Chapter 6
Allgrove J, Shaw NJ (eds): Calcium and Bone Disorders in Children and Adolescents. 2nd, revised edition.
Endocr Dev. Basel, Karger, 2015, vol 28, pp 84100 (DOI: 10.1159/000380997)
A Practical Approach to Hypocalcaemia in
Children
Nick J. Shaw
Department of Endocrinology and Diabetes, Birmingham Childrens Hospital, Birmingham, UK
Abstract
Hypocalcaemia is one of the commonest disorders of
mineral metabolism seen in children and may be a con-
sequence of several different aetiologies. These include a
lack of secretion or function of parathyroid hormone, dis-
orders of vitamin D metabolism and abnormal function
of the calcium-sensing receptor. A practical approach to
the investigation, diagnosis and subsequent manage-
ment of hypocalcaemic disorders is presented.
2015 S. Karger AG, Basel
Introduction
Hypocalcaemia is one of the commonest disor-
ders of calcium and phosphate metabolism seen
in children. It may be asymptomatic or manifest
with a variety of different symptoms that can vary
with the age of the child. Although the differential
diagnosis is quite expansive, the cause can usually
be categorised into one of a small list of broad ae-
tiologies. An understanding of the key determi-
nants of the regulation of plasma calcium and the
normal physiological response to hypocalcaemia
will lead to an appropriate interpretation of ex-
amination results and subsequent diagnosis and
management of hypocalcaemia.
Physiological Response to Hypocalcaemia
A fall in plasma calcium will lead to several phys-
iological changes that act in conjunction to re-
store the plasma calcium level rapidly to the nor-
mal range. These changes take place in the three
key organs that are involved in the maintenance
of plasma calcium, i.e. the kidney, bone and the
small intestine (fig.1). Thus, a fall in the level of
ionised calcium is detected by the calcium-sens-
ing receptor, which is localised to the parathyroid
glands and the renal tubules. In the parathyroid
glands, this event leads to the increased synthesis
and secretion of parathyroid hormone (PTH).
The increased circulating levels of PTH then act
in three different ways.
PTH alters the renal tubular reabsorption of
calcium in the kidney, leading to increased re-
absorption of filtered plasma calcium and re-
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Fig. 1. The physiological response to hypocalcaemia.

duced excretion of calcium in the urine. As a
consequence, there is a reciprocal effect on the
tubular reabsorption of phosphate (TRP), and
a fall in the TRP leads to increased urinary
phosphate excretion. Thus, markers of elevat-
ed serum PTH levels include low levels of plas-
ma phosphate and TRP.
PTH acts on the skeleton, stimulating
osteoclasts to increase bone resorption, leading
to the release of calcium from bone into the
circulation.
The increased level of circulating PTH also
stimulates the activity of the 1-hydroxylase
enzyme in the proximal renal tubule, leading
to increased secretion of 1,25-dihydroxyvitamin
D (1,25(OH)2D), which then increases
intestinal calcium absorption.
Thus, alterations in renal calcium reabsorp-
tion, bone resorption and intestinal calcium ab-
sorption result in the restoration of the ionised
calcium level. Although the synthesis and secre-
tion of PTH are the key factors in this response, it
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Hypocalcaemia 85
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Allgrove J, Shaw NJ (eds): Calcium and Bone Disorders in Children and Adolescents. 2nd, revised edition.
Endocr Dev. Basel, Karger, 2015, vol 28, pp 84100 (DOI: 10.1159/000380997)
can be appreciated that this process also requires
a functional calcium-sensing receptor, the appro-
priate synthesis of 1,25(OH)2D and a normal re-
sponse of peripheral tissues to secreted PTH.
Signs and Symptoms of Hypocalcaemia
The symptoms of hypocalcaemia often reflect the
key role of calcium in the processes of nerve con-
duction and muscle function, as a low plasma cal-
cium level results in increased neuromuscular ex-
citability. Paraesthesia, a tingling sensation, usu-
ally presenting around the mouth, fingers and
toes, is a common symptom of hypocalcaemia.
Muscle cramps caused by sustained muscle con-
tractions, often in the hands, can be experienced
and can progress to tetany in some children. Ei-
ther focal or generalised convulsions can be a
manifestation of hypocalcaemia at any age, par-
ticularly during infancy and adolescence. Other
less common symptoms include laryngospasm,
stridor and apnoea in neonates. Hypocalcaemia
can also lead to disturbances of cardiac rhythm
and prolongation of the QT interval on electro-
cardiography. Chronic hypocalcaemia can lead to
basal ganglia calcification, subcapsular cataracts,
papilloedema and dental enamel hypoplasia, par-
ticularly of the primary dentition.
Two manifestations of latent hypocalcaemia
that can be evoked on clinical examination are
the signs of Chvostek and Trousseau. The former
consists of gentle repeated tapping with a forefin-
ger on the lateral cheek over the course of the fa-
cial nerve 0.51.0 cm below the zygomatic pro-
cess and 2 cm anterior to the ear lobe. A positive
sign is twitching of the corner of the mouth on
the ipsilateral side due to contractions of the cir-
cumoral muscles. However, this sign is not a reli-
able marker of hypocalcaemia, as one study has
shown that 29% of individuals with laboratory
confirmed hypocalcaemia are negative for this
sign [1]. Trousseaus sign is evoked by inflating a
sphygmomanometer cuff above the systolic pres-
86
Allgrove J, Shaw NJ (eds): Calcium and Bone Disorders in Children and Adolescents. 2nd, revised edition.
Endocr Dev. Basel, Karger, 2015, vol 28, pp 84100 (DOI: 10.1159/000380997)
Table 1. Investigations in hypocalcaemia
Plasma calcium, phosphate and magnesium
Plasma albumin
Plasma or serum alkaline phosphatase
Plasma creatinine
Plasma 25-hydroxyvitamin D
Serum parathyroid hormone
Serum samples for 1,25-dihydroxyvitamin D3, etc.
Blood samples for DNA studies as appropriate
Urine samples for calcium/creatinine ratio
X-ray of wrist or knee
sure for three minutes. A positive sign is the
adoption of the main daccoucheur position,
consisting of flexion of the wrist and the metacar-
pophalangeal joints and extension of the inter-
phalangeal joints and adduction of the fingers
due to carpopedal spasm. Note that this sign can
be painful for the individual if sustained for too
long. Trousseaus sign is believed to be a more
specific marker of hypocalcaemia than Ch-
vosteks sign, as one study showed that 94% of
individuals with hypocalcaemia were positive for
Trousseaus sign [2].
