Pseudohypoparathyroidism

At a glance

A very rare disorder characterized by renal and/or bony anomalies caused by their insensitivity to parathyroid hormone. Features include obesity, short stature, brachydactyly, cognitive impairment, and heterotopic ossification.

Synonym

Albright Hereditary Osteodystrophy.

Incidence

Estimated at 7:1,000,000 live births.

Classification

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

• Type 1 (PHP I): Caused by the inability of parathyroid hormone to activate renal cell adenylyl cyclase.

  • Type 1A (☞Albright Hereditary Osteodystrophy): The most frequent. It is caused by a defect in the α subunit of the membrane bound stimulatory G protein.

  • Type 1B (PHP IB): Probably caused by abnormalities at the parathyroid hormone receptor, sometimes thyroid stimulating hormone resistance, normal physical appearance.

  • Type 1C (PHP IC): Likely variant of the Type Ia with a resistance to PTH.

• Type 2 (PHP II): Characterized by the inability of cAMP to initiate the metabolic events caused by stimulation of the parathyroid hormone receptor.

Genetic inheritance

PHP Type 1 are caused by autosomal dominant mutations. PHP Type 1A occurs only if the mutation is inherited from a female carrier. Pseudopseudohypoparathyroidism occurs if the mutation is inherited from a male carrier.

Pathophysiology

Mutations of the GNAS1 gene on chromosome 20q13.3 encoding for the alpha-subunit of the stimulatory heterotrimeric G protein (Gsα). GNAS gives rise to additional gene products that exhibit exclusively maternal or paternal expression, such as XLαs, a large variant of Gsα that shows exclusively paternal expression and is partly identical to the latter. Because the stimulatory Gα protein involved in Type 1A is required for responsiveness to other hormones, hypothyroidism and gonadal dysfunction are common in this type of PHP. The skeletal and developmental features of Type 1A are those of the classic ☞Albright Hereditary Osteodystrophy.

Diagnosis

Hypocalcemia, hyperphosphatemia, and elevated parathyroid hormone levels.

Clinical aspects

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 1B and 2 have a normal physical appearance. PHP Type 1 or 2 is treated with vitamin D and oral phosphate binders. Spontaneous amelioration of hypocalcemia may occur with time.

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