Review
Arch Dis Child: first published as 10.1136/archdischild-2019-317482 on 3 January 2020. Downloaded from http://adc.bmj.com/ on January 4, 2020 at Agence Bibliographique de l
1
Department of Endocrinology
and Diabetes, Birmingham
Women’s and Children’s NHS
Foundation Trust, Birmingham,
UK
2
Institute of Metabolism and
Systems Research, University of
Birmingham, Birmingham, UK
Correspondence to
Professor Nick Shaw,
Department of Endocrinology
and Diabetes, Birmingham
Women’s and Children’s NHS
Foundation Trust, Birmingham
B4 6NH, UK;
​nick.​shaw@n​ hs.​net
Received 10 October 2019
Revised 4 December 2019
Accepted 5 December 2019
© Author(s) (or their
employer(s)) 2020. No
commercial re-­use. See rights
and permissions. Published
by BMJ.
To cite: Nadar R, Shaw N.
Arch Dis Child Epub ahead of
print: [please include Day
Month Year]. doi:10.1136/
archdischild-2019-317482
Investigation and management of hypocalcaemia
Ruchi Nadar,1 Nick Shaw1,2
Abstract
Hypocalcaemia is a common clinical scenario in children
with a range of aetiological causes. It will often present
with common symptoms but may occasionally be
identified in an asymptomatic child. An understanding
of the physiological regulation of plasma calcium is
important in understanding the potential cause of
hypocalcaemia and its appropriate management. The
age of presentation will influence the likely differential
diagnosis. We have presented a stepwise approach to
the investigation of hypocalcaemia dependent on the
circulating serum parathyroid hormone level at the time
of presentation. The acute and long-­term management of
the underlying condition is also reviewed.
Introduction
Hypocalcaemia is a commonly encountered clinical
scenario in children. In this review, we highlight the
evaluation of a child with hypocalcaemia based on
the clinical setting, age of presentation and focused
investigations, such as parathyroid hormone (PTH)
assay and bone profile (serum magnesium, phos-
phate and alkaline phosphatase levels).
Physiology
An understanding of physiological mechanisms of
calcium homeostasis and the interplay between
regulatory hormones and target organs is central
to the interpretation of investigations. There are
three key components in the regulation of plasma
calcium, disturbances in which may lead to hypo-
calcaemia. These are the calcium-­sensing receptor
CaSR (an extracellular G protein coupled receptor),
PTH and the active metabolite of vitamin D: 1,25
dihydroxyvitamin D3 (1,25(OH)2D3). In addition
to hormonal mechanisms, adequate dietary intake
and gastrointestinal absorption of calcium are both
imperative in maintaining calcium homeostasis.
A fall in plasma calcium leads to a cascade of
events terminating in the action of PTH on target
organs leading to the restoration of plasma calcium
to normal (figure 1).
The initial response occurs at the level of the
CaSR present in the renal tubules and the chief cells
of the parathyroid glands. In the kidney, CaSR is
located in the basolateral membrane of the cortical
and medullary thick ascending nephron.1 Here in
response to low ambient calcium levels it stimu-
lates increased tubular calcium reabsorption. At the
same time, the chief cells of the parathyroid gland
respond by rapid synthesis and release of PTH. Its
action on osteoclasts in bone to increase resorp-
tion and the renal tubule to increase tubular reab-
sorption of calcium is mediated by PTH receptors.
When PTH acts on bone, phosphate is also released
Nadar R, Shaw N. Arch Dis Child 2020;0:1–7. doi:10.1136/archdischild-2019-317482
along with calcium. This can bind with calcium,
again preventing correction of hypocalcaemia. This
is counteracted by PTH action on renal tubules to
produce phosphaturia. The other indirect mech-
anism is to stimulate the renal 1-­alpha hydroxy-
lase enzyme to synthesise 1,25(OH)2D3 leading
to increased intestinal absorption of calcium.
Additionally 1,25(OH)2D3 also acts on the distal
convoluted tubule (DCT) to enhance calcium reab-
sorption.2 Thus by these important physiological
actions, plasma calcium returns to normal.
Magnesium metabolism is linked with calcium
metabolism, at the level of the CaSR. Severe hypo-
magnesaemia impairs PTH secretion in response
to hypocalcaemia by raising the threshold for PTH
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secretion. Genetic forms of hypomagnesaemia are
associated with mutations in genes encoding TRPM6
and EGF which are involved in active reabsorption
of magnesium in the DCTs.3 4 Hypomagnesaemia
may be seen with the use of certain drugs (diuretics,
gentamicin or cisplatin) in diabetic ketoacidosis,
post-­renal transplant and urinary tract obstruction.
When low plasma magnesium is associated with
hypocalcaemia, correction of hypomagnesaemia is
essential to normalise plasma calcium.
Disorders causing hypocalcaemia
A classification of disorders based on the status of
PTH function (table 1) is useful for the clinician.
Approach to a child with hypocalcaemia
A logical stepwise approach will lead to the right
diagnosis in most cases. Important points to
consider are the following: the clinical setting
(critical illness, renal failure, sick neonate), age at
presentation, pertinent points in the history and
physical examination along with specific investiga-
tions (figure 2).
Hypocalcaemia is common in acute critical
illness. Its aetiology is multifactorial and includes
abnormal PTH secretion, hypomagnesaemia,
hypoalbuminaemia, sepsis, transfusions, acid–base
imbalance and medications and dietary calcium
intake.5 Both acute and chronic renal failure can
manifest with hypocalcaemia so renal function must
be assessed as a baseline in every child.
Occasionally, hypocalcaemia is incidentally
discovered in children who are completely asymp-
tomatic. Others present with subacute onset of
symptoms such as muscle cramps, tingling numb-
ness and carpopedal spasms. Acute symptomatic
hypocalcaemia presents with seizures which are
multifocal in neonates or generalised tonic clonic
in older children. Neonates and infants may also
present with stridor, apnoea or respiratory distress.
Congestive cardiac failure due to hypocalcaemic
cardiomyopathy may also be a presenting feature.
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Arch Dis Child: first published as 10.1136/archdischild-2019-317482 on 3 January 2020. Downloaded from http://adc.bmj.com/ on January 4, 2020 at Agence Bibliographique de l
(group B; table 1). Short stocky habitus, obesity, brachydac-
tyly or ectopic calcifications are characteristic of the Albright
hereditary osteodystrophy (AHO) phenotype seen in pseudohy-
poparathyroidism (PHP) type IA. Chovstek’s sign (twitching of
ipsilateral facial muscles by tapping of the facial nerve in the
parotid region) and Trousseau’ sign (induction of carpal spasm
by maintaining the pressure in a sphygmomanometer cuff to
above systolic pressure for more than 3 min) are useful signs but
are not specific.6