Investigations
There are several important investigations re-
quired for the management of a child with hypo-
calcaemia, and the majority of these exams are
biochemical in nature (table1). The total plasma
calcium level is usually measured in the blood, al-
though some laboratories and near-patient test-
ing facilities measure ionised calcium, which is
usually 50% of the total plasma calcium. Calcium
is predominantly bound to albumin in plasma,
and therefore, deviation of plasma albumin from
the normal range affects the total plasma calcium
level. Some laboratories automatically adjust for
this deviation and report a corrected plasma cal-
cium level. However, in the absence of such a fa-
cility, there are several simple correction factors
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that can be applied. One of the most well known
methods is to correct the plasma calcium level by
0.02 mmol/l for every 1 gm/l that the plasma al-
bumin level deviates from the normal value of
40 gm/l; e.g. for a total plasma calcium level of
2.2mmol/L and a plasma albumin level of 30gm/l,
the corrected calcium level is 2.2+[0.02*(30
40)]= 2.4 mmol/l.
The measurement of plasma phosphate is use-
ful as an indirect index of PTH activity; a low
phosphate level reflects an elevated serum PTH
level, and a high phosphate level reflects a reduced
serum PTH level. Hypomagnesaemia is a rare but
important cause of hypocalcaemia. Therefore,
plasma magnesium should be included in the list
of examinations. Plasma or serum alkaline phos-
phatase is usually included as part of the standard
bone profile produced by many laboratories as a
marker of bone turnover. This factor is often ele-
vated when hypocalcaemia is secondary to a dis-
order of vitamin D and is often within the normal
range when hypocalcaemia is secondary to hypo-
parathyroidism. Plasma creatinine is an essential
measure to exclude the possibility of renal failure
as the cause of hypocalcaemia.
The measurement of 25-hydroxyvitamin D
(25OHD) is an important routine investigation
given the frequency of disorders of vitamin D in
the aetiology of hypocalcaemia in children. It is
the main circulating form of vitamin D and is the
metabolite that best reflects an individuals vita-
min D status. Although a 25OHD level of less
than 50 nmol/l (20 ng/ml) is regarded as consis-
tent with vitamin D deficiency, hypocalcaemia
does not usually occur until the 25OHD levels are
less than 25 nmol/l (10 ng/ml). Once vitamin D
deficiency has been excluded as a cause of hypo-
calcaemia, most of its remaining causes have a ge-
netic basis, and blood should be collected for ap-
propriate genetic analysis.
Serum PTH is the most critical investigation in
determining the aetiology of hypocalcaemia, and
as indicated subsequently in this chapter, this fac-
tor is used here as the main means of classifica-
Hypocalcaemia
Allgrove J, Shaw NJ (eds): Calcium and Bone Disorders in Children and Adolescents. 2nd, revised edition.
Endocr Dev. Basel, Karger, 2015, vol 28, pp 84100 (DOI: 10.1159/000380997)
Table 2. Aetiology of hypocalcaemia
PTH disorder
Reduced PTH secretion
Impaired PTH function
Vitamin D disorder
Vitamin D deficiency
Impaired vitamin D metabolism
Impaired renal function
Abnormality of the calcium-sensing receptor (CaSR)
Gain-of-function mutations in the gene
encoding the CaSR
Activating antibodies to the CaSR
tion. There are three additional investigations
that may prove to be helpful. Additional serum
samples should be routinely obtained and stored
in the laboratory when the initial investigations
are performed. These samples can then be used
for subsequent analysis, such as the measurement
of 1,25(OH)2D, when the initial investigations
have not clarified the aetiology of hypocalcaemia.
Attempting to measure such a metabolite at a lat-
er stage when a child has received initial treat-
ment is often compromised by the effect of the
treatment. A measurement of the urine calcium/
creatinine ratio, ideally using a second morning
urine sample obtained in the fasting state, is a use-
ful marker of renal calcium excretion and, con-
versely, of renal tubular calcium reabsorption [3].
Finally, an X-ray of the metaphysis of a long bone,
such as at the wrist or the knee, may identify pre-
viously unsuspected pathology, such as the pres-
ence of rickets or of a dense skeleton in an infant
with osteopetrosis.
Aetiology of Hypocalcaemia: Classification
It is possible to divide the causes of hypocalcae-
mia into three broad categories that reflect the
three main important components of the regula-
tion of plasma calcium, i.e. serum PTH, vitamin
D and the calcium-sensing receptor (table 2).
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Table 3. Categorisation of the causes of hypocalcaemia
Undetectable or low PTH levels
Hypoparathyroidism
Hypomagnesaemia
Normal PTH levels
Abnormality of the calcium-sensing receptor
Elevated PTH levels
Pseudohypoparathyroidism
Vitamin D deficiency
Impaired vitamin D metabolism
Chronic renal failure
Osteopetrosis
Within each of these categories, it is possible to
stratify the causes of hypocalcaemia further.
Thus, the category related to PTH encompasses a
reduction in PTH secretion, as seen in hypopara-
thyroidism, and an impairment in PTH function,
as seen in pseudohypoparathyroidism (PHP).
The category related to vitamin D can also be
subdivided into a lack of the essential substrate
25OHD, as seen in vitamin D deficiency, or an
impairment of its metabolism, as in 1-hydroxylase
deficiency, or the loss of end organ vitamin D
function. The category related to the calcium-
sensing receptor encompasses congenital disor-
ders due to mutations in the relevant gene, as
seen in autosomal dominant hypocalcaemia, and
acquired disorders, such as activating antibodies
to the calcium-sensing receptor.
However, a more practical approach in deter-
mining the aetiology of hypocalcaemia is to adopt
a classification dependent on the level of serum
PTH in the presence of hypocalcaemia (table3).
Thus, a serum PTH level that is either undetect-
able or low can be seen in both hypoparathyroid-
ism and hypomagnesaemia. An inappropriately
normal serum PTH is often seen when there is an
abnormality affecting the function of the calci-
um-sensing receptor. Finally, an elevated serum
PTH level is the appropriate physiological re-
sponse when there is a disorder of vitamin D or a
failure of end organ PTH function, as seen in PHP
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Allgrove J, Shaw NJ (eds): Calcium and Bone Disorders in Children and Adolescents. 2nd, revised edition.
