CHAPTER

589

Hypoparathyroidism
Daniel A. Doyle

Etiology
Hypocalcemia is common in neonates between 12 and 72 hr of life, especially
in premature infants, in infants with asphyxia, and in infants of diabetic mothers
(early neonatal hypocalcemia ; see Chapter 119.4 ; Table 589.1 and Fig. 589.1
). After the 2nd to 3rd day and during the 1st wk of life, the type of feeding also
is a determinant of the level of serum calcium (late neonatal hypocalcemia ).
The role played by the parathyroid glands in these hypocalcemic infants is
unclear, although functional immaturity of the parathyroid glands is invoked as 1
pathogenetic factor. In a group of infants with transient idiopathic
hypocalcemia (1-8 wk of age), serum levels of parathyroid hormone (PTH) are
significantly lower than those in normal infants. It is possible that the functional
immaturity is a manifestation of a delay in development of the enzymes that
convert glandular PTH to secreted PTH; other mechanisms are possible.

Table 589.1
Causes of Hypocalcemia
I. Neonatal
A. Maternal Disorders
Diabetes mellitus
Toxemia of pregnancy
Vitamin D deficiency
High intake of alkali or magnesium sulfate
Use of anticonvulsants
Hyperparathyroidism
B. Neonatal Disorders
Low birthweight: prematurity, intrauterine growth restriction
Peripartum asphyxia, sepsis, critical illness
Hyperbilirubinemia, phototherapy, exchange transfusion
 Hypomagnesemia, hypermagnesemia
Acute/chronic renal failure
Nutrients/medications: high phosphate intake, fatty acids, phytates, bicarbonate infusion, citrated blood,
anticonvulsants, aminoglycosides
Hypoparathyroidism
Vitamin D deficiency or resistance
Osteopetrosis type II
II. Hypoparathyroidism
A. Congenital
1. Transient neonatal
2. Congenital hypoparathyroidism
a. Familial isolated hypoparathyroidism
(1) Autosomal recessive hypoparathyroidism (GCMB, PTH)
(2) Autosomal dominant hypoparathyroidism (CaSR)
(3) X-linked hypoparathyroidism (SOX3)
b. DiGeorge syndrome (TBX1)
c. Sanjad-Sakati syndrome (short stature, retardation, dysmorphism; HRD); Kenny-Caffey syndrome 1
(short stature, medullary stenosis) (TBCE)
d. Barakat syndrome (sensorineural deafness, renal dysplasia; HDR) (GATA3)
e. Lymphedema-hypoparathyroidism-nephropathy, nerve deafness
f. Mitochondrial disorders (Kearns-Sayre, Pearson, MELAS)
3. Insensitivity to PTH
a. Blomstrand chondrodysplasia (PTHR1)
b. Pseudohypoparathyroidism type IA (GNAS)
Pseudohypoparathyroidism type IB
Pseudohypoparathyroidism type IC
Pseudohypoparathyroidism type II
Pseudopseudohypoparathyroidism
c. Acrodysostosis with hormone resistance (PRKAR1A)
d. Hypomagnesemia
4. CaSR-activating mutation
a. Sporadic
b. Autosomal dominant (G protein subunit α11 mutation)
B. Acquired
1. Autoimmune polyglandular syndrome type I (AIRE gene mutation)
2. Activating antibodies to the CaSR
3. Postsurgical, radiation destruction
4. Infiltrative—excessive iron (hemochromatosis, thalassemia) or copper (Wilson disease) deposition;
granulomatous inflammation, neoplastic invasion; amyloidosis, sarcoidosis
5. Maternal hyperparathyroidism
6. Hypomagnesemia/hypermagnesemia
III. Vitamin D Deficiency
IV. Other Causes of Hypocalcemia
A. Calcium Deficiency
1. Nutritional deprivation
2. Hypercalciuria
B. Disorders of Magnesium Homeostasis
1. Congenital hypomagnesemia
2. Acquired
a. Acute renal failure
b. Chronic inflammatory bowel disease, intestinal resection
c. Diuretics
C. Hyperphosphatemia
1. Renal failure
2. Phosphate administration (intravenous, oral, rectal)
3. Tumor cell lysis
 4. Muscle injuries (crush, rhabdomyolysis)
D. Miscellaneous
1. Hypoproteinemia
2. Hyperventilation
3. Drugs: furosemide, aminoglycosides, bisphosphonates, calcitonin, anticonvulsants, ketoconazole,
antineoplastic agents (plicamycin, asparaginase, cisplatinum, cytosine arabinoside, doxorubicin), citrated
blood products
4. Hungry bone syndrome
5. Acute and critical illness: sepsis, acute pancreatitis, toxic shock
a. Organic acidemia: propionic, methylmalonic, isovaleric
HDR, hypoparathyroidism, sensorineural deafness, and renal anomaly; HRD,
hypoparathyroidism, retardation, dysmorphism; MELAS, mitochondrial encephalomyopathy with
lactic acidosis and stroke-like episode; PTH, parathyroid hormone.
Modified from Root AW, Diamond Jr FB: Disorders of mineral homeostasis in children and
adolescents. In Sperling MA, editor: Pediatric endocrinology , ed 4, Philadelphia, 2014, Elsevier,
Table 18.2A.

