Current Paediatrics (2001) 11, 357d363
^

2001 Harcourt Publishers Ltd

doi:10.1054/cupe.2001.0206, available online at http://www.idealibrary.com on

Parathyroid disorders

J. Allgrove

Consultant Paediatric Endocrinologist and Honorary Senior Lecturer, St Bartholomew’s and the Royal London Hospitals,
Whitechapel, London E1 1BB, UK, and Newham General Hospital, Glen Road, Plaistow, London E13 8RU, UK

KEYWORDS
parathyroid hormone,
cyclic AMP,
hyperparathyroidism,
phosphate,
hypoparathyroidism,
pseudohypoparathyroidism,
calcium,
parathyroid localization
scans,
magnesium

Summary

The parathyroid glands play a crucial role in maintaining plasma calcium

within the narrow limits required to allow normal neuromuscular activity. Their principal
product is parathyroid hormone which is secreted in response to hypocalcaemia.
Disorders of the parathyroid glands may therefore result in both hypocalcaemia and
hypercalcaemia. In children the former is more common than the latter.

Hypoparathyroidism usually results either from failure of development of the glands or

from their destruction by antibodies. Pseudohypoparathyroidism is the consequence of
end-organ unresponsiveness to parathyroid hormone. Magnesium deficiency may also
interfere with parathyroid hormone secretion, causing functional hypoparathyroidism. In
hyperparathyroidism excess parathyroid hormone secretion results from either gland
hyperplasia, adenoma or, occasionally, carcinoma. Both hypercalcaemia and hypocal-
caemia can result from abnormalities in the calcium-sensing receptor located on the
parathyroid gland. Many of these conditions seen in children are genetic in origin and are
frequently associated with abnormalities of other organs.

^

2001 Harcourt Publishers Ltd

PRACTICE POINTS

E Vitamin D deficiency should always be suspected

and, if necessary, corrected when patients present
with hypocalcaemia

E Magnesium deficiency must be excluded as a cause

of hypocalcaemia. The serum calcium will only be
correctable once significant hypomagnesaemia has
been corrected

E Investigation of unexplained convulsions in children

should always include a measurement of plasma
calcium

E Mothers of infants with unexplained hypocalcaemia

should have plasma calcium measured

E The other conditions discussed here are mostly

very rare and require diagnosis and management in
a specialist centre

INTRODUCTION

Calcium is not only an important component of bone
providing, with phosphorus, the major mineral content,

(E-mail: [e-mail])

but it is also an essential element of extracellular fluid.
Any serious depletion of bone mineral, for whatever
reason, results in a tendency to deformation and
fracture, whilst changes in the extracellular fluid content
of calcium may result in dysfunction of neuromuscular
tissues. The parathyroid glands, which are situated within
the thyroid gland, have the principal task of maintaining
normal concentrations of serum calcium in order to
prevent adverse effects on nerves and muscles.
Disorders of the parathyroid glands may therefore have
serious consequences.

THE PARATHYROID GLANDS

The parathyroid (PT) glands, of which there are usually
four, are derived embryologically from the third and
fourth branchial arches and are usually situated as
discrete entities within the thyroid gland. Their principal
function in postnatal life is to secrete parathyroid
hormone (PTH) whose main effect is to raise serum
calcium concentrations. A second hormone, parathyroid-
related peptide (PTHrP) is also secreted, mainly during
fetal life, and probably has a role in maintaining the
normal positive gradient of calcium across the placenta.

PTHrP may be partly responsible for the hypercalcaemia
of malignancy although this is usually the result of direct
secretion by tumour cells and not by the PT glands.

Parathyroid hormone

Parathyroid hormone is a polypeptide consisting of
a single chain of 84 amino acids. It has a short half-life
(about 90 s) within the circulation and is rapidly broken
down to a number of fragments. Only the first 34 (N-
terminal) amino acids are required for full biological
action and most current assays of PTH measure ‘intact’
PTH by using at least two antibodies which recognize
opposite ends of the molecule.