Endocr Dev. Basel, Karger, 2015, vol 28, pp 84100 (DOI: 10.1159/000380997)
or osteopetrosis. The next section of this chapter
will examine this classification in more detail,
with descriptions of the individual conditions.
Hypocalcaemia with Low or Undetectable
Parathyroid Hormone Levels
Congenital Hypoparathyroidism
This disorder may occur as an isolated defect or
in association with other developmental defects.
A number of genetic abnormalities have now
been identified that can be broadly categorized as
abnormal forms of PTH, defects in intracellular
transcription factors or abnormalities that pre-
vent normal development of the parathyroid
glands.
Isolated Congenital Hypoparathyroidism
Isolated congenital hypoparathyroidism (#146200)
may be sporadic or familial, and autosomal domi-
nant (168450.0001), recessive (168450.0002) and
X-linked recessive (#307700) forms have been rec-
ognised. Homozygous mutations in the gene for
preproPTH, located on chromosome 11p15
(*168450), are responsible for an autosomal reces-
sive form [4]. The autosomal dominant inherited
form is due to point mutations in the signal se-
quence of preproPTH, which prevent the process-
ing and translocation of PTH across the endoplas-
mic reticulum and the cell membrane for exocyto-
sis [5]. The most common cause of isolated
hypoparathyroidism, which is inherited in an au-
tosomal recessive or a dominant manner, has been
shown to be mutations of the glial cell missing 2
gene (*603716), which is located on chromosome
6p24.2 and which encodes a transcription factor
responsible for parathyroid gland development
[6]. Originally, homozygous mutations of this
gene were reported to cause autosomal recessive
hypoparathyroidism (see Cases 197; 198), but
subsequently, autosomal dominant forms were re-
ported due to the dominant negative effect of cer-
tain heterozygous mutations [7] (see Case 199).
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 The X-linked recessive form has now been
identified to be due to an interstitial deletion-in-
sertion involving chromosomes 2p25.3 and
Xq27.1 [8]. This mutation is thought to affect the
expression of SOX3, a transcription factor ex-
pressed in the developing parathyroid glands. All
of these conditions present during the neonatal
period or childhood without any signs of other
organs being affected, and the treatment of hypo-
calcaemia with vitamin D analogues is usually all
that is required.
22q Deletion (Di George) Syndrome
The most well known syndrome associated with
congenital hypoparathyroidism is Di George syn-
drome (DGS) (#188400), which overlaps with velo-
cardiofacial syndrome (#192430). DGS is the most
common chromosome deletion syndrome and af-
fects 1 in 45,000 live births. Maldevelopment of
the 3rd and 4th branchial pouches causes hypopla-
sia of the parathyroid glands and the thymus in as-
sociation with congenital conotruncal cardiac de-
fects and a distinctive facial phenotype. Most DGS
cases are sporadic, but familial cases with apparent
autosomal dominant inheritance have been de-
scribed. The majority of DGS cases are due to dele-
tions at chromosome 22q11 (DGS Type 1), al-
though deletions at a second locus, 10p13 (DGS
Type 2), have been found in some patients. The de-
letion in chromosome 22q is hemizygous and en-
compasses a variable length of the chromosome.
However, it is now considered that the majority of
cases of DGS1 are due to a common deletion of the
TBX1 gene (*602054), which is a transcription fac-
tor involved in the development of the pharyngeal
arches and pouches and the otic vesicles.
The clinical features of DGS are variable. Hy-
pocalcaemia may be present in the neonatal peri-
od but is often transient, although hypocalcaemia
may recur during puberty or adulthood [9], or pe-
riods in which growth is the most rapid and the
demand for calcium is the greatest. Occasionally,
Hypocalcaemia
Allgrove J, Shaw NJ (eds): Calcium and Bone Disorders in Children and Adolescents. 2nd, revised edition.
Endocr Dev. Basel, Karger, 2015, vol 28, pp 84100 (DOI: 10.1159/000380997)
when hypocalcaemia presents clinically at adoles-
cence, retrospective assessment of the case history
strongly suggests that symptoms have been pres-
ent for several years (see Cases 194; 195). How-
ever, hypocalcaemia may be overlooked in the
neonatal period if the condition is accompanied
by serious cardiac anomalies. It is thought that up
to 70% of patients who survive the neonatal period
have some degree of parathyroid hypoplasia.
Other Forms of Familial Hypoparathyroidism
Hypoparathyroid, deafness, and renal anomalies
syndrome (#146255) is inherited in an autosomal
dominant manner and is due to mutations in the
gene coding for the transcription factor GATA3
on chromosome 10p1410pter (*131320); this
gene is critical for parathyroid, kidney and otic
vesicle development [10]. Affected individuals
usually have hypoparathyroidism in association
with bilateral sensorineural deafness and renal
anomalies such as bilateral cysts that compress the
glomeruli and tubules, leading to renal impair-
ment in some patients. Some patients do not have
all of the major clinical features, i.e. hypoparathy-
roidism, deafness and renal abnormalities, but
over 90% of patients with two or three of these fea-
tures have a GATA3 mutation (see Case 1910).
Another syndrome that includes hypoparathy-
roidism, mental and growth retardation and dys-
morphic features, hypoparathyroidism-retarda-
tion-dysmorphism syndrome (#241410), is inher-
ited in an autosomal recessive manner. This
disorder was originally reported from the Middle
East in children of consanguineous parents and
was termed Sanjad-Sakati syndrome (character-
ized by growth failure, ocular malformations, mi-
crocephaly and mental retardation) (#241410).
The genetic defect responsible for these cases was
localised to chromosome 1q42-q43 and was sub-
sequently identified as a mutation in tubulin-spe-
cific chaperone E (TBCE) (*604934), which causes
loss of function and likely alters microtubule as-
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sembly in affected tissues [11]. Kenny-Caffey syn-
drome (KCS) includes short stature, osteosclerosis
and ocular abnormalities. An autosomal recessive
form of this condition has been reported (KCS1
#244460) to overlap with Sanjad-Sakati syndrome,
as defects in TBCE have also been reported for
KCS1 [11]. More recently, an autosomal domi-
nant form of KCS has been identified (KCS2
#127000) to be due to mutations in FAM111A on
chromosome 11q12 [12]. It is thought that the two
proteins TBCE and FAM111A might interact in a
common regulatory pathway.