FIG. 589.1 Evaluation of hypocalcemia. Abs, autoantibodies; CaSR, calcium-sensing

receptor; PTH, parathyroid hormone. (From Bilezikian JP, Khan A, Potts Jr JT, et al.
Hypoparathyroidism in the adult: epidemiology, diagnosis, pathophysiology, target-
organ involvement, treatment, and challenges for future research. J Bone Miner Res
26:2317–2337, 2011, Fig. 1.)
Aplasia or Hypoplasia of the Parathyroid
Glands
Aplasia or hypoplasia of the parathyroid glands is often associated with the
DiGeorge/velocardiofacial syndrome . This syndrome occurs in 1 in 4,000
newborns. In 90% of patients, the condition is caused by a deletion of
chromosome 22q11.2. Approximately 25% of these patients inherit the
chromosomal abnormality from a parent. Neonatal hypocalcemia occurs in 60%
of affected patients, but it is transitory in the majority; hypocalcemia can recur or
can have its onset later in life. Associated abnormalities of the 3rd and 4th
pharyngeal pouches are common; these include conotruncal defects of the heart
in 25%, velopharyngeal insufficiency in 32%, cleft palate in 9%, renal anomalies
in 35%, and aplasia of the thymus with severe immunodeficiency in 1%. This
syndrome has also been reported in a small number of patients with a deletion of
chromosome 10p13, in infants of diabetic mothers, and in infants born to
mothers treated with retinoic acid for acne early in pregnancy.

X-Linked Recessive Hypoparathyroidism

Familial clusters of hypoparathyroidism with various patterns of transmission
have been described. In 2 large North American pedigrees, this disorder appears
to be transmitted by an X-linked recessive gene located on Xq26-q27. In these
families, the onset of afebrile seizures characteristically occurs in infants from 2
wk to 6 mo of age. The absence of parathyroid tissue after detailed examination
of a boy with this condition suggests a defect in embryogenesis.

Autosomal Recessive
Hypoparathyroidism With Dysmorphic
Features
Autosomal recessive hypoparathyroidism with dysmorphic features has been
described in Middle Eastern children. Parental consanguinity occurred for almost
all of several dozen affected patients. Profound hypocalcemia occurs early in
life, and dysmorphic features include microcephaly, deep-set eyes, beaked nose,
micrognathia, and large floppy ears. Intrauterine and postnatal growth restriction
are severe, and cognitive impairment is common. The putative gene is on
chromosome 1q42-43. The autosomal recessive form of hypoparathyroidism that
occurs with type I polyglandular autoimmune disease is described subsequently.
In a few patients with autosomal recessive inheritance of isolated
hypoparathyroidism, mutations of the PTH gene have been found.

Hypoparathyroidism, Sensorineural
Deafness, and Renal Anomaly Syndrome
Hypoparathyroidism, sensorineural deafness, and renal anomaly occur owing to
mutations of the GATA3 gene. The protein encoded by this gene is essential in
the development of the parathyroids, auditory system, and kidneys. The GATA3
gene is located at chromosome 10p14 and is nonoverlapping with the DiGeorge
critical region at 10p13 (see Fig. 588.1 ). Congenital ichthyosis and HDR have
also been reported.

