Pseudohypoparathyroidism overview
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mazia Fatima, MBBS [2]
Overview
Pseudohypoparathyroidism is characterized by end-organ resistance to the parathyroid hormone. Patients have a low serum calcium and high phosphate, but the parathyroid hormone level is appropriately high. Pseudohypoparathyroidism type 1a presents with the characteristic phenotypic appearance of Albright's hereditary osteodystrophy. Pseudohypoparathyroidism type 1b lacks the physical appearance of type 1a, but is biochemically similar. The term pseudopseudohypoparathyroidism is used to describe a condition where the individual has the phenotypic appearance of pseudohypoparathyroidism type 1a, but is biochemically normal. There are three types of pseudohypoparathyroidism, type 1a, type 1b and type 2. All forms of pseudohypoparathyroidism are very rare and are caused by abnormal genes. Usual signs and symptoms include numbness, tetany, seizures, cataracts and dental problems. Patients with pseudohypoparathyroidism type 1a, which is also called Albright's hereditary osteodystrophy, may show signs of short stature. Blood tests of minerals, genetic testing and head MRI may help diagnose the disorder. Treatment for pseudohypoparathyroidism includes taking calcium carbonate and vitamin D supplements to normalize blood levels of calcium and phosphorus.
Historical Perspective
In 1942, Fuller albright, an American endocrinologist, first discovered pseudohypoparathyroidim and associated clinical features of Albright hereditary osteodystrophy.
Classification
Pseudohypoparathyroidism is classified based on the measurement of serum and urinary cAMP and phosphate excretion levels after the injection of biologically active parathyroid hormone into pseudohypoparathyroidism type I and pseudohypoparathyroidism type II. Pseudohypoparathyroidism type 1 may be classified into type 1a, type 1b, and type 1c.
Pathophysiology
Pseudohypoparathyroidism is characterized by end-organ resistance to parathyroid hormone. Gene mutation results in failure of signal transduction. Blomstrand's chondrodystrophy results in intrauterine death and is characterized by abnormal endochondral bone formation with prematurely occurring mineralization of the cartilaginous bone templates. Acrodysostosis patients have resistance to parathyroid hormone with normal calcium and phosphorus, in addition to resistance thyroid-stimulating hormone and growth hormone releasing hormone.
Causes
Pseudohypoparathyroidism is caused by mutations involving primarily the GNAS gene that results in end organ resistance to parathyroid hormone.
Differentiating Pseudohypoparathyroidism from Other Diseases
Pseudohypoparathyroidism can be differentiated from other causes of increased parathyroid hormone (PTH) and parathyroid hormone resistance like Blomstrand chondrodysplasia, acrodysostosis, hypomagnesemia, hypoparathyroidism and hyperparathyroidism.
Epidemiology and Demographics
The worldwide incidence and prevalence of pseudohypoparathyroidism is unknown. In Japan, the prevalence of pseudohypoparathyroidism ranges from a low of 0.26 per 100,000 persons to a high of 0.42 per 100,000 persons with an average prevalence of 0.34 per 100,000 persons. In Italy, the estimated prevalence of Pseudohypoparathyroidism type 1a, pseudohypoparathyroidism type1b, and pseudopseudohypoparathyroidism is 0.67 per 100,000
Risk Factors
The most potent risk factor in the development of pseudohypoparathyroidism is a positive family history for GNAS mutation.
Screening
There is insufficient evidence to recommend routine screening for pseudohypoparathyroidism.
Natural History, Complications, and Prognosis
Patients with pseudohypoparathyroidism type Ia have an increased rate of other endocrine abnormalities (such as hypothyroidism and hypogonadism). Complications of hypocalcemia associated with pseudohypoparathyroidism may include seizures and other endocrine problems, leading to decrease libido and delayed sexual development, fatigue, and obesity.
Diagnosis
Diagnostic Study of Choice
Pseudohypoparathyroidism diagnosis is mainly a clinical diagnosis. The confirmatory diagnostic study of choice for pseudohypoparathyroidism is genetic testing.
History and Symptoms
A positive family history of pseudohypoparathyroidism is suggestive of the autosomal dominant inheritance. The most common symptoms of pseudohypoparathyroidism type 1a include short stature, short limbs, mental retardation associated with Albright hereditary osteodystrophy phenotype.
Physical Examination
Patients with pseudohypoparathyroidism type1a, type 1c and pseudopseudohypoparathyroidism present by the second decade of life with characteristic physical features of Albright's hereditary osteodystrophy. Pseudohypoparathyroidism type 1b isolated resistance to parathyroid hormone without the associated clinical features of Albright's osteodystrophy. Mild brachydactyly is seen in some cases. Blomstrand's chondrodystrophy presents with short limbs due to characteristic growth impairment. Secondary hyperplasia of the parathyroid glands occurs as a result of associated hypocalcemia.
Laboratory Findings
The diagnosis of pseudohypoparathyroidism is made by measurement of variations in serum calcium, phosphorus, cAMP and calcitriol and in urinary cAMP and phosphorus excretion helps in assessment of skeletal and renal responsiveness to parathyroid hormone.
Elecetrocardiogram
An ECG may be helpful in the diagnosis of cardiac dysfunction associated with the pseudohypoparathyroidism. Findings on an ECG suggestive of cardiac dysfunction due to hypocalcemia associated with pseudohypoparathyroidism include prolonged QT interval.
X ray
CT-scan
MRI
Other imaging findings
Findings on an x-ray include short distal phalanx of thumb and short third to fifth metacarpals associated with features of Albright hereditary osteodystrophy. Findings on an x-ray of hand in acrodysostosis, include shortened metacarpals with cone epiphyses. In acrodysostosis the spine may also be affected by loss of caudal widening of interpedicular distance, which may correlate with stenosis of the spinal canal. Findings on CT scan suggestive of pseudohypoparathyroidism in some patients includes include symmetric calcifications in basal ganglia, perivascular calcifications in soft tissues. MRI in pseudohypoparathyroidism Ia patients may include Chiari Malformation-Type I.
Other Diagnostic Studies
Other diagnostic studies include genetic testing, platelet aggregation testing for Gsα defects and bone densitometry testing.
Treatment
Medical Therapy
The mainstay of treatment for pseudohypoparathyroidism is oral calcium and 1 alpha-hydroxylated vitamin D analogs, such as calcitriol. Other forms of Vitamin D cannot be used as parathyroid hormone resistance in the proximal tubule decreases the efficiency of production of 1,25(OH)2 vitamin D from 25-hydroxyvitamin D. Intravenous calcium is recommended for all patients who develop severe symptomatic hypocalcemia.
Surgery
Surgical resection of enlarged parathyroid glands is usually reserved for patients that develop tertiary hyperparathyroidism in pseudohypoparathyroidism 1b. Rarely, excision of extraskeletal osteomas is done to relieve associated pressure symptoms in patients.
Primary Prevention
Effective measures for the primary prevention of pseudohypoparathyroidism include genetic counseling in inherited cases. Secondary prevention of measures in pseudohypoparathyroidism includes regular serum and urinary calcium measurements monitoring.