Finally, a number of mitochondrial disorders
are associated with congenital hypoparathyroid-
ism. These include Kearns-Sayre syndrome (char-
acterised by progressive external ophthalmoplegia,
heart block or cardiomyopathy see Case 1911)
(#530000), mitochondrial encephalopathy, lactic
acidosis and stroke-like episodes (#540000) and
mitochondrial trifunctional protein deficiency
syndrome (#609015). As these disorders result
from mitochondrial gene defects, they are mater-
nally inherited. In all of these conditions, hypo-
parathyroidism is often a relatively minor feature
and may be overlooked in light of the other prob-
lems present.
A rare form of congenital, but not genetically
mediated, hypoparathyroidism has been reported
secondary to maternal hyperparathyroidism [13].
Affected infants have presented in the neonatal
period with hypocalcaemia due to transient hy-
poparathyroidism that, upon investigation of the
mother, have been identified to suffer from previ-
ously unrecognised hyperparathyroidism, which
presumably suppresses the foetal parathyroid
glands in utero (see Case 191).
Acquired Hypoparathyroidism
This disorder can be a consequence of surgery on
the thyroid gland (e.g. total thyroidectomy for
thyrotoxicosis) or the parathyroid glands (e.g. to
treat primary hyperparathyroidism) due to their
90
Allgrove J, Shaw NJ (eds): Calcium and Bone Disorders in Children and Adolescents. 2nd, revised edition.
Endocr Dev. Basel, Karger, 2015, vol 28, pp 84100 (DOI: 10.1159/000380997)
inadvertent removal or damage to their blood
supply. Rarely, in children, this disorder may be
related to radical neck dissection for malignancy.
Therefore, the plasma calcium level should be
routinely estimated following thyroidectomy in
children. Hypoparathyroidism may also be a
complication of iron deposition in the parathy-
roid glands of children with thalassaemia major
who receive repeated blood transfusions. This
usually presents in the second decade, often in
conjunction with other end organ complications
such as hypogonadism and diabetes mellitus. This
disorder has also been reported as a rare compli-
cation of Wilsons disease due to copper deposi-
tion or iodine131 therapy for thyroid disease.
Autoimmune hypoparathyroidism can be ei-
ther isolated or as part of the autoimmune polyen-
docrinopathy type 1 syndrome (#240300). This
latter condition may be sporadic or familial with
an autosomal recessive mode of inheritance (see
Case 196). There is a triad of principal features,
mucocutaneous candidiasis, hypoparathyroidism
and adrenal insufficiency [14]. Ectodermal dys-
trophy of the nails is often present, leading to an
alternative term for this syndrome, autoimmune
polyendocrinopathy-candidiasis-ectodermal dys-
trophy (APECED). It usually presents in early
childhood; mucocutaneous candidiasis (mean age
5 years) with hypoparathyroidism (mean age 9
years) represents the earliest endocrine manifesta-
tion, followed by the development of adrenal in-
sufficiency (at a mean age of 14 years). Additional
autoimmune features that may occur include mal-
absorption, chronic active hepatitis, thyroid dis-
ease, hypogonadism and diabetes mellitus. Anti-
bodies against the parathyroid, thyroid and adre-
nal glands are present in many patients. The
underlying genetic defect is due to mutations in
the autoimmune regulator gene on chromosome
21q22.3 (*607358) [15]. This gene regulates the
elimination of organ-specific T cells in the thy-
mus, and therefore, this condition is likely caused
by a failure of this mechanism to delete forbidden
T cells and to establish immune tolerance. There
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are reports of affected individuals who have not
been recognised to have this condition dying of
adrenal insufficiency. Therefore, it is important
that all children with apparent idiopathic acquired
hypoparathyroidism undergo genetic testing for
this condition and receive regular assessments of
adrenal function. In affected children with
APECED who are receiving treatment for hypo-
parathyroidism, the first manifestation of adrenal
insufficiency may be the development of hyper-
calcaemia due to volume depletion as a conse-
quence of mineralocorticoid deficiency. It is also
important to be aware that many affected individ-
uals have functional hyposplenism and are more
vulnerable to pneumococcal infections and should
therefore be immunised using Pneumovax [16].
Hypomagnesaemia
A rare but important cause of hypocalcaemia in
children is a low plasma magnesium level. Magne-
sium is essential for PTH secretion and for PTH
receptor activation by a ligand. There is an inad-
equate PTH response to hypocalcaemia in the
presence of hypomagnesaemia, which is corrected
when the plasma magnesium level is returned to
the normal range. This disorder may present as a
congenital defect with neonatal hypocalcaemia or
may be an acquired defect in an older child. The
causes of hypomagnesaemia can be broadly divid-
ed into those affecting intestinal magnesium ab-
sorption and those producing an excessive leak of
magnesium from the renal tubules. In the context
of a child with hypocalcaemia secondary to a low
plasma magnesium level, the easiest way to distin-
guish between these two possible causes is to as-
sess urinary magnesium excretion based on the
urine magnesium/creatinine ratio in a spot urine
sample for which normative paediatric data are
available [3]. The normal response in the setting
of hypomagnesaemia is for the kidneys to reab-
sorb as much magnesium as possible. Therefore, a
high magnesium/creatinine ratio would point to a
Hypocalcaemia
Allgrove J, Shaw NJ (eds): Calcium and Bone Disorders in Children and Adolescents. 2nd, revised edition.
Endocr Dev. Basel, Karger, 2015, vol 28, pp 84100 (DOI: 10.1159/000380997)
renal tubular leak. Hypercalciuria is also present
in some of these conditions, and this condition is
not always associated with hypermagnesuria.
Hypomagnesaemia with Hypomagnesuria
Hypomagnesaemia with secondary hypocalciuria
(#602014) (HOMG1) is caused by a selective defect
in magnesium absorption in the small intestine
with no evidence of any additional malabsorption.
Affected infants present with hypocalcaemic fits in
the first few weeks of life and are found to have re-
markably low plasma magnesium levels of less than
0.5 mmol/l [17]. These patients may initially re-
quire parenteral magnesium treatment and may
then be maintained on an oral magnesium prepa-
ration, which sustains the plasma calcium level in
the normal range despite the fact that the plasma
magnesium level remains subnormal at around 0.5
mmol/l (see Case 1915). The inheritance of this
condition is autosomal recessive, and this disorder
often occurs in consanguineous families. The ge-
netic defect has been identified as a mutation in
TRPM6 on chromosome 9q22 (*607009), which is
expressed in intestinal epithelia and renal tubules
[18] (see Chapter 3 for further details). Renal cal-
cium excretion is low in this condition.