Figure 1 Physiological response to hypocalcaemia. 25(OH)D,
25-­hydroxyvitamin D; 1,25(OH)2D3, 1,25 dihydroxyvitamin D3; PTH,
parathyroid hormone.
Approach to investigations
Once hypocalcaemia is detected, first-­line investigations should
be collected before any oral or intravenous correction. This
includes blood samples for intact PTH, bone profile (corrected
calcium, magnesium, phosphate and alkaline phosphatase
(ALK)), renal function and 25-­ hydroxyvitamin D (25(OH)
D) must be collected before any intravenous or oral correction
(table 3). Sample should be collected in plain tubes as serum
calcium is generally measured, and it is important to rule out
EDTA contamination of the blood sample.
Based on serum PTH, the approach to diagnosis can be divided

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The age at presentation provides clues to the possible aetiol-
ogies (table 2). Vitamin D deficiency continues to be a common
cause of symptomatic hypocalcaemia, especially during periods
of rapid growth of infancy and adolescence.
Features like frontal bossing, wide open anterior fontanelle,
costochondral beading and knee deformities suggest rickets
into three groups (figures 2 and 3): (1) low, (2) normal, or (3)
high PTH. It is important to bear in mind that an elevated PTH
in the presence of hypocalcaemia is the appropriate physiolog-
ical response to low plasma calcium (figure 1).
In hypoparathyroidism, PTH levels are low or ‘inappropri-
ately normal’ for the low plasma calcium. As PTH is also essential
for renal phosphate excretion, plasma phosphate levels are high

