professional development
case study: bone health
This clinical module has been sponsored by an unrestricted educational grant from
and makers of
Metabolic bone disease as a
differential in childhood illness
Dr Ciara McDonnell identifies underlying metabolic bone disease in a vitamin D deficient child
Case report
A two-year old-boy presents at paediatric outpatients following GP referral for gross motor
delay, specifically delayed walking. He is on the 10th
centile for height and weight. His fine motor and
social development reach milestones. His speech is
slightly delayed. His parents are first cousins and
speak both Urdu and English at home.
A review of past medical history reveals term delivery with a birth weight of 3.5kg. He was breast
fed for the first six months of life and was reported
to be in good physical health until four months of
age when he presented to the Paediatric Emergency Department with seizure like activity. This
consisted of intercurrent spasmodic jerks of the
upper and lower limbs noted over the previous two
weeks. Neurological examination and subsequent
EEG were reported normal and he was discharged
back to the GP at eight months of age.
On physical examination he is a cheerful interactive child. He has no evident dysmorphism. Eye,
ear, nose and throat examination is normal. His
respiratory examination is normal. His cardiovascular review reveals a soft systolic flow murmur of
grade 1/6 intensity. He does not exhibit organomegaly on palpation of the abdomen. He does however
have bilateral swelling of his wrist and knee joints.
He cannot weight bear but can crawl without difficulty. Power of the lower limbs is reduced compared to the upper limbs but his reflexes are elicited
without difficulty.
He is booked to attend for routine bloods, metabolic work-up, creatinine kinase and chromosome
analysis. However, 10 days later he is admitted to
the paediatric unit with an acute intercurrent viral
illness. He is noted to be excessively lethargic and
tachypnoeic with a grade 4/6 pansystolic murmur,
displaced apex beat and hepatomegaly.
X-rays of the chest show an enlarged cardiac
shadow and increased swelling of the costochondral junctions. X-rays of the wrist and knee joints
indicate flaring of the distal ends of the bones with
an irregularity of the epiphyses, suggestive of rickettsial change.
Discussion
This case underlines the
complexity of vitamin D
disorders and the importance of including vitamin
D pathology in the differential diagnosis of many paediatric disorders. The child
in question did have a rare
underlying enzyme disorder of 1,25-(OH)2-vitamin
D metabolism but this was
masked and complicated
by the more common nutritional 25-OH-vitamin D
deficiency.
The gross motor delay in
walking is due to an inability
of the lower limbs to support
the weight of the child due to
the softening of the bones.
This is associated with muscle weakness and bone pain.
With regard to the past
medical history, it should be
noted that neonates and adolescents with hypocalcaemia secondary to vitamin
D deficiency often present
with seizures or spasmodic
type episodes and a bone
profile should always be included in the investigation
of such events. It is likely
that serum calcium at the
acute stage would have led
to an earlier diagnosis of the
underlying condition.
The speech delay could
be attributed to the combination of languages spoken
at home. The symptomatic
presentation of dilated cardiomyopathy was precipitated by the acute viral illness, although the cause was
the underlying severe nutritional vitamin D deficiency
which is noted as one of the
few reversible causes of this
type of cardiomyopathy.
At this stage an underlying
cardiomyopathy due to vitamin D deficiency may have
resolved asymptomatically
with vitamin D replacement.
However, the intercurrent
illness increased cardiac output and exacerbated the condition to a symptomatic level.
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Table 1 shows blood test results. An echocardiogram study indicates a dilated cardiomyopathy
with reduction in function of the left ventricle. He
requires in-patient treatment with calcium supplementation and an ACE inhibitor, and makes a
steady recovery over the next 10 days.
Dietary calcium review suggests adequate calcium intake, so further tests are planned. Two
weeks later, following intravenous then oral calcium supplementation, his hypocalcaemia is again
investigated (see Table 2).
The secondary hyperparathyroidism is considered to be an appropriate response to the sustained
hypocalcaemia. A diagnosis of nutritional rickets
is made and the causative vitamin D deficiency is
treated with 3000IU cholecalciferol daily for three
months, then reduced to maintenance vitamin D
therapy of 400IU cholecalciferol daily.
On paediatric review six months later he has no
overt symptoms of cardiac failure but remains on a
maintenance dose of ACE inhibitor treatment. The
swelling of his wrists and knees has persisted. He
has still not attained full weight bearing and mobility remains limited to crawling. Repeat bloods indicate a normal full blood count and renal function.
Bone parameters are listed in Table 3.
