelcer MD FRCPC
Farid H Mahmud MD FRCPC
Department of Paediatrics, University of Western Ontario,
Children’s Hospital of Western Ontario, London, Ontario
CASE 2 DIAGNOSIS:
TUBEROUS SCLEROSIS COMPLEX
The initial electroencephalogram showed hypsarrhythmia
consistent with infantile spasms, and vigabatrin was
initiated. Infantile spasms, in the context of hemihypertrophy and skin hypopigmentation, prompted a targeted evaluation for tuberous sclerosis complex (TSC).
A head ultrasound showed a focal area of hypoechogenicity in the anterior basal ganglia. Magnetic resonance imaging
showed multiple cortical and subcortical tubers, and
enhancing subependymal nodules adjacent to the foramen of
Monro. Slit lamp examination showed a disc-size (1.8 mm)
round lesion on the left eye consistent with a hamartoma.
Six hypopigmented lesions were identified on Wood’s lamp
examination of the skin. No fibrous tumours or
angiofibromata were seen. An echocardiogram was positive
for four tumours in both ventricles, with no outflow tract
obstructions noted. An abdominal ultrasound revealed
multiple renal cortical cysts, but there was no evidence of
angiomyolipoma.
Endocrine workup for hypercalcemia included adrenocorticotropic hormone (ACTH) stimulation, 1,25 dihydroxy vitamin D, cortisol, parathyroid hormone and urine
osmolality, all within normal limits. The cause of the hypercalcemia was not determined, and it resolved over time
with no therapy. Genetic workup was positive for female
karyotype (46 XX), Beckwith-Wiedemann syndrome
(methylation defect at the KvDMR1 locus) and TSC
(TSC2 gene mutation).
TSC is an autosomal dominant neurocutaneous disorder
characterized pathologically by the presence of hamartomas
in multiple organs. Historically, TSC was defined by the
triad of mental retardation, epilepsy and facial angiofibromas, although now the disorder is known to exhibit a wide
variability in clinical expression. Although TSC has a
known genetic basis with autosomal dominant inheritance,
two-thirds of cases are the result of new mutations in one of
two known tumour suppressor genes, TSC1 (encoding
hamartin) and TSC2 (encoding tuberin).
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TABLE 1
Diagnostic criteria for tuberous sclerosis complex
Major features
Minor features
Facial angiomas or forehead plaques
Confetti skin lesions (multiple
Shagreen patch
Three or more hypomelanotic macules
Nontraumatic ungual or periungual
fibromas
Lymphangiomyomatosis
1 mm to 2 mm hypomelanotic
macules)
Gingival fibromas
Multiple randomly distributed
pits in the dental enamel
Cardiac rhabdomyoma
Hamartomatous rectal polyps
Multiple retinal nodular hamartomas
Multiple renal cysts
Cortical tuber
Nonrenal hamartomas
Subependymal nodule
Bone cysts
Subependymal giant cell astrocytoma
Retinal achromic patch
Renal angiomyolipoma
Cerebral white matter radial
the advent of vigabatrin, ACTH was the mainstay in the
treatment of infantile spasms. Significant side effects limit
the use of ACTH, making vigabatrin the drug of choice.
Advantages of vigabatrin include the ability to rapidly escalate the dosage at the initiation of treatment, rapid efficacy,
suitability for outpatient treatment and good tolerability.
The most concerning side effect of vigabatrin is the potential for retinal toxicity, with the magnitude of the risk estimated to be 10%.
In our patient, there was resolution of infantile spasms
with vigabatrin. She remained stable without any signs of
neurological or cardiac compromise. She continues to be
monitored for signs of retinal toxicity as well as subependymal nodule growth. She is followed by the neurology, cardiology, genetics and dermatology departments.
migration lines
Adapted from reference 1
In 1998, a consensus conference developed clinical diagnostic criteria for TSC based on specific clinical features
(Table 1) (1). A diagnosis of definite TSC requires two
major features or one major and two minor features.
Children with probable TSC have one major plus one
minor feature and a possible TSC diagnosis has either one
major feature or two or more minor features. Our patient
met the diagnostic requirements for definite TSC, with five
major features (six hypomelanotic macules, cortical tubers,
subependymal nodules, retinal hamartoma and four cardiac
rhabdomyomata) and one minor feature (multiple renal
cysts). Subsequent molecular genetic testing confirmed the
diagnosis of TSC.
Management of TSC includes expedient diagnosis, management of neurological symptoms, genetic counselling and
follow-up. Surveillance for subependymal nodules is an
important part of ongoing follow-up for patients with TSC.
Subependymal nodules have been noted to cause obstruction of cerebrospinal fluid flow leading to hydrocephalus,
increased intracranial pressure and even death in approximately 10% of patients with TSC due to proliferative
astrocytes and giant cells that protrude from the walls of the
lateral and third ventricles. To date, there have been no
conclusive guidelines for surveillance. The Tuberous
Sclerosis Alliance suggests annual magnetic resonance
imaging of the brain until 21 years of age, and then every
two to three years to diagnose or monitor growth (2).
Our patient presented with infantile spasms, one of the
most common presenting features of TSC in infancy.
Infants with TSC who present with infantile spasms
respond particularly well to therapy with vigabatrin. Before
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CLINICAL PEARLS
• The diagnosis of TSC in infancy requires a high
index of suspicion. TSC should be considered in any
infant presenting with seizures, particularly infantile
spasms.
• Although TSC is inherited in an autosomal
dominant fashion, two-thirds of cases are the result
of new mutations in the TSC1 or TSC2 genes. The
diagnosis of TSC in a child should prompt the
investigation of TSC in first-degree relatives.
• Long-term follow-up, including monitoring of
subependymal nodules, is an essential part of
management.
REFERENCES
1. Roach ES, Gomez MR, Northrup H. Tuberous sclerosis complex
consensus conference: Revised clinical diagnostic criteria.
J Child Neuro 1998;13:624-8.
2. Crino P, Nathanson K, Henske E. The tuberous sclerosis complex.
N Engl J Med 2006:355:1345-56.
RECOMMENDED READING
1. MacKay M, Weiss S, Adams-Webber T, et al. Practice parameter:
Medical treatment of infantile spasms: Report of the American
Academy of Neurology and the Child Neurology Society.
Neurology 2004;62:1668-81.
Dianne Lim MD
PGY2 Paediatrics, The Hospital for Sick Children,
The University of Toronto, Toronto, Ontario
Carolyn E Beck MD MSc FRCPC
Division of Paediatric Medicine, The Hospital for Sick Children,
The University of Toronto, Toronto, Ontario
Paediatr Child Health Vol 13 No 7 September 2008