Table 1 Examples of disorders which present with hypocalcaemia

Group PTH levels Mechanism/genetic basis
A. Reduced PTH secretion/action
Familial isolated hypoparathyroidism Low Reduced PTH synthesis/secretion
►► GCM-2 mutations
►► PTH gene mutations
►► Idiopathic hypoparathyroidism
Normal/low Impaired CaSR function: ADH due to
►► CaSR gene-­activating mutations: type 1 ADH
►► GNA11 mutations: type 2 ADH
Hypoparathyroidism with syndromic association Low Reduced PTH synthesis
►► HDR due to GATA3 mutations
►► DiGeorge syndrome (22q deletion)
►► Sanjad Sakati syndrome due to TBCE gene mutation
►► Kearns-­Sayre syndrome (mitochondrial disorder)
►► Kenney-­Caffey syndrome (TBCE and FAM111A mutations)
Acquired hypoparathyroidism Low Reduced PTH synthesis
►► APECED
►► Post-­thyroidectomy
►► Transfusional haemosiderosis
Transient hypoparathyroidism Low Transient reduction in PTH synthesis
►► Sick/high-­risk neonates
►► Maternal hyperparathyroidism
►► Post-t­ hyroidectomy
►► Hypomagnesaemia
PHP High Resistance to the action of PTH
►► PHP1A and PHP1B due to GNAS mutation
B. Intact PTH secretion/action
Disorders with impaired calcium absorption: High CaSR function and PTH secretion are normal in this group. Hypocalcaemia is a result of one or
►► Vitamin D deficiency more of these mechanisms:
►► Dietary calcium deficiency ►► Low dietary calcium intake
►► Vitamin D dependent rickets ►► Malabsorption of dietary calcium
►► Chronic renal disease ►► Low levels or lack of action of 1,25(OH)2D3
►► Chronic liver disease Rickets is a common feature in this group
►► Malabsorption (congenital infantile lymphangiectasia)
►► Osteopetrosis
ADH, autosomal dominant hypocalcaemia; APECED, autoimmune polyendocrinopathy with candidiasis and ectodermal dystrophy; CaSR, calcium sensing receptor; FAM111A, family with sequence
similarity 111 member A; GATA3, GATA-­binding protein 3; GCM-2, glial cell missing 2 gene; GNA11, G protein subunit alpha 11; GNAS, guanine nucleotide binding protein alpha subunit;
HDR, hypoparathyroidism, deafness and renal dysplasia; 1,25(OH)2D3, 1,25 dihydroxyvitamin D3; PHP1A, pseudohypoparathyroidism type 1A; PHP1B, pseudohypoparathyroidism type 1B; PTH,
parathyroid hormone; TBCE, tubulin-­specific chaperone E.

2 Nadar R, Shaw N. Arch Dis Child 2020;0:1–7. doi:10.1136/archdischild-2019-317482

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Enseignement Superieur (ABES). Protected by copyright.
Figure 2 Hypocalcaemia with normal or inappropriately low parathyroid hormone (PTH). AIRE, autoimmune regulator gene; APECED,
autoimmunepolyendocrinopathy with candidiasis and ectodermal dystrophy; Ca/Cr, calcium/creatinine; CaSR, calcium sensing receptor; GATA-3,
GATA-­binding protein 3; GCM-2, glial cell missing 2 gene.