Hypomagnesaemia with Hypermagnesuria
Associated with Hypocalciuria
Hypomagnesaemia with associated hypocalciuria
(#154020) (HOMG2) is the other main congenital
form of hypomagnesaemia. In this condition, hy-
pomagnesaemia is associated with isolated renal
magnesium loss and high urinary magnesium ex-
cretion. This is an autosomal dominant disorder
due to mutations in the FXYD2 gene on chromo-
some 11q23 [19] (*601814). This gene encodes the
-subunit of the Na+/K+-ATPase on the inner
membrane of the renal tubule and causes hypo-
magnesaemia with reduced urinary calcium excre-
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tion. The clinical manifestations are generally
milder than those of hypomagnesaemia with sec-
ondary hypocalciuria and may not become appar-
ent until adulthood.
Isolated recessive renal hypomagnesaemia
(#611718) (HOMG4) is a rare autosomal recessive
condition caused by a mutation in the epidermal
growth factor gene (*131530), which controls
magnesium reabsorption via TRPM6 (see Chapter
3 for details). Isolated hypomagnesaemia is associ-
ated with normal plasma and urine calcium levels,
but these patients have psychomotor retardation
and seizures with brisk reflexes, presumably as a
result of other effects of epidermal growth factor.
Renal hypomagnesaemia (#613882) (HOMG6)
is an autosomal dominant condition caused by
mutations in the CNNM2 gene (*607803) on
chromosome 10q24. Affected individuals show
an inappropriately normal urinary magnesium
excretion level, demonstrating a defect in tubular
reabsorption.
Gitelmans syndrome (#263800) has some
overlap with Bartter syndrome, although it is a
separate entity. Mutations in the thiazide-sensi-
tive sodium chloride transporter (*600968) result
in hypokalaemic alkalosis with salt wasting, hy-
pomagnesaemia and hypocalciuria. Patients usu-
ally present after the age of 5 years with episodes
of muscle weakness, lethargy, tetany and muscle
cramps. Dermatitis may be present and, although
Gitelmans syndrome is described as benign, a
prolonged cardiac Q-T interval may give rise to
arrhythmias and syncopal attacks. Chondrocalci-
nosis is a feature shared between these patients
and those with chronic hypomagnesaemia. Uri-
nary calcium excretion is low. Treatment consists
of correcting the biochemical abnormalities, par-
ticularly the potassium and magnesium deficien-
cies, with oral supplementation.
Associated with Hypercalciuria
Hypomagnesaemia with hypercalciuria and neph-
rocalcinosis (#248250) (HOMG3) is caused by
mutations in the gene for claudin 16 (paracellin 1)
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Endocr Dev. Basel, Karger, 2015, vol 28, pp 84100 (DOI: 10.1159/000380997)
(*603959), which is localized to the tight junctions
of the epithelium of the ascending loop of Henle.
As a consequence, there is excessive excretion of
both magnesium and calcium. Several different
homozygous or compound heterozygous muta-
tions have been described for this disorder, and
the severity of the condition varies according to
the genotype. In some cases, the problem is self-
limiting, whilst in other cases, progressive renal
failure may ensue, resulting in the need for renal
replacement therapy in 50% of cases by the second
decade. Hypocalcaemia is occasionally present.
Renal hypomagnesaemia with ocular involve-
ment (#248190) (HOMG5) is also autosomal re-
cessive and is similar to Hypomagnesaemia with
hypercalciuria and nephrocalcinosis but also in-
cludes ocular abnormalities such as coloboma,
myopia and horizontal nystagmus. No mutations
are found in the claudin 16 gene, but mutations
are found in the similar claudin 19 gene (*610036),
which is mainly localized to the collecting ducts
of the renal tubule.
Acquired Hypomagnesaemia
Hypomagnesaemia may also occur as a conse-
quence of either malabsorption, as in Crohns
Disease or Whipples Disease, or as an acquired
renal defect secondary to the induction of excess
renal magnesium wasting by certain drugs, in-
cluding cisplatinum, amphotericin B, cyclosporin
and tacrolimus. Severe burn injury has also been
reported to cause hypocalcaemia secondary to
hypomagnesaemia [20].
Hypocalcaemia with Normal Parathyroid
Hormone Levels
Autosomal Dominant Hypocalcaemia
Individuals with this condition were often previ-
ously believed to have idiopathic hypoparathy-
roidism with a serum PTH level that was inappro-
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priately normal in the setting of hypocalcaemia.
Then, linkage analysis of large families with auto-
somal dominant hypoparathyroidism mapped a
candidate gene to a locus on chromosome 3q13,
which corresponded to the region known to in-
clude the gene coding for the calcium-sensing re-
ceptor. Subsequently, it was identified that this
condition was due to gain of function mutations
in the gene for the calcium-sensing receptor [21]
(#601198) which is referred to as autosomal dom-
inant hypocalcaemia (ADH) type 1. Most of these
mutations alter the set point of the calcium-sens-
ing receptor in the parathyroid glands and the
kidneys, leading to a reduced plasma calcium lev-
el prior to PTH release and decreased tubular cal-
cium reabsorption, which cause relative hypercal-
ciuria (see Chapter 3 for details). In greater than
40% of ADH1 subjects, the serum PTH concen-
trations are within the normal range; levels below
the lower limit of the normal range are observed
in the remaining fewer than 60% of subjects. A
low or low-normal range plasma magnesium lev-
el is often also present in this condition. Approx-
imately 50% of subjects have asymptomatic hypo-
calcaemia, but the other 50%, especially children
during febrile episodes or neonates, exhibit hypo-
calcaemic symptoms, particularly seizures and
neuromuscular irritability. Approximately 10%
of ADH1 subjects have hypercalciuria, which
may be associated with nephrocalcinosis or kid-
ney stones. Therefore, treatment should be re-
served for symptomatic subjects and should only
include a vitamin D analogue and calcium sup-
plements together with close monitoring of uri-
nary calcium excretion and renal ultrasounds to
detect nephrocalcinosis. Although this condition
is rare, it may account for a significant proportion
of cases of idiopathic hypoparathyroidism (see
Case 192). In one study of nineteen unrelated
cases of isolated hypoparathyroidism in France,
eight subjects (42%) had activating mutations of
the calcium-sensing receptor [22]. Thiazide di-
uretics have been effectively used to reduce hy-
percalciuria in treated individuals. An alternative
Hypocalcaemia
Allgrove J, Shaw NJ (eds): Calcium and Bone Disorders in Children and Adolescents. 2nd, revised edition.