Suppression of Neonatal Parathyroid

Hormone Secretion Because of Maternal
Hyperparathyroidism
Neonatal PTH secretion can be suppressed by maternal hyperparathyroidism,
resulting in transient hypocalcemia in the newborn infant. It appears that
neonatal hypocalcemia results from suppression of the fetal parathyroid glands
by exposure to elevated levels of calcium in maternal and hence fetal serum.
Tetany usually develops within 3 wk but may be delayed by 1 mo or more if the
infant is breastfed. Hypocalcemia can persist for weeks or months. When the
cause of hypocalcemia in an infant is unknown, measurements of calcium,
phosphorus, and PTH should be obtained from the mother. Most affected
mothers are asymptomatic, and the cause of their hyperparathyroidism is usually
a parathyroid adenoma.

Autosomal Dominant
Hypoparathyroidism
Patients with autosomal dominant hypoparathyroidism have an activating (gain-
of-function) mutation of the Ca2+ -sensing receptor, forcing the receptor to an on
state with subsequent depression of PTH secretion even during hypocalcemia.
The patients have hypercalciuria. The hypocalcemia is usually mild and might
not require treatment beyond childhood (see Fig. 588.1 ).

Hypoparathyroidism Associated With

Mitochondrial Disorders
Mitochondrial DNA mutations in Kearns-Sayre syndrome, MELAS (myopathy,
encephalopathy, lactic acidosis, and stroke-like episodes) syndrome, and in
mitochondrial trifunctional protein–deficiency syndrome is associated with
hypoparathyroidism. A diagnosis of mitochondrial cytopathy should be
considered in patients with unexplained symptoms, such as ophthalmoplegia,
sensorineural hearing loss, cardiac conduction disturbances, and tetany (see Fig.
588.1 ).

Surgical Hypoparathyroidism
Removal or damage of the parathyroid glands can complicate thyroidectomy.
Hypoparathyroidism has developed even when the parathyroid glands have been
identified and left undisturbed at the time of operation. This may be the result of
interference with the blood supply or of postoperative edema and fibrosis.
Symptoms of tetany can occur abruptly postoperatively and may be temporary or
permanent. In some instances, symptoms develop insidiously and go undetected
until months after thyroidectomy. Occasionally, the first evidence of surgical
hypoparathyroidism may be the development of cataract. The status of
parathyroid function should be carefully monitored in all patients undergoing
thyroidectomy.
Deposition of iron pigment or of copper in the parathyroid glands
(thalassemia, Wilson disease) can also produce hypoparathyroidism.

Autoimmune Hypoparathyroidism
An autoimmune mechanism for hypoparathyroidism is strongly suggested by the
finding of parathyroid antibodies and by its frequent association with other
autoimmune disorders or organ-specific antibodies. Autoimmune
hypoparathyroidism is often associated with Addison disease and chronic
mucocutaneous candidiasis. The association of at least 2 of these 3 conditions
has been classified as autoimmune polyglandular disease type I (see Chapter
586 ). It is also known as autoimmune polyendocrinopathy, candidiasis, and
ectodermal dystrophy (APECED). This syndrome is inherited in an autosomal
recessive fashion and is not related to any single human leukocyte antigen–
associated haplotype. One-third of patients with this syndrome have all 3
components; 66% have only 2 of 3 conditions. The candidiasis almost always
precedes the other disorders (70% of cases occur in children younger than 5 yr of
age); the hypoparathyroidism (90% of cases occur after 3 yr of age) usually
occurs before Addison disease (90% of cases occur after 6 yr of age). A variety
of other disorders, including alopecia areata or totalis, malabsorption disorder,
pernicious anemia, gonadal failure, chronic active hepatitis, vitiligo, and insulin-
dependent diabetes, occur at various times. Some of these associations might not
appear until adult life. Autoimmune thyroid disease is a rare concomitant
finding.
Affected siblings can have the same or different constellations of disorders
(hypoparathyroidism, Addison disease). The disorder is exceptionally prevalent
among Finns and Iranian Jews. The gene for this disorder is designated AIRE
(autoimmune regulator); it is located on chromosome 21q22. It appears to be a
transcription factor that plays an essential role in the development of
immunologic tolerance. Patients with Addison disease as part of
polyendocrinopathy syndrome type I have demonstrated adrenal-specific
autoantibody reactivity directed against the side-chain cleavage enzyme.