in this situation. In vitamin D deficiency with hypocalcaemia,
the serum phosphate levels are low due to renal phosphate loss
mediated by elevated PTH and reduced phosphate absorption.
Another characteristic of this group is elevated ALK levels. In
PTH resistance syndromes (PHP), renal phosphate excretion is
impaired, explaining the combination of low calcium, high phos-
phate and high PTH levels in this group.
The parent’s bone profile should be checked when hypo-
calcaemia presents in neonates and infants, as it may provide
important diagnostic information.
Clinical scenario I: a neonate with hypocalcaemic
seizures
History and investigations
A male neonate aged 10 days on formula milk feeds presented
with hypocalcaemic seizures. He was born by full-­term vaginal
delivery and had an uneventful perinatal period. Investigations
showed adjusted plasma calcium 1.49 mmol/L (2.2–2.7), PTH
2 ng/L (11–35 ng/L), phosphate 3.5 mmol/L (1.3–2.6) and ALK
230 IU/L (50–230).
Neonatal hypocalcaemia
Early (within 72 hours of birth) neonatal hypocalcaemia is
a common occurrence in high-­risk situations such as infants
of diabetic mothers, prematurity and birth asphyxia.7 This
is transient and the pathological basis is immaturity of the
parathyroid gland. It is managed with calcium supplements
given on a short-­term basis. On the other hand, late neonatal
hypocalcaemia (occurring after 72 hours) is caused by a high
phosphate diet (such as cow’s milk), congenital hypoparathy-
roidism, maternal hyperparathyroidism and vitamin D defi-
ciency (table 2).

Table 2 Examples of causes of hypocalcaemia depending on age of presentation

Neonatal period Infancy Childhood Adolescence
1. Vitamin D deficiency 1. Delayed presentation of FIH/ADH/ 1. APECED 1. PHP type 1B
2. Congenital hypoparathyroidism (FIH/ADH/ syndromic hypoparathyroidism 2. PHP type 1A 2. Vitamin D deficiency
syndromic hypoparathyroidism) 2. Vitamin D deficiency/related rickets 3. Idiopathic hypoparathyroidism
3. Maternal hyperparathyroidism
4. High-­risk neonates with transient hypocalcaemia
5. Osteopetrosis
ADH, autosomal dominant hypocalcaemia; APECED, autoimmune polyendocrinopathy candidiasis and ectodermal dystrophy; FIH, familial isolated hypoparathyroidism; PHP,
pseudohypoparathyroidism.

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Table 3 Investigations in a case of hypocalcaemia
First-­line investigations at initial presentation in all
cases Further tests Radiology
1. Bone profile: plasma calcium, magnesium, phosphate, 1. Screening of siblings and parents with bone profile, 1. X-­ray wrist and knee for rickets
alkaline phosphatase, albumin PTH, 25(OH) vitamin D and urine calcium/creatinine 2. Renal ultrasound to identify nephrocalcinosis
2. Serum creatinine, electrolytes ratio (indicated in APECED, vitamin D deficiency, ADH) 3. Chest X-­ray in infants for cardiomegaly
3. Serum intact PTH 2. Genetic studies
4. Urine calcium/creatinine ratio
5. Plasma 25(OH) vitamin D
6. Stored serum for 1,25(OH)2D3
ADH, autosomal dominant hypocalcaemia; APECED, autoimmune polyendocrinopathy candidiasis and ectodermal dystrophy; 25(OH)D, 25-­hydroxyvitamin D; 1,25(OH)2D3, 1,25
dihydroxyvitamin D3; PTH, parathyroid hormone.

Congenital hypoparathyroidism
Congenital hypoparathyroidism is caused by a group of geneti-
cally mediated defects in PTH synthesis, which lead to perma-
nent hypocalcaemia. It typically presents as acute symptomatic
hypocalcaemia in the neonatal period but may be delayed in
onset up to later infancy. It may be an isolated entity or occur in
association with other developmental defects. Familial isolated
hypoparathyroidism involves several genes that can be inherited
deafness and renal anomalies (HDR) syndrome due to an auto-
somal dominantly inherited GATA3 mutation on chromosome
10.13 Sanjad-­
Sakati syndrome also known as the hypopara-
thyroidism, retardation and dysmorphism syndrome due to a
mutation in the tubulin-­specific chaperone E (TBCE) gene on
chromosome 1 is inherited in an autosomal recessive manner
and is common in the Middle East.14

Enseignement Superieur (ABES). Protected by copyright.