Secretion of PTH is principally determined by the

circulating concentration of ionized calcium. Calcium-
sensing receptors (CaSR) on the gland mediate the
secretion of hormone in response to hypocalcaemia via
a

magnesium-dependent adenylate

cyclase

second

messenger. Abnormalities of magnesium interfere with
PTH secretion and genetic or acquired abnormalities
of the calcium sensor result in persistent hyper- or
hypocalcaemia. Persistent

hyperphosphataemia also

stimulates PTH secretion and leads to PT gland
hyperplasia. This is of particular importance in chronic
renal failure.

Actions of PTH

Parathyroid hormone has three main actions.

1) It stimulates osteoclasts to increase calcium (and

phosphorus) resorption from bone. In doing so, bone
turnover generally is increased.

2) It promotes renal tubular phosphate excretion and,

to a lesser extent, calcium reabsorption.

3) It increases 1

a-hydroxylation of 25-hydroxy vitamin

D

(25-OHD)

in

renal

cells.

This

increases

concentrations of circulating 1

a, 25-dihydroxyvitamin

D (1,25(OH)

2

D) which promotes calcium absorption

in the gut, thereby increasing calcium levels.

These actions are principally mediated via adenylate
cyclase within target cells via a guanine-nucleotide
stimulatory (Gs) second messenger. Genetic abnormal-
ities of the

a component (Gsa) result in resistance of

target cells to the actions of PTH, a condition known as
pseudohypo-parathyroidism (PsHP). Resistance is also
induced as a result of ‘down-regulation’ by PTH itself if
this is present in high concentrations for any length of
time (see below). This is particularly important in some
situations of vitamin D deficiency or chronic renal failure.

PARATHYROID DISORDERS

Many abnormalities of the parathyroid glands are now
known to have a genetic basis. These may result in either

hyper- or hypocalcaemia. They are summarized in
Table 1. For the purposes of this article, however, the
principal consideration will be whether or not the
conditions are associated with low or high serum calcium
concentrations

and

the

genetically

determined

conditions will be discussed in the appropriate sections.

HYPOCALCAEMIA

In children, in contrast to adults, hypocalcaemia occurs
much more frequently than hypercalcaemia. Outside the
neonatal period, this is most frequently associated with
nutritional vitamin D deficiency, at least in those areas of
the UK where large ethnic minority groups live. This
most commonly leads to rickets, which is associated with
a variable degree of hypocalcaemia. This is usually mild
and asymptomatic but can sometimes be associated with
profound hypocalcaemia resulting in convulsions with
which the patients present. This profound hypocalcaemia
may, in part, be caused by the secondary resistance to
PTH and is not always associated with radiological
evidence of rickets. Hypocalcaemia and rickets, if
present, are corrected by treatment with adequate
amounts of vitamin D and sensitivity to PTH is restored
as the calcium concentrations rise and PTH levels fall.
Further discussion of vitamin D related disorders is
beyond the scope of this article and will not be
considered further.

Hypoparathyroidism

The

biochemical

abnormalities

associated

with

hypoparathyroidism are

hypocalcaemia, hyperphos-

phataemia and reduced urinary calcium excretion.
Alkaline phosphatase (AP) activity is usually normal or
relatively low. The latter must be interpreted with
caution as there are considerable age-related changes
in AP which are generally increased according to the
child’s growth velocity. PTH concentrations are low or
undetectable and vitamin D status (as measured by 25-
OHD) is normal.

The hypocalcaemia may be sufficient to cause con-

siderable neuromuscular irritability. In infants this usually
presents as convulsions although in older children and
adolescents, the more typical carpopedal spasm or
tetany may occur. A plasma calcium measurement (in
addition to blood glucose) should be part of the
investigation of any child who has an unexplained
convulsion.

