Pseudohypoparathyroidism

A very rare disorder characterized by renal and/or bony anomalies caused by their insensitivity to parathyroid hormone.

Pseudohypoparathyroidism (PHP) is a group of diseases in which target cells (renal tubular or osseous) are insensitive to parathyroid hormone.

• Type I (PHP I) is caused by the inability of parathyroid hormone to activate renal cell adenylcyclase.

  Type Ia (Albright Hereditary Osteodystrophy) is the most frequent, is because of a defect in the α subunit of the membrane-bound stimulatory G protein.

  Type Ib (PHP IB) is probably caused by abnormalities at the parathyroid hormone receptor.

  Type II (PHP II) is because of the inability of cAMP to initiate the metabolic events caused by stimulation of the parathyroid hormone receptor.

PHP type Ia and pseudopseudohypoparathyroidism are caused by heterogenous mutations in the Gsα encoding exons of GNAS1 (chromosome 20q13.3); PHP type Ia occurs only if the mutation is inherited from a female carrier.

Pseudopseudohypoparathyroidism occurs if the mutation is inherited from a male carrier. PHP type Ib has the same pattern of inheritance as is observed as for PHP type Ia but the mutation has not been identified yet.

The skeletal and developmental features of type Ia are those of the classic Albright hereditary osteodystrophy. Because the stimulatory G protein involved in type Ia is required for responsiveness to other hormones, hypothyroidism and gonadal dysfunction are common in this type of PHP.

Hypocalcemia, hyperphosphatemia, and elevated parathyroid hormone levels.

Children with PHP type Ia present with the classic Albright hereditary osteodystrophy appearance: small stature with moderate obesity, mild mental deficiency, rounded face with short neck, dental aplasia or enamel dysplasia, and subcapsular cataracts. Radiography shows osteoporosis, short metacarpal bones, and cone-shaped epiphyses. Cervical vertebral anomalies may be present. Cutaneous or subcutaneous calcifications. Hypocalcemia, which usually develops in the first years of life, may lead to tetany, muscle cramps, or seizures. Children with PHP types Ib and II have a normal physical appearance. PHP type I or II is treated with vitamin D and oral phosphate binders. Spontaneous amelioration of hypocalcemia may occur with time.

Check calcium and phosphate blood levels and correct them as required; in a case of PHP type Ia, assess the presence of other endocrinopathies (mainly hypothyroidism).

Hypocalcemia may lead to prolonged QT, tetany, and laryngospasm. Hyperventilation should be avoided. In type Ia, obesity may make venous access, mask ventilation, and laryngoscopy difficult.

Beware of hypocalcemia if there is rapid administration of blood or fresh-frozen plasma.

Pseudopseudohypoparathyroidism: The patient has the phenotype of Albright hereditary osteodystrophy but has normal calcium and phosphate levels. It represents a variant of PHP type Ia.

Pseudohypohyperparathyroidism: Resistance to parathyroid hormone is limited to the renal tubules; the bony response to elevated parathyroid hormone levels is thus normal, leading to subperiosteal resorption and osteitis fibrosa cystica.