as autosomal dominant, recessive or X-­linked recessive.8–10 The
most common cause is due to mutations in the glial cell missing 2
gene (GCM2) which codes for a transcription factor responsible
for parathyroid gland development—this can be dominantly or
recessively inherited.11
The most well-­known syndrome associated with congenital
hypoparathyroidism is DiGeorge syndrome in which hypoplasia
of the parathyroid glands occurs during development.12 Here,
hypocalcaemia is often identified in infancy when the child pres-
ents with the associated cardiac defects. This may require treat-
ment with calcium supplements and/or a vitamin D analogue
but will often resolve in early childhood to recur during puberty
or adulthood. Another condition is the hypoparathyroidism,
Osteopetrosis
Osteopetrosis can sometimes present in neonates with hypocal-
caemia and elevated PTH levels.15
Diagnosis in case 1
Suppressed PTH and elevated plasma phosphate suggested hypo-
parathyroidism. His father had a normal bone profile, whereas
mum had high PTH 240 ng/L (12–65), high plasma calcium
(3.04 mmol/L) and low phosphate (0.57 mmol/L, normal range
0.8–1.5) suggesting primary hyperparathyroidism. He had tran-
sient neonatal hypoparathyroidism due to maternal hyperpara-
thyroidism. This occurs due to increased transplacental calcium

Figure 3 Hypocalcaemia with a high PTH. 25(OH)D, 25-­hydroxyvitamin D; alk phos, alkaline phosphatase; GNAS, guanine nucleotide binding protein
alpha subunit; PTH, parathyroid hormone.
4 Nadar R, Shaw N. Arch Dis Child 2020;0:1–7. doi:10.1136/archdischild-2019-317482