Neonatal hypocalcaemia

Neonatal hypocalcaemia may result from a variety of
causes related to PTH. Sick or premature infants are
more prone than well term babies because the demand

358

CURRENT PAEDIATRICS

Ta

b

le

1

Genet

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synd

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ro

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pr

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t

Inher

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C

al

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2q11

.2

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2

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Low

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APS

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ype

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2

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se

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for calcium for bone mineralization is greater. The
maternal supply of calcium is abruptly and completely
interrupted at birth and these infants must switch off
bone mineralization temporarily in order to prevent
symptomatic hypocalcaemia until calcium supplies can be
restored from food intake. The PT glands play an
important role in preventing hypocalcaemia and sick
infants are more prone to failure of the PT glands to be
effective in this respect.

Hypercalcaemia in the mother may result in transient

hypocalcaemia in the infant as a result of suppression of
fetal parathyroid activity. This may take several weeks
to recover fully during which time the infant will re-
quire supportive treatment. The mother of any infant
suffering from unexplained hypocalcaemia should have
a measurement taken of serum calcium.

Developmental anomalies

DiGeorge syndrome

The CATCH22 syndrome (Cardiac anomalies, Abnormal
facies, Thymic hypoplasia, Cleft palate and Hypocal-
caemia associated with microdeletions in the long arm of
the number 22 chromosome) encompasses a group
of

conditions

including

the

DiGeorge

(DGS),

velocardiofacial (VCFS) and conotruncal anomaly facial
(CTAFS) syndromes and a number of non-syndromic
cardiac conditions such as pulmonary atresia with
ventricular septal defect, Fallot’s tetralogy, truncus
arteriosus and interrupted aortic arch.

1

They are all

linked by failure of normal development of the third
and fourth branchial arches. The very variable nature of
these conditions is seen from their original clinical
descriptions.

In DGS the emphasis is on PT and thymus glands and

the cardiac anomalies. The severity of the condition
varies, but most infants with this syndrome present
with cardiac abnormalities, which may require urgent
attention. Often the developing hypocalcaemia does
not become immediately apparent and is frequently
overlooked. Thymus gland aplasia is suspected by the
absence of a thymic shadow on chest X-ray and can be
confirmed by a low T-cell count, although the total
lymphocyte count may be normal.

Acquired hypoparathyroidism

Failure of the parathyroid glands may be isolated or
associated with deficiencies in other endocrine glands.
Autoimmunity is usually responsible for and often
associated with other conditions such as mucocutaneous
candidiasis. The antibodies may be directed to the glands,
PTH or CaSR. Infiltration of the PT glands may also cause
failure. In

b-thalassaemia major, iron overload caused by

multiple transfusions may be responsible.

PARATHYROID DISORDERS

359

Table 2

Classification of pseudohypoparathyroid syndromes

Name

Gs

a defect

AHO

cAMP response

Phosphaturic response

Calcium

PsHP Ia

Yes

Yes

Neg

Neg

Low

PsHP Ib

No

No

Neg

Neg

Low

PsHP Ic

No

Yes

Neg

Neg

Low

PsHP II

No

No

Pos

Neg

Low

PsPsHP

Yes

Yes

Variable

Variable

Normal

APECED syndrome

Several

autoimmune

polyendocrine

disorders

are

described of which only Type I, the (Autoimmune
PolyEndocrinopathy,

Candidiasis

and

Ectodermal

Dystrophy (APECED) syndrome, usually affects the
parathyroid glands.

2

It is the only known multiple

autoimmune disease which is caused by a single gene
defect. It is caused by a mutation in the AutoImmune
REgulator (AIRE) gene. This results in a variety of
autoantibodies which are associated with variable
degrees of hypoparathyroidism, Addison’s disease and,
to a lesser extent, diabetes mellitus.