Endocr Dev. Basel, Karger, 2015, vol 28, pp 84100 (DOI: 10.1159/000380997)
option to consider if standard treatment is prob-
lematic is the use of synthetic PTH, which has ap-
peared to benefit some subjects [23].
An additional form of autosomal dominant
hypocalcaemia, designated as ADH2 (#615361),
has been identified. ADH2 is due to gain-of-
function mutations of the G protein subunit
11, encoded by the gene GNA11 on chromo-
some 19p13.3 [24]. These subjects have similar
features to ADH1 subjects, although hypercalci-
uria has not been reported as a feature in the
limited number of affected individuals identi-
fied to date.
Antibodies to the Calcium-Sensing Receptor
A biochemical profile similar to that of familial
hypocalcaemia with hypercalciuria has been re-
ported in individuals who have been found to car-
ry antibodies to the calcium-sensing receptor, of-
ten in the context of another autoimmune disease
[25]. In at least one individual, hypocalcaemia
was transient.
Hypocalcaemia with a High Parathyroid
Hormone Level
Pseudohypoparathyroidism
This condition was first reported in 1942 and was
the first example of hormone resistance identified
in humans. It has similar biochemical features to
hypoparathyroidism with hypocalcaemia and hy-
perphosphataemia, except that in PHP, the serum
levels of PTH are elevated. PHP refers to several
distinct but related disorders in which resistance
to PTH is the predominant feature. Unlike most
hormone-resistant conditions, the corresponding
defect is not in the PTH receptor but rather in the
signalling protein Gs, which is downstream of
many different G protein-coupled hormone re-
ceptors and which acts by stimulating the pro-
duction of adenylyl cyclase, thereby activating its
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 q11.22
q11.23
p11.23

q11.21

q13.32
q13.33
p11.21

q13.12

q13.31
q13.13

q13.2
p12.2
p12.3

p12.1

q12
p13
Fig. 2. Schematic representation of
imprinting Gs mutation expression
in renal tubules. The black square
represents a Gs mutation. The
imprinted human GNAS locus on NESP55
chromosome 20 (upper panel) close Gsa
to the STX16 gene (middle panel)
NESP55
and coding maternal (NESP), Gsa
paternal (AB, AS and XL) and Mat 5-4A 4-2 AS-1 XL A/B 2 3 N14 5-13
biallelic (Gs) transcripts. Black Pat
boxes= coding exons; white
boxes= non-coding exons; Mat + + +
grey boxes (+)= methylated Pat
+ Gsa
promoters; empty grey boxes ()= AS
unmethylated promoters; arrows= A/B
transcription (direction and parental
XLas
origin) [reproduced from reference
26].

second messenger cyclic AMP. PHP often pres-
ents in mid-childhood as hypocalcaemic fits or
muscle spasms.
PHP is subdivided into two types dependent
on the renal tubular response to infused exoge-
nous PTH. In PHP Type I, there is blunting of
both cyclic AMP generation and urinary phos-
phate excretion; alternatively, in PHP Type II,
there is only impaired urinary phosphate excre-
tion. All of the PHP Type I subtypes have been
linked to a genetic or epigenetic defect in the
GNAS gene on chromosome 20. This is an exam-
ple of a gene that undergoes imprinting; i.e. there
is repression of gene expression from one paren-
tal allele. The imprinted GNAS locus in humans
produces several transcripts, including Gs, A/B,
XL, AS and NESP. XL, A/B and AS, which are
transcribed from only the paternal allele, and
NESP, which is transcribed from only the mater-
nal allele [26] (fig.2). Gs expression, although it
arises from both alleles in most tissues, is restrict-
ed to the maternal allele in several tissues includ-
ing the proximal renal tubule, the thyroid, the pi-
tuitary and the gonads. The category of PHP Type
I is currently subdivided into PHP Types Ia, Ib
and Ic.
Pseudohypoparathyroidism Type Ia
(#103580)
In this subtype, affected individuals, in addition
to PTH resistance, have features of Albrights
hereditary osteodystrophy (AHO), which is a
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94 Shaw
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Allgrove J, Shaw NJ (eds): Calcium and Bone Disorders in Children and Adolescents. 2nd, revised edition.
Endocr Dev. Basel, Karger, 2015, vol 28, pp 84100 (DOI: 10.1159/000380997)

Fig. 3. The imprinted human
GNAS locus on chromosome 20.
constellation of physical features including a
rounded face, truncal obesity, short stature,
shortening of the 4th and 5th metacarpals and
metatarsals, heterotopic ossification and/or
mental retardation (see Case 1912). Evidence
of additional hormone resistance, particularly
hypothyroidism and hypogonadism, is usually
present, and there may also be evidence of
growth hormone deficiency due to resistance at
the GHRH receptor. The underlying genetic de-
fect is due to heterozygous mutations of the ma-
ternal coding sequence of the gene GNAS on
chromosome 20q13.2 (139320), which encodes
for the Gs subunit; these mutations are seen in
up to 70% of affected subjects [27]. Some affect-
ed subjects have now been identified as having
methylation defects in GNAS [28]. Skin fibro-
blasts and erythrocytes from affected individu-
als have a 50% reduction in Gs mRNA expres-
sion. A related disorder is pseudopseudohypo-
parathyroidism (#612463), in which individuals
have AHO features but no evidence of hormone
resistance. Heterozygous mutations in the
GNAS gene are also present, and affected indi-
viduals can be found among the kindred of those
with PHP Type Ia. The phenotype expressed is
dependent on the gender of the parent transmit-
Hypocalcaemia
Allgrove J, Shaw NJ (eds): Calcium and Bone Disorders in Children and Adolescents. 2nd, revised edition.
Endocr Dev. Basel, Karger, 2015, vol 28, pp 84100 (DOI: 10.1159/000380997)
p Hormone
resistance
p
Normal
hormone
response
m
ting the gene defect; paternal transmission
causes pseudopseudohypoparathyroidism, and
maternal transmission causes PHP Type Ia [29].