His cholecalciferol supplementation is therefore
discontinued and he commences alfacalcidol supplementation in the form of 1-alpha drops [30ng/
kg/day]. Over the next six months his calcium, PTH
and alkaline phosphatase normalise and repeat xrays one year after his initial presentation show evidence of healing rickets. On return to OPD at three
years of age he is walking without difficulty.
Genetic studies identify that the boy is homozygous
for a mutation in the CYP27B1 gene on chromosome 12q13.1-q13.3 consistent with a diagnosis of
1-α-hydroxylase deficiency. Both parents are carriers of this mutation.
Table 2: Hypocalcaemia investigation results
Result
Units
Reference
range
Corrected Calcium
1.98
mmol/L
2.15-2.55
Ionised calcium
0.93
mmol/L
1.10-1.30
Table 1: Investigation results
Result
Units
Reference
range
Haemoglobin
 10.5
g/dl
11.1-14.1
pmol/L
1.1-6.8
74.5
Fl
72.0-84.0
Parathyroid
hormone [PTH]
20.4
MCV
MCH
26.6
Pg
25.0-29.0
25 OH Vitamin D
2
nmol/L
50-200
Sodium
140.9
mmol/L
133-145
Potassium
3.8
mmol/L
3.3-5.1
Creatinine
42
Umol/L
35-96
Calcium
 1.32
mmol/L
2.15-2.55
Phosphate
1.5
mmol/L
1.3-2.0
CK
236
IU/L
<400
Albumin
44
g/L
34-38
Alkaline
phosphatase
 3208
U/L
35-281
The mild anaemia evident on
the first set of investigations
was a normochromic, normocytic anaemia due to the
chronic disease state associated with vitamin D deficiency and hypocalcaemia,
which resolved at an early
stage in treatment.
Treatment with calcium
leads to a transient increase
in serum calcium levels as
high levels of calcium in the
intestine can bypass the vitamin D receptor dependent
mechanism via paracellular
transport mechanisms that
are not completely defined
[claudin proteins].
High calcium diets can
ameliorate some effects of
rickets but without vitamin
D treatment, will not definitively treat the condition,
result in bone healing or
normalise the parathyroid
hormone levels.
This child was at risk of nutritional vitamin D deficiency
due to his ethnic background
and history of breastfeeding for the first six months
of life. However, the lack
of response to adequate vitamin D therapy suggested
either non-compliance or an
underlying metabolic bone
disease which is increasingly
likely due to the consanguineous relationship of the
parents. With the increasing prevalence of nutritional
vitamin D deficiency, repeat
investigations should always
be carried out after three
months of treatment to ensure that bone biochemistry
has normalised. Persistent
raised PTH or alkaline phosphatase are clues to a persisting problem.
Table 3: Bone parameters
Result Units
Reference
range
Corrected calcium
1.75
mmol/L
2.15-2.55
Ionised calcium
0.94
mmol/L
1.10-1.30
Parathyroid hormone
18.7
pmol/L
1.1-6.8
Alkaline phosphatase
1823
U/L
35-281
25 OH Vitamin D
63
nmol/L
50-200
1,25 (OH)2 Vit D
36
pmol/L
43-144
• Metabolic disorders
• Emotional deprivation
• Duchenne muscular
dystrophy
Dilated cardiomyopathy:
• Autoimmune disease
• Rheumatoid arthritis
• SLE
• Phaeochromocytoma
• End stage kidney disease
• Genetic cardiomyopathy
• Infection e.g. Coxsackie
virus, ECHO virus, HIV
infection, Lyme disease
• Muscular dystrophy
• Chemotherapy drugs
Important differentials of
this presentation include:
Hypocalcaemia:
• Hypomagnesaemia
• Calcium sensing receptor
abnormalities
• Vitamin D deficiency
• Chronic renal failure
• Osteopetrosis
Delayed walking:
• Cerebral palsy
• Hypotonia
• Chromosomal disorders
Chronic renal failure and
muscular dystrophy are important differentials which
would link the combination
Differentials
of symptoms listed here. As
recovery takes place over
months, it is important to
ensure possible differentials are excluded at an early
stage. In this case, a normal
renal profile and CK level
would have been adequate
evidence to exclude these
pathologies.
Rickets
This is a disease of childhood which can only occur
before the epiphyses fuse.
Rickets occur during development of bones due to an
interruption in the mineralisation process or lack of
mineral substrate in growing bones.
The adult correlate of this
disease is osteomalacia.
There are several subtypes
of rickets:
• Congenital rickets
• Calcium deficiency rickets
• Vitamin D deficiency rickets
• Vitamin D dependent rickets type 1
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