PTH resistance

Pseudohypoparathyroidism and
pseudo-pseudohypoparathyroidism

Pseudohypoparathyroidism (PsHP) is characterized by
end-organ resistance to PTH. The biochemical findings
are those of hypoparathyroidism but with raised PTH
concentrations. Several forms are described. The various
features are summarized in Table 2. In Type I PsHP
neither cAMP nor urinary phosphate increases in
response to PTH infusion. In the classical form (PsHP
Type Ia), a number of dysmorphic features (short stature
and obesity, round facies and shortening of the fourth
and/or fifth metacarpals and phalanges), known as
Albright’s

hereditary

osteodystrophy

(AHO),

are

present. Soft tissue calcification, which presents clinically
as osteoma cutis, may be present and CT scan
demonstrates the presence of intracranial calcification,
particularly in the basal ganglia and frontal lobes. This
may also occur in hypoparathyroidism. In one variant of
this condition, pseudohypohyperparathyroidism or PsHP
with raised AP, renal responsiveness to PTH is lost but
bone responsiveness is retained. In these cases the
patients have evidence of hyperparathyroidism in bone
(raised AP and bone cysts) in the presence of the other
features of PsHP.

The underlying mechanism is a mutation within the

gene for Gs

a.

3

Unresponsiveness to other hormones,

particularly TSH, the gonadotrophins and growth

hormone releasing hormone, is sometimes also present
and should be looked for. Mutations within this gene
may also be activating and one particularly inter-
esting mutation results in a combination of PsHP and
testotoxicosisethe former because of inactivation of
the Gs

a at normal body temperature and the latter

because, at the lower temperature of the testis (343C),
activation of the protein occurs.

Pseudo-pseudohypoparathyroidism (PsPsHP) is the

term given to those patients who have the features of
AHO but without hypocalcaemia. Both conditions may
occur in the same family and one may transform itself to
the other. The same underlying genetic abnormality has
been found in the two conditions where they occur in
the same family and the variable clinical expression of the
two conditions may be partly related to gene imprinting.

In PsHP Type Ib, AHO is not present and the genetic

abnormality is not known, but may be related to Gs

a.

In Type Ic, all the clinical features of type Ia are present,
but without an abnormality of the Gs

a gene. In Type II,

the unresponsiveness appears to be related to a quite
different

mechanism

since,

in

this

condition,

responsiveness of cAMP to PTH is retained whilst the
phosphaturic effects are lost.

Hypomagnesaemia

Magnesium

4

is present in bone in much smaller quantities

than calcium and is released from bone along with
calcium under the influence of PTH. It is absorbed in the
GI tract and reabsorbed in the renal tubule by specific
mechanisms separate from that of calcium. Magnesium
deficiency inhibits adenylate cyclase-dependent PTH re-
lease in response to hypocalcaemia in a biphasic manner.

5

At concentrations which are only slightly lower than
normal (0.3d0.5 mmol/l), PTH secretion is partially
inhibited such that, although PTH levels are raised, they
are not sufficiently so to prevent hypocalcaemia. Resist-
ance to PTH may also be induced under these circum-
stances.

At

lower

concentrations

of

magnesium

((0.3 mmol/l) PTH release is completely inhibited but
sensitivity to PTH is retained.

The principal cause of hypomagnesaemia in children is

malabsorption which can be secondary to a variety of

360

CURRENT PAEDIATRICS

conditions. Magnesium supplements are usually given to
patients

with

malabsorption

syndromes.

Diabetic

ketoacidosis is rarely a significant factor and alcoholism is
unlikely! Several cytotoxic drugs are also toxic to the
renal tubule and cause excessive loss of magnesium into
the urine thus potentially causing hypomagnesaemia.
Renal tubular loss of magnesium may also cause
problems in the variant of Bartter’s syndrome known as
the Gitelman syndrome.

6

Primary hypomagnesaemia is caused by a specific

intestinal transport defect in magnesium. These patients
present with intractable hypocalcaemia which can be
difficult to treat although it is usually possible, after initial
correction, to maintain satisfactory levels with oral
supplementation with a suitable salt such as magnesium
glycerophosphate. Initial treatment can be given as
intramuscular magnesium sulphate 50% solution which
contains 2 mmol/ml. Further treatment can then be given
as an appropriate oral salt such as glycerophosphate, the
principal limitation being the tendency for these salts to
cause diarrhoea. Under no circumstances should
magnesium be administered intravenously since it is
a potent vasodilator.