transfer, suppressing fetal parathyroid glands. Treatment with
oral calcium supplements and 1-­alpha hydroxyvitamin D3 (alfa-
calcidol) is required in the initial weeks but often will resolve
after 3 to 6 months as the parathyroid glands recover and resume
normal secretion of PTH.16
Clinical scenario II: an infant with a
hypocalcaemic seizure and congestive cardiac
failure
An Asian female infant of 5 months who was exclusively breast
fed presented with hypocalcaemic seizures, failure to thrive
and congestive cardiac failure. Her investigations revealed low
adjusted plasma calcium 1.96 (2–2.7 mmol/L) and phosphate
0.69 (1.3–2.4) mmoL/L with elevated ALK 1391 (105–420 IU/L)
and PTH 51.1 (<5 pmol/L) levels suggesting rickets. Two-­
dimensional echocardiography showed dilated cardiomyopathy
due to chronic hypocalcaemia. Her 25(OH) vitamin D levels was
12.5 nmol/L (>50 nmol/L).
The differential diagnosis at this age is vitamin D deficiency,
congenital hypoparathyroidism and autosomal dominant hypo-
calcaemia (ADH).
Disorders of vitamin D presenting as hypocalcaemia
Although vitamin D deficiency will most often present with
rickets in children, it can present with symptomatic hypocal-
caemia particularly during the rapid growth periods of infancy
and puberty.17 This will be usually as hypocalcaemic convulsions
or episodes of tetany. Another important presentation in infancy
is with cardiomyopathy which can be life threatening.18 A
phenomenon that can be seen in these age groups is the presence
of a raised plasma phosphate despite a high PTH level which
occasionally can cause confusion with PHP. Vitamin D levels
should always be checked before making a diagnosis of PHP.
This PTH resistance in the renal tubules appears to be due to
associated dietary calcium deficiency which will correct when
adequate calcium intake is supplied.19
Any of the calcipenic forms of rickets due to defects in vitamin
D metabolism or action may present with hypocalcaemia.
Chronic renal or liver failure can also present with hypocal-
caemia although rickets is a more common presenting feature. In
the former, it is due to inadequate synthesis of 1,25(OH)2D3 and
the failure to excrete phosphate while in liver failure is predomi-
nantly due to malabsorption of calcium and vitamin D.
Autosomal dominant hypocalcaemia
This condition is suspected when PTH levels are inappropriately
normal during hypocalcaemia and is due to gain of function
mutations of the CaSR. The most common form, ADH type 1 is
due to a mutation in the CaSR gene, whereas a second form ADH
type 2 is due to a mutation in the GNA11 (G protein subunit
alpha 11) gene.20 In this condition, there is an altered set point
in the parathyroid glands and kidneys such that a lower plasma
calcium is required to trigger PTH release (figure 4). Such indi-
viduals have plasma calcium below the normal range often 1.8
to 2.0 mmol/L and increased renal calcium excretion (although
urinary calcium excretion may be normal in ADH type 2). In at
least 40% of affected individuals, the PTH is within the normal
range whereas the rest will have a low PTH. Approximately
50% of individuals with ADH are asymptomatic, whereas the
other 50% especially children will be symptomatic during febrile
episodes or in the neonatal period.21 Treatment with a vitamin
D analogue and/or calcium supplements should be reserved for
symptomatic individuals due to the high risk of hypercalciuria
Nadar R, Shaw N. Arch Dis Child 2020;0:1–7. doi:10.1136/archdischild-2019-317482
Review
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Figure 4 Relationship between ionised calcium and serum
parathyroidhormone (PTH) with shift in relationship seen in autosomal
dominant hypocalcaemia.34 Also note the effect of inactivating calcium
sensing receptor (CaSR) mutations causing the pathophysiologically
opposite condition, familial hypocalciuric hypercalcaemia.
Enseignement Superieur (ABES). Protected by copyright.
and nephrocalcinosis. An alternative treatment option is the use
of synthetic PTH by subcutaneous injection or infusion with a
pump.
Normally there is incremental PTH release in response to a
decrease in plasma calcium levels. However in activating muta-
tions of the CaSR, the set point for PTH release is altered such
that the curve shifts to the left, reducing PTH output, resulting
in ambient hypocalcaemia (figure 4).
Diagnosis in case II
This infant had severe vitamin D deficiency resulting in conges-
tive cardiac failure due to hypocalcaemic cardiomyopathy. Mum
and sibling also had severe vitamin D deficiency.
Clinical scenario III: a 6-year old with carpopedal
spasms
A female child aged 6 years presented with carpopedal spasms
during an episode of acute gastroenteritis. She reported similar
episodes over the past few weeks. She was previously fit and
well. Her plasma calcium level was 1.23 mmol/L (2.2–2.7), phos-
phate 2.75 mmol/L (0.90–1.80), PTH 5.0 ng/L (11–35), 25(OH)
vitamin D 31 nmol/L (>50 nmol/L) and creatinine 46 μmol/L
(18–51). The presence of low PTH levels during concomitant
hypocalcaemia suggested hypoparathyroidism. She was started
on a vitamin D analogue (alfacalcidol) and calcium supplementa-
tion. The differential diagnosis at this age is acquired hypopara-
thyroidism and ADH.
Acquired hypoparathyroidism
The most important cause of acquired hypoparathyroidism is
the autoimmune polyendocrinopathy syndrome (autoimmune
polyendocrinopathy with candidiasis and ectodermal dystrophy
(APECED)) due to mutations in the autoimmune regulator
gene (AIRE) inherited in an autosomal recessive manner.22 This
condition often presents with hypoparathyroidism as the first
endocrine manifestation with the subsequent potential devel-
opment of adrenal insufficiency, hypogonadism, thyroid disease
and diabetes mellitus over several decades.23 Non-­endocrine
manifestations include malabsorption, chronic active hepatitis
and hyposplenism. It is important to consider this condition in
any child presenting with hypoparathyoidism in early to mid-­
childhood (table 2) and once a gene defect is identified to ensure
5
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that any siblings are investigated. Any child with this condition
should undergo annual screening for adrenal insufficiency with a
Synacthen test and plasma renin. Some children with congenital
hypoparathyroidism may also present at this age with a delayed
presentation.
Acquired hypoparathyroidism may also be a consequence of