Idiopathic Hypoparathyroidism
The term idiopathic hypoparathyroidism should be reserved for the small
residuum of children with hypoparathyroidism for whom no causative
mechanism can be defined. Most children in whom onset of hypoparathyroidism
occurs after the 1st few years of life have an autoimmune condition.
Autoantibodies to the extracellular domain of the calcium-sensing receptor have
been identified in some patients with acquired hypoparathyroidism. One should
always consider incomplete forms of DiGeorge syndrome or an activating
calcium-sensing receptor mutation in the differential diagnosis.

Clinical Manifestations
There is a spectrum of parathyroid deficiencies with clinical manifestations
varying from no symptoms to those of complete and long-standing deficiency.
Mild deficiency may be revealed only by appropriate laboratory studies.
Muscular pain and cramps are early manifestations; they progress to numbness,
stiffness, and tingling of the hands and feet. There may be only a positive
Chvostek or Trousseau sign or laryngeal and carpopedal spasms. Convulsions
with or without loss of consciousness can occur at intervals of days, weeks, or
months. These episodes can begin with abdominal pain, followed by tonic
rigidity, retraction of the head, and cyanosis. Hypoparathyroidism is often
mistaken for epilepsy. Headache, vomiting, increased intracranial pressure, and
papilledema may be associated with convulsions and might suggest a brain
tumor.
In patients with long-standing hypocalcemia, the teeth erupt late and
irregularly. Enamel formation is irregular, and the teeth may be unusually soft.
The skin may be dry and scaly, and the nails might have horizontal lines.
Mucocutaneous candidiasis, when present, antedates the development of
hypoparathyroidism; the candidal infection most often involves the nails, the
oral mucosa, the angles of the mouth, and less often, the skin; it is difficult to
treat.
Cataracts in patients with long-standing untreated disease are a direct
consequence of hypoparathyroidism; other autoimmune ocular disorders such as
keratoconjunctivitis can also occur. Manifestations of Addison disease,
lymphocytic thyroiditis, pernicious anemia, alopecia areata or totalis, hepatitis,
and primary gonadal insufficiency may also be associated with those of
hypoparathyroidism.
Permanent physical and mental deterioration occurs if initiation of treatment is
long delayed.

Laboratory Findings
The serum calcium level is low (5-7 mg/dL), and the phosphorus level is
elevated (7-12 mg/dL). Blood levels of ionized calcium (usually approximately
45% of the total) more nearly reflect physiologic adequacy but also are low. The
serum level of alkaline phosphatase is normal or low, and the level of 1,25(OH)2
D3 is usually low, but high levels have been found in some children with severe
hypocalcemia. The level of magnesium is normal but should always be checked
in hypocalcemic patients. Levels of PTH are low when measured by
immunometric assay. Radiographs of the bones occasionally reveal an increased
density limited to the metaphyses, suggesting heavy metal poisoning, or an
increased density of the lamina dura. Radiographs or CT scans of the skull can
reveal calcifications in the basal ganglia. There is a prolongation of the QT
interval on the electrocardiogram, which disappears when the hypocalcemia is
corrected. The electroencephalogram usually reveals widespread slow activity;
the tracing returns to normal after the serum calcium concentration has been
within the normal range for a few weeks, unless irreversible brain damage has
occurred or unless the parathyroid insufficiency is associated with epilepsy.
When hypoparathyroidism occurs concurrently with Addison disease, the serum
level of calcium may be normal, but hypocalcemia appears after effective
treatment of the adrenal insufficiency.