This is due to the imprinted nature of the Gs
protein in different tissues, as the maternal allele
is predominantly expressed in the proximal re-
nal tubules, the thyroid gland, the gonads and
the pituitary. Therefore, an individual carrying
a maternally transmitted Gs mutation will ex-
hibit hormone resistance, but an individual car-
rying a paternally expressed mutation, which
will not be expressed in the proximal renal tu-
bule, will have no hormone resistance because
only the normal maternally expressed allele will
be expressed (fig. 3). The paternal silencing of
Gs expression in the proximal renal tubule is
established postnatally, which explains the de-
layed presentation of hypocalcaemia in this con-
dition [30]. The development of AHO features
is thought to be due to defective PTH-related
peptide signalling during endochondral bone
formation. Most children with PHP Type Ia
have normal stature prior to puberty but under-
go premature closure of the epiphyses during
puberty, leading to short stature in adulthood.
About 70% of affected subjects show moderate
to severe cognitive impairment.
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Pseudohypoparathyroidism Type Ib
(#603233)
This second subtype of PHP Type I is character-
ised by PTH resistance usually in the absence of
AHO features. These patients have normal Gs
activity. Additional hormone functions, such as
those of TSH, can also be impaired although TSH
resistance is usually mild (see Case 1913). PTH
resistance develops over time, and affected indi-
viduals often do not present with hypocalcaemia
until their teenage years. In contrast to those with
PHP Type Ia, subjects affected by PHP Type Ib
maintain biallelic expression of Gs in most tis-
sues, particularly in bone. Their bones respond
appropriately to elevated PTH levels, resulting in
increased bone resorption and demineralisation
that may resemble primary hyperparathyroidism.
The majority of PHP Type Ib cases (8085%) are
sporadic, but familial cases with autosomal dom-
inant inheritance have been reported. The sever-
ity of this condition can vary significantly. As in
PHP Type Ia, PTH resistance only occurs when
there is maternal transmission. In familial cases,
the genetic cause is a methylation change at the
GNAS locus, either the loss of methylation at the
A/B region or the maternal deletion of NESP and/
or AS [28]. In a few sporadic cases, paternal uni-
parental disomy of segments or the entirety of
chromosome 20 is the cause of the lack of mater-
nal Gs expression [31].
Pseudohypoparathyroidism Type Ic
(#612462)
These patients have similar characteristics to
those with PHP Type Ia with AHO and multiple
hormone resistance and have normal Gs activi-
ty. It had previously been postulated that PHP
Type Ic was due to the impairment of distinct
components of the G protein-coupled receptor
signalling pathway, and some individuals were
shown to have mutations in exon 13 of the GNAS
96
Allgrove J, Shaw NJ (eds): Calcium and Bone Disorders in Children and Adolescents. 2nd, revised edition.
Endocr Dev. Basel, Karger, 2015, vol 28, pp 84100 (DOI: 10.1159/000380997)
locus that affected receptor coupling but not cy-
clic AMP synthesis. However, more recent stud-
ies have shown evidence of GNAS methylation
defects in this type [32].
It has been increasingly recognised that there
is considerable overlap between the different sub-
types of PHP Type I, as similar genetic mecha-
nisms occur in each type. This has led to a call for
a new classification based on not only phenotypic
features but also the genetic and epigenetic causes
of GNAS.
Pseudohypoparathyroidism Type II (#203330)
This is a rarely reported condition with no identi-
fied genetic basis. These patients do not have fea-
tures of AHO, and their resistance to PTH is con-
fined to the phosphaturic response because these
patients exhibit a normal cyclic AMP response. It
has been pointed out that a biochemical profile
similar to this condition can be seen in severe Vi-
tamin D deficiency with hypocalcaemia and a
high plasma phosphate level despite an elevated
serum PTH level, suggesting renal resistance to
PTH [33]. As these abnormalities rapidly respond
to the administration of vitamin D, whether PHP
Type II actually exists or is another manifestation
of vitamin D deficiency remains speculative.
Acrodysostosis
This condition is characterised by short stature,
severe brachydactyly and facial dysostosis. Its
phenotype shares some similarities to the pheno-
type seen in AHO, and affected individuals may
have hormone resistance and hypocalcaemia.
Two types of acrodysostosis have been identified,
both of which are due to gene defects downstream
of Gs and which affect cyclic AMP synthesis. Ac-
rodysostosis-1 (#188830) is caused by a heterozy-
gous mutation in the PRKAR1A gene on chro-
mosome 17q24 [34] (see Case 1914). Affected
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individuals often have nasal hypoplasia and obe-
sity. Acrodysostosis-2 (#614613) is due to a het-
erozygous mutation in the PDE4D gene on chro-
mosome 5q12 [35]. Affected individuals may
have spinal stenosis and intellectual disability.
Disorders of Vitamin D Supply or Metabolism
Vitamin D Deficiency
Although children with vitamin D deficiency
usually present with rickets, symptomatic hypo-
calcaemia may also be the first manifestation.
This presentation is particularly the case during
infancy and puberty, during which the rapid
growth that characterises these periods may be
responsible for increased requirements for calci-
um for bone mineralisation and longitudinal
growth [36]. It is often the case in these groups
that radiological evidence of rickets is absent at
the time of presentation. Another phenomenon
often seen in these age groups is the presence of a
high plasma phosphate level despite a high circu-
lating level of PTH. This characteristic implies
that there is resistance to the activity of PTH in
the renal tubules. There is evidence to suggest that
this phenotype occurs as a consequence of dietary
calcium deficiency, which corrects when ade-
quate calcium intake is supplied [37].
Any of the additional forms of calciopaenic
(PTH-dependent) rickets caused by defects in vi-
tamin D metabolism or activity can have hypocal-
caemia as a feature. These disorders are described
in more detail in Chapter 8.
Chronic renal failure and chronic liver disease
can also present with a biochemical profile of hy-
pocalcaemia and a high serum PTH level. In the
former, hypocalcaemia is a consequence of the
lack of adequate synthesis of 1,25(OH)2D, and the
rise in the plasma phosphate level is due to the
failure to excrete a phosphate load. Chronic renal
failure is usually managed using a phosphate
binder such as calcium carbonate in conjunction
with a vitamin D analogue such as alfacalcidol. In
Hypocalcaemia
Allgrove J, Shaw NJ (eds): Calcium and Bone Disorders in Children and Adolescents. 2nd, revised edition.