surgery to the neck, for example, for thyroid disease or due to
iron deposition in the parathyroid glands from repeated blood
transfusions in children with thalassaemia major or rarely as a
complication of Wilson’s disease.
Diagnosis in case III
An AIRE gene mutation confirmed APECED. Two years later,
she became acutely unwell with dehydration and hypercal-
caemia. Her urea 9.2 mmol/L and plasma calcium 2.9 mmol/L
(2.2–2.7) were elevated, with normal creatinine and serum elec-
trolytes, high plasma renin 35 nmol/L/hour (0.5–2.2) and plasma
adrenocorticotrophic hormone 663 nmol/L (9-–52) indicating
the development of primary adrenal insufficiency.
Clinical scenario IV: a 15-year old with muscle
cramps
A boy aged 15 years presented with a 1 year history of muscle
cramps and jaw locking. He had an uneventful previous medical
history and normal intelligence. His plasma calcium was
1.4 mmol/L, phosphate 3.15 mmol/L (0.90–1.80), creatinine
68 μmol/L (43–75), 25(OH) vitamin D 49 nmol/L (>50 nmol/L),
PTH 378 ng/L (11–35) and urine calcium/creatinine ratio
0.06 mmol/mmol (<0.7).
At this age, the differential diagnosis would be vitamin D defi-
ciency, hypoparathyroidism or PHP.
The term PHP
PHP covers a number of related disorders in which resistance to
PTH is the predominant feature. Those who present with hypo-
calcaemia resemble hypoparathyroidism with an elevated plasma
phosphate but instead of a low PTH have a high PTH. Most of
the disorders are due to a genetic or epigenetic defect in the
GNAS (guanine nucleotide binding protein alpha subunit) gene
on chromosome 20 and are an example of imprinting, that is,
repression of gene expression from one parental allele.24 25 There
are several types with distinctive features. The most well-­known
type is PHP type 1A in which affected individuals have features
of AHO. Resistance to other hormones may also be found such
as hypothyroidism and hypogonadism and growth hormone
deficiency. Although this is a congenital disorder, hypocalcaemia
does not usually present until mid-­childhood due to the fact that
paternal silencing of Gs alpha expression in the proximal renal
tubule occurs postnatally.26
PHP type 1B does not have AHO features but may also have
additional hormone resistance particularly hypothyroidism.
PTH resistance develops over time and affected individuals
often do not present with symptomatic hypocalcaemia until
their teenage years. It is now recognised that there is consid-
erable overlap in the different types of PHP which has led to a
revised classification.27
Diagnosis in case IV
This boy has PHP type 1B. The late age of presentation is likely
due to an increased demand for calcium at the time of increased
linear growth from the pubertal growth spurt.
His thyroid function tests were normal. Genetic testing
confirmed loss of maternal methylation pattern in GNAS
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Arch Dis Child: first published as 10.1136/archdischild-2019-317482 on 3 January 2020. Downloaded from http://adc.bmj.com/ on January 4, 2020 at Agence Bibliographique de l
(PHP1B). He was treated with long-­term vitamin D analogue
and calcium supplements.
Treatment of hypocalcaemia
This is dependent on two factors: (1) whether there are severe
symptoms such as convulsions and the (2) the underlying cause.
Intravenous calcium gluconate is used in acute symptomatic
hypocalaemia. Various calcium salts are available for oral treat-
ment. It is important to calculate the dose based on the elemental
calcium content and not the calcium salt. (The equivalence of
1 mmol of elemental calcium is 40 mg.)
Urgent correction
It is given using an intravenous bolus of 10% calcium gluco-
nate (1 mL of 10% calcium gluconate contains 0.22 mmol of
elemental calcium) in a dose of 0.5 to 2 mL/kg over 5 to 10 min
(with a maximum of 20 mL) followed by a continuous infusion
of 1.0 mmol/kg under cardiac monitoring (maximum 8.8 mmol,
occasionally higher doses may be needed) over 24 hours. A
continuous intravenous infusion (preferably through a central
line) must be started after a bolus to prevent recurrent symp-
toms. It is important to try and discontinue an intravenous infu-
Enseignement Superieur (ABES). Protected by copyright.
sion once the severe symptoms have settled, in favour of oral
calcium supplements due to the risk of extravasation of calcium
causing damage to skin and subcutaneous tissues.
Non-urgent correction
It is used in asymptomatic or mildly symptomatic children as
oral calcium supplements given in a dose ranging from 0.2 to
10 mmol/kg per dose every 6 hours . The dose should be titrated
based on response. When stopping high doses of oral calcium, it
is important to do so gradually with intermittent monitoring of
serum calcium levels.
Hypomagnesaemia
Hypomagnesaemia can be treated with intramuscular or intra-
venous infusion of 50% magnesium sulfate 0.1–0.2 mL/kg
(50–100 mg/kg). This should be followed by oral magnesium at
the dose of 0.2 to 0.4 mmol/kg/day. Primary hypomagnesaemia
requires long-­term oral magnesium supplementation in a dose of
0.7 to 3.5 mmol/kg/day.
Long-term management of hypoparathyroidism and PHP
Though recombinant PTH preparations are available, their
routine use in clinical practice is limited by cost and pharmaco-
kinetic properties necessitating a subcutaneous route of adminis-
tration. The cornerstone of treatment remains life-­long treatment
with vitamin D analogues, such as alfacalcidol or 1,25(OH)2D3
(calcitriol) in a dose of 25–50 ng/kg/day. These drugs primarily
increase intestinal calcium absorption. Calcium supplements are
usually required initially but can often be discontinued when the
plasma calcium is normal if there is an adequate dietary calcium
intake. The aim should be to maintain the plasma calcium at
the lower end of the normal range (2.0 to 2.2 mmol/L) as renal
calcium reabsorption remains low due to the lack of PTH
activity with the risk of hypercalciuria. Monitoring should there-
fore include periodic assessment of the urine calcium/creatinine
ratio and renal ultrasounds to detect nephrocalcinosis. During
periods of intercurrent illness, these children tend to develop
hypocalcaemia and may require increased doses of the vitamin D
analogue.28 It is important that after recovery from intercurrent
illnesses dose of medication is reduced to original doses or there
would be risk of hypercalcaemia and nephrocalcinosis.

