Hypoparathyroidism

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Chapter 565 Hypoparathyroidism

Daniel A. Doyle

Etiology

Hypocalcemia is common between 12 and 72 hr of life, especially in premature infants, in infants with asphyxia, and in infants of diabetic mothers (early neonatal hypocalcemia) (Chapter 100) (Table 565-1). 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 remains to be clarified, although functional immaturity of the parathyroid glands is invoked as one 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 565-1 ETIOLOGIC CLASSIFICATION OF HYPOCALCEMIA

PARATHYROID HORMONE DEFICIENCY

Aplasia or hypoplasia of parathyroids

• With 22q11 deletion

DiGeorge syndrome
Velocardiofacial syndrome
Conotruncal-face syndrome

• With 10p13 deletion
• With maternal diabetes mellitus or retinoic acid embryopathy
• With X-linked isolated hypoparathyroidism
• With mutation of GCMB (glial cell missing B), autosomal recessive
• With retardation and dysmorphism (Sanjad-Sakati syndrome), autosomal recessive
• With deafness and renal dysplasia (GATA3 mutation)
• With osteosclerosis (Kenny-Caffey syndrome), TBCE mutation

Suppression of neonatal PTH secretion due to maternal hyperparathyroidism
Preproparathyroid hormone gene mutation

• Autosomal dominant

Ca2+-sensing receptor activating mutation

• Sporadic
• Autosomal dominant

Autoimmune parathyroiditis

• Isolated
• With type 1 autoimmune polyendocrinopathy, APECED

Mutation of AIRE gene

Infiltrative lesions

• Hemosiderosis (treatment of thalassemia)
• Copper deposition (Wilson disease)

PARATHYROID HORMONE RECEPTOR DEFECTS (PSEUDOHYPOPARATHYROIDISM)

Type 1a (inactivating mutation of Gsα)

• With gonadotropin-independent precocious puberty

Type 1b (paternal imprinting of GNAS1)
Type 2 (normal cAMP response)

MITOCHONDRIAL DNA MUTATIONS

Kearns-Sayre syndrome
Pearson marrow pancreas syndrome
Mutation of long-chain 3-hydroxyacylcoenzyme A dehydrogenase

MAGNESIUM DEFICIENCY

Renal magnesium loss (autosomal dominant)
Magnesium malabsorption (autosomal recessive)
Aminoglycoside therapy

EXOGENOUS INORGANIC PHOSPHATE EXCESS

Laxatives
Soft drinks with phosphoric acid

VITAMIN D DEFICIENCY

Nutritional
Vitamin D dependency (rickets)
Mutation of 1α-(OH)ase (cytochrome P-450)

APECED, autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy; cAMP, cyclic adenosine monophosphate; PTH, parathyroid hormone.

Aplasia or Hypoplasia of the Parathyroid Glands

Aplasia or hypoplasia of the parathyroid glands is often associated with the DiGeorge/velocardiofacial syndrome (see Fig. 564-1). This syndrome occurs in 1/4,000 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 two 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 retardation are severe, and mental retardation 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.

Hdr 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. 564-1).

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