Treatment
Emergency treatment of neonatal tetany consists of intravenous injections of 5-
10 mL or 1-3 mg/kg of a 10% solution of calcium gluconate (elemental calcium
9.3 mg/mL) at the rate of 0.5-1.0 mL/min while the heart rate is monitored and a
total dose not to exceed 20 mg of elemental calcium/kg. Additionally, 1,25-
dihydroxycholecalciferol (calcitriol) should be given. The initial dosage is 0.25
µg/24 hr; the maintenance dosage ranges from 0.01-0.10 µg/kg/24 hr to a
maximum of 1-2 µg/24 hr. Calcitriol has a short half-life and should be given in
2 equal divided doses; it has the advantages of rapid onset of effect (1-4 days)
and rapid reversal of hypercalcemia after discontinuation in the event of
overdosage (calcium levels begin to fall in 3-4 days). Calcitriol is supplied as an
oral solution.
An adequate intake of calcium should be ensured. Supplemental calcium can
be given in the form of calcium gluconate or calcium glubionate to provide 800
mg of elemental calcium daily, but it is rarely essential. Foods with high
phosphorus content such as milk, eggs, and cheese should be reduced in the diet.
Clinical evaluation of the patient and frequent determinations of the serum
calcium levels are indicated in the early stages of treatment to determine the
requirement for calcitriol or vitamin D2 . If hypercalcemia occurs, therapy
should be discontinued and resumed at a lower dose after the serum calcium
level has returned to normal. In long-standing cases of hypercalcemia, repair of
cerebral and dental changes is not likely. Pigmentation, lowering of blood
pressure, or weight loss can indicate adrenal insufficiency, which requires
specific treatment. Patients with autosomal dominant hypocalcemic
hypercalciuria can develop nephrocalcinosis and renal impairment if treated with
vitamin D.

Differential Diagnosis
Magnesium deficiency must be considered in patients with unexplained
hypocalcemia. Concentrations of serum magnesium <1.5 mg/dL (1.2 mEq/L) are
usually abnormal. Familial hypomagnesemia with secondary hypocalcemia has
been reported in approximately 50 patients, most of whom developed tetany and
seizures at 2-6 wk of age. Administration of calcium is ineffective, but
administration of magnesium promptly corrects both calcium and magnesium
levels. Oral supplements of magnesium are necessary to maintain levels of
magnesium in the normal range. Two genetic forms have been described. One is
caused by an autosomal recessive gene on chromosome 9, resulting in a specific
defect in absorption of magnesium. The other is caused by an autosomal
dominant gene on chromosome 11q23, resulting in renal loss of magnesium.
Hypomagnesemia also occurs in malabsorption syndromes such as Crohn
disease and cystic fibrosis. Patients with autoimmune polyglandular disease type
I and hypoparathyroidism can also have concurrent steatorrhea and low
magnesium levels. Therapy with aminoglycosides causes hypomagnesemia by
increasing urinary losses.
It is not clear how low levels of magnesium lead to hypocalcemia. Evidence
suggests that hypomagnesemia impairs release of PTH and induces resistance to
the effects of the hormone, but other mechanisms also may be operative.
Poisoning with inorganic phosphate leads to hypocalcemia and tetany. Infants
administered large doses of inorganic phosphates, either as laxatives or as
sodium phosphate enemas, have had sudden onset of tetany, with serum calcium
levels <5 mg/dL and markedly elevated levels of phosphate. Symptoms are
quickly relieved by intravenous administration of calcium. The mechanism of
the hypocalcemia is not clear (see Chapter 68.6 ).
Hypocalcemia can occur early in the course of treatment of acute
lymphoblastic leukemia. Hypocalcemia is usually associated with
hyperphosphatemia resulting from destruction of lymphoblasts.
Episodic symptomatic hypocalcemia occurs in the Kenny-Caffey syndrome,
which is characterized by medullary stenosis of the long bones, short stature,
delayed closure of the fontanel, delayed bone age, and eye abnormalities.
Idiopathic hypoparathyroidism and abnormal PTH levels have been found.
Autosomal dominant and autosomal recessive modes of inheritance have been
reported. Mutations of the TBCE gene (1q43-44) perturb microtubule
organization in diseased cells.

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