Abnormalities of the calcium sensing
receptor (CaSR)d1

Autosomal dominant hypocalcaemia (ADH)

The CaSR protein identifies circulating concentrations of
ionized calcium and, in the PT gland, regulates secretion
of PTH.

7

In the renal tubule it regulates urinary excretion

of calcium. Three conditions caused by abnormalities of
the CaSR gene have been described. In one of these, the
Autosomal Dominant Hypocalcaemia (ADH) syndrome,
mutation of the CaSR gene causes activation of the
receptor. These patients are therefore effectively
hypoparathyroid but have high urinary calcium excretion.
They may exhibit symptoms of hypocalcaemia and
treatment is directed towards preventing this without
causing undue hypercalciuria. The other two conditions
cause hypercalcaemia and will be discussed in the next
section.

Treatment of hypoparathyroidism

Vitamin D deficiency must be excluded as a cause of
hypocalcaemia and corrected if necessary. Treatment
of hypoparathyroidism itself, whether caused by failure
of PTH secretion or resistance to its action, is essentially
similar and consists of the use of active metabolites of
vitamin D. The most commonly used of these is
alphacalcidol (1

a-hydroxycholecalciferol) which is usually

required in doses of between 15 and 50 ng/kg per 24 h
for maintenance although higher doses may be required
initially. It can be given as a single daily dose since it has

a half-life of about 36 h as it has to be converted to
1,25(OH)

2

D

before

being

effective.

Alternatively,

1,25(OH)

2

D (calcitriol) itself may be used. Usually, only

half the dose is required but it should be given in
two divided doses as its half-life is much shorter. Monitor-
ing of therapy consists in checking that plasma
calcium concentrations remain normal and that urinary
calcium excretion does not become elevated. This
is most conveniently measured as the calcium/creatinine
ratio in a spot sample of urine. This should be

(

0.7 mmol/mmol.

HYPERCALCAEMIA

Abnormalities of

the

calcium

sensing

receptor (CaSR)d2

Familial benign hypocalciuric hypercalcaemia (FBHH)

This condition is the counterpart of ADH. However, the
CaSR gene mutation here results in inactivation of the
calcium sensor. As a consequence the ‘set-point’ for PTH
secretion is raised so plasma calcium has to increase
higher than normal to inhibit PTH release. PTH
concentrations are usually normal and have normal
bioactivity. It is autosomal dominant with almost
complete penetrance before the age of 10 y. It is a benign
condition, often identified accidentally on routine
biochemical testing, following which other members
of the family are found also to be hypercalcaemic.
Its

principal

distinguishing

feature

from

primary

hyperparathyroidism is the absence of hypercalciuria.
Plasma magnesium concentrations are often slightly
elevated since urinary excretion of magnesium is also
impaired. It does not usually require any treatment. The
only significant associated problem is that of pancreatitis.

Neonatal severe primary hyperparathyroidism (NSPHP)

This condition is the homozygous form of FBHH. It
presents in the neonatal period with failure to thrive and
poor weight gain, vomiting and dehydration. Plasma
calcium and PTH are elevated and the bones show
evidence of hyperparathyroidism. This can sometimes be
mistaken for rickets. Treatment consist in correcting the
dehydration and reducing plasma calcium followed by
total parathyroidectomyesubtotal parathyroidectomy is
usually insufficient to correct the problem. This may
render the patient hypoparathyroid which will then
require appropriate treatment.

Primary hyperparathyroidism

Autonomous hypersecretion of PTH results from either
hyperplasia of the glands or of a single parathyroid
adenoma. There is now increasing evidence that many of

PARATHYROID DISORDERS

361

these tumours are genetically determined by mutations
in one or other of the tumour suppressor genes. These
mutations may occur in germ-cell lines, in which case the
tumours are familial, or as somatic mutations in sporadic
cases. In a number of instances, PT gland tumours are
associated with tumours of other endocrine disorders in
the multiple endocrine neoplasia (MEN) disorders.

