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Pseudohypoparathyroidism type 1B

Orpha number ORPHA94089
Synonym(s) -
Prevalence Unknown
Inheritance Autosomal dominant
Not applicable
Age of onset Neonatal
Infancy
Childhood
Adolescent
ICD-10
  • E20.1
ICD-O -
OMIM
UMLS
  • C2932715
MeSH
  • C548075
MedDRA -

Summary

Pseudohypoparathyroidism type 1B (PHP-1b) is a type of pseudohypoparathyroidism (PHP; see this term) characterized by localized resistance to parathyroid hormone (PTH) mainly in the renal tissues which manifests with hypocalcemia, hyperphosphatemia and elevated PTH levels. About 60-70% of patients also present with elevated TSH levels due to TSH resistance.

The prevalence is unknown. The estimated prevalence of PHP (1a, 1b and PPHP) in Italy is 1/150,000.

PHP1b usually presents in childhood with symptoms of hypocalcemia, including numbness, seizures, tetany, cataracts, and dental problems. Patients may present with skeletal abnormalities, similar to those that occur in patients with hyperparathyroidism, such as reduced bone mineral density and osteitis fibrosa. TSH resistance is usually asymptomatic in PHP1b. Severity of symptoms can vary greatly between patients and even among kindreds.

The majority of cases of PHP1b are sporadic, but an autosomal dominant transmission has also been described. About 70% of PHP-Ib patients display methylation defects, sporadic or genetic-based, at GNAS (20q13.2-q13.3) differentially methylated regions (DMRs). PHP-Ib familial form is typically characterized by an isolated loss of methylation at the A/B DMR, secondary to genetic deletions disrupting the upstream imprinting control region in the STX16 gene (20q13.32). Hormonal resistance seen in PHP-1b develops after maternal inheritance of the disease, while paternal inheritance is not associated with any endocrine abnormalities. In sporadic cases, broad methylation alterations at all GNAS DMRs are usually detected and in a subset of such patients, paternal uniparental disomy of chromosome 20 (see this term) may explain this pattern of alteration.

Diagnosis of PTH resistance is based on measurement of serum calcium, phosphate and PTH. After infusion of biosynthetic PTH (which may be useful in difficult cases), nephrogenic cAMP and urinary excretion of phosphate do not increase. Gs-alpha activity in erythrocytes and fibroblasts is usually normal. Mild TSH resistance is often present at birth and may be diagnosed through neonatal screening of congenital hypothyroidism (see this term). Genetic testing can confirm diagnosis.

Differential diagnoses include primary hypoparathyroidism (which can be ruled out by the absence of hypercalciuria), secondary hyperparathyroidism, autoimmune polyendocrinopathy (see this term), and vitamin D deficiency. It should also be excluded from other forms of PHP (see this term) based on the absence of Albright hereditary osteodystrophy (AHO; see this term) and normal expression of Gs protein.

Antenatal diagnosis is possible only in those families with known deletions within GNAS or upstream of this locus.

The majority of cases of PHP1b are sporadic but familial transmission, following an autosomal dominant pattern of inheritance, has also been described and genetic counseling is possible in these cases.

Treatment is based on maintaining normocalcemia and normalizing serum levels of PTH with active vitamin D metabolites (alfacalcidol or calcitriol) and calcium supplementation. Patients should be treated for other associated endocrinopathies when present, particularly hypothyroidism, with levothyroxine. Blood biochemistries and urinary calcium excretion should be monitored annually. Treatment is lifelong but calcium and calcitriol dosages can usually be progressively lowered over time.

With treatment the prognosis is good and life expectancy is predicted to be comparable with the normal population, provided that endocrine disorders are correctly treated.

Expert reviewer(s)

  • Dr Giovanna MANTOVANI

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Detailed information

Guidance for genetic testing
  • EN (2013,pdf)
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