Endocr Dev. Basel, Karger, 2015, vol 28, pp 84100 (DOI: 10.1159/000380997)
chronic liver disease, hypocalcaemia occurs in
combination with rickets. This disorder is pri-
marily caused by malabsorption of vitamin D and
calcium rather than a deficiency in the activity of
the 25-hydroxylase enzyme in the liver, which
only occurs in cases of end stage liver failure.
Chronic liver disease is often treated with a vita-
min D analogue such as alfacalcidol or calcitriol.
Osteopetrosis
A rare but important cause of hypocalcaemia that
presents in the neonatal period is infantile osteo-
petrosis [38]. In this condition, there is a deficien-
cy in osteoclast function and, therefore, a lack of
bone resorption. There have been several reports
of infants with this condition who initially pres-
ent with neonatal hypocalcaemic convulsions, in-
dicating the importance of bone resorption to
maintain adequate plasma levels of calcium in the
neonatal period. Affected infants usually have
raised levels of serum PTH but are unable to re-
sorb bone due to an osteoclast defect, represent-
ing another form of PTH resistance. An X-ray of
the wrist or the knee will demonstrate the charac-
teristic dense bones (see Cases 1988 to 1991).
Osteopetrosis is an important condition to diag-
nose early, as preservation of eyesight is depen-
dent on the timing of diagnosis and the availabil-
ity of bone marrow transplantation (see Chapter
14 for a more detailed description of the various
forms of osteopetrosis).
Treatment
The treatment of hypocalcaemia is dependent on
two factors: (1) whether hypocalcaemia causes se-
vere symptoms such as convulsions and (2) the
underlying cause of hypocalcaemia.
If urgent correction of the plasma calcium lev-
el is required, an intravenous bolus of 10% calci-
um gluconate should be administered from 0.5
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ml/kg (0.11 mmol/kg) to a maximum of 20 ml/kg
over 510 minutes, followed by a continuous in-
travenous infusion of 1.0 mmol/kg (maximum
8.8 mmol) for 24 hours. It is important to note
that the extravasation of intravenous calcium can
cause a considerable reaction and subsequent
scarring of the skin and subcutaneous tissues;
therefore, the infusion site should be regularly
checked. In addition, once the severe symptoms
have resolved, the intravenous route should be
discontinued in favour of oral calcium supple-
ments. For a child in whom urgent correction of
the plasma calcium level is not required, oral cal-
cium supplementation should be administered
from 0.2 mmol/kg to a maximum of 10 mmol/kg
four times daily.
In the management of hypoparathyroidism
or PHP, the use of a vitamin D analogue
such as 1-hydroxyvitamin D (alphacalcidol) or
1,25(OH)2D3 (calcitriol) as a dose of 2550 ng/kg/
day with or without calcium supplementation is
the conventional approach to prevent hypocalcae-
mia by increasing intestinal calcium absorption.
The aim is to maintain the plasma calcium level at
the lower end of the normal range, between 2.0
and 2.2 mmol/l, as renal calcium reabsorption in
the distal renal tubule will be low under these con-
ditions due to the lack of activity of PTH, resulting
in a risk for hypercalciuria. Monitoring should in-
clude periodic assessment of the urine calcium/
creatinine ratio and renal ultrasonography to de-
tect nephrocalcinosis. One study of the long term
outcome of 120 subjects with hypoparathyroidism
identified that 31% had evidence of renal calcifica-
tion, either renal stones or nephrocalcinosis [39].
Significantly higher rates of renal impairment
were seen in these subjects than in healthy con-
trols. Whilst many patients can be satisfactorily
treated with an oral vitamin D analogue, some pa-
tients with hypoparathyroidism may have prob-
lems with such an approach. This is particularly
seen in some subjects with autosomal dominant
hypocalcaemia, in whom it can be difficult to
maintain the plasma calcium level without trou-
98
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Endocr Dev. Basel, Karger, 2015, vol 28, pp 84100 (DOI: 10.1159/000380997)
blesome hypercalciuria, and in those with
APECED, in whom malabsorption may be a fea-
ture. An alternative approach in these individuals
is the use of synthetic PTH; good results have been
achieved using this compound when given either
as a twice daily injection [40] or as a continuous
infusion using an insulin pump [41] (see Chapter
17 for further details). Hypomagnesaemia will
usually respond to oral magnesium supplementa-
tion such as magnesium glycerophosphate ad-
ministration at a dose of 0.2 mmol/kg three times
daily. The use of oral magnesium salts is some-
times limited by diarrhoea. If hypomagnesaemic
symptoms are severe and do not respond to oral
magnesium supplementation, the intramuscular
injection of a 50% solution of 2 mmol/ml magne-
sium sulphate (MgSO47H2O) can be performed.
Vitamin D deficiency should be treated with
ergocalciferol (D2) or colecalciferol (D3), which
are the fastest ways to replenish deficient stores of
25OHD. There is a liquid preparation suitable for
infants and young children containing 3,000
units/ml. A dose of 3,000 units daily for infants
less than 6 months and 6,000 units daily for age
6months to 12 years given for an initial period of
6 to 8 weeks is often adequate. In adolescents with
hypocalcaemia secondary to vitamin D deficien-
cy, a dose of ergocalciferol of 10,000 units would
be appropriate. Calcium supplementation is also
often required in the initial management of these
disorders until the plasma calcium level has re-
turned to the normal range.
Conclusions
As seen from this chapter, there are many differ-
ent disorders that can cause hypocalcaemia in a
child. It is important that all appropriate investi-
gations are undertaken prior to the initiation of
any treatment. A stepwise logical approach in the
interpretation of the relevant investigations will
often lead to the correct diagnosis. Some of these
conditions are congenital in origin, e.g. congeni-
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tal hypoparathyroidism and infantile osteopetro-
sis, and are likely to present early in life, whereas
other conditions are acquired, e.g. vitamin D de-
ficiency and autoimmune polyendocrinopathy,
and can therefore present at any time during
childhood or adolescence. Some of these condi-
tions have important associated features, e.g. ad-
renal insufficiency and hyposplenism in autoim-
mune polyendocrinopathy, that need to be moni-
tored in the long term management of the
condition. Finally, many of these disorders have
an identified genetic basis; therefore, once a pro-
visional diagnosis is made, it is important to un-
dertake genetic studies to confirm the suspected
diagnosis and to inform appropriate genetic
counselling.

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Steelhouse Lane
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E-Mail nick.shaw@bch.nhs.uk
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