8

Multiple endocrine neoplasia type I (MEN-I)

In this condition PT gland tumours are associated with
tumours of the endocrine pancreas and pituitary.

9

Parathyroid adenomas are most commonly seen. It is
frequently familial, inherited in an autosomal dominant
manner. Screening of families in which MEN-I is found has
been useful in identifying members at risk, who need to
be carefully monitored, and excluding those not at risk,
who can be reassured.

Multiple endocrine neoplasia type II
(MEN-IIa and MEN-IIb)

Parathyroid hyperplasia most commonly occurs in this
condition which is associated with tumours of the
thyroid and adrenal medulla. Germ-line point mutations
are responsible for MEN-II and also for Medullary
Carcinoma of the Thyroid. The presence of muco-
cutaneous neurofibromas and dysmorphic features
distinguish MEN-IIb from MEN-IIa.

Hyperparathyroidism-jaw tumour syndrome (HPT-JT)

This condition has a combination of either parathyroid
adenoma

or

carcinoma

associated

with

ossifying

fibromas of the jaw and various types of renal lesions,
including benign cysts, Wilm’s tumour and hamartomas.

10

It is caused by a mutation in another tumour suppressor
gene.

Investigation and treatment of primary
hyperparathyroidism

Plasma calcium is raised and phosphate is low. Alkaline
phosphatase is often slightly elevated and urinary calcium
excretion may be sufficiently high to cause nephro-
calcinosis. Radiological evidence of hyperparathyroidism
can be seen in the form of microcysts along the
subperiosteal borders of the phalanges. In more severe
cases the changes may be seen more obviously in the
region of the growth plate and can be confused with
rickets.

Localization of parathyroid tumours is best under-

taken with the aid of radionuclide scanning with

99m

Tc-MIBI

(methoxyisobutyl

isonitrile)

or

99m

Tc-tetrofosmin.

11

These

methods

are

more

sensitive

than

either

ultrasonography or MRI scanning and have proved
invaluable in locating persistent tumours especially after
primary surgery has failed to eradicate the problem.
They are sometimes combined with thyroid subtraction
scintigraphy and, if performed shortly before surgery, can
be combined with the use of a hand-held gamma camera
to pinpoint the tumour at operation.

Treatment of hyperparathyroidism depends largely on

the nature of the symptoms. In severe cases, rehydration
with intravenous fluids may be required. This will usually
have some effect in reducing plasma calcium but, if this
persists and is likely to cause problems at surgery,
intravenous pamidronate can be effective in temporarily
reducing plasma calcium until definitive treatment can be
undertaken.

Secondary hyperparathyroidism

If the PT glands remain functional and hypocalcaemia
persists, the glands may hypertrophy in an attempt to
maintain sufficient PTH secretion to maintain a normal
plasma calcium. This is particularly so in chronic renal
failure where the persistent hyperphosphataemia may
also contribute to the PT gland hyperplasia. Following
reversal of the hypocalcaemic drive (e.g. by renal
transplantation) the activity of the PT glands may not
revert to normal and their removal may be required.

Parathyroid carcinoma

This is a rare condition in children but may occur in some
of the conditions associated with tumour suppressor
gene abnormalities. They usually present with the
features of hyperparathyroidism and treatment consists
in the removal of the glands if possible.

Hypercalcaemia of malignancy

Some children with tumours may develop hypercal-
caemia as a consequence of their disease. Plasma calcium
may be very elevated (up to 5 mmol/l) and result in
severe symptoms. It is often the result of secretion of
PTHrP. In these cases, PTH will be undetectable, but
PTHrP will be raised. If treatment of the underlying
tumour is possible, reversal of the hypercalcaemia is
likely.

As

an

interim

measure,

treatment

with

intravenous pamidronate (0.5 mg/kg per 24 h) is often
extremely effective after 1d3 doses.

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