Recombinant full-­length human PTH (1–84) has a short half
life of 2.5 to 3 hours and it has to be administered as twice daily
injections.29 It has not been used in children. Clinical trials in
adults have shown good efficacy, however long term safety needs
to be further studied.30 Continuous subcutaneous infusion of
recombinant PTH1–34 has successfully been used in children with
hypoparathyroidism who were difficult to manage on conven-
tional therapy31 32; however, its use is not licensed in children
and no randomised trials have been performed .
Vitamin D disorders
Vitamin D deficiency should be treated with ergocalciferol (D2)
or cholecalciferol (D3) in doses ranging from 3000 to 10 000
units daily for 8 to 12 weeks or as a single large bolus dose of
150 000 to 3 00 000 units. Calcium supplements should also be
given initially.33 Activated vitamin D (alfacalcidol) must not be
used to treat vitamin D deficiency. Its role is limited to short-­
term use to correct severe, symptomatic hypocalcaemia. Stores
of cholecalciferol are not replenished with analogue therapy,
predisposing to recurrent vitamin D deficiency.
Vitamin D 1-­alpha hydroxylase deficiency (vitamin D depen-
dant rickets type 1) requires alfacalcidol or calcitriol in conjunc-
tion with calcium supplements. Hereditary 1,25(OH)2D3
resistant rickets (vitamin D dependant rickets type II) may
respond to alfacalcidol or calcitriol in the milder forms but will
often require intravenous calcium infusions via a central line to
heal the rickets and correct the hypocalcaemia.
Contributors Both authors have contributed to the entire process of planning,
review of literature and manuscript preparation for this article.
Funding The authors have not declared a specific grant for this research from any
funding agency in the public, commercial or not-­for-­profit sectors.
Competing interests None declared.
Patient consent for publication Not required.
Provenance and peer review Commissioned; externally peer reviewed.
Data availability statement Data sharing not applicable as no datasets
generated and/or analysed for this study.
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