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Pseudohypoparathyroidism type 1B (PHP1B) is a disorder characterized by lack of response (resistance) to parathyroid hormone (PTH) and other hormones such as thyroid-stimulating hormone (TSH). Resistance mainly occurs in the kidneys, causing low blood calcium levels (hypocalcemia), high blood phosphate levels (hyperphosphatemia), and elevated PTH levels (hyperparathyroidism). Some people with PHP1B also have elevated TSH levels due to TSH resistance. Each of these abnormalities can cause a variety of symptoms, which can be viewed by clicking on the terms above.
Severity can vary considerably, even among people in the same family. Symptoms usually begin in childhood due to low calcium levels and may include numbness, seizures, tetany, cataracts, and dental problems. Excessive growth or weight has been described in some newborns or during early infancy and childhood. Some children have skeletal problems, such as reduced bone mineral density and osteitis fibrosa.
The inheritance and genetics of PHP1B is complex. PHP1B is usually sporadic (not inherited), but familial cases with autosomal dominant inheritance, from the mother only, have been reported. When the parent from which a gene is inherited affects the way a gene acts, it is called genomic imprinting. PHP1B may be caused by randomly inheriting both copies of the long arm of chromosome 20 from the father rather than a copy from each parent (paternal 20q disomy), genetic mutations or epigenetic changes involving the GNAS or STX16 gene, or by unidentified genetic or epigenetic factors.
Treatment is lifelong, aiming to normalize calcium and PTH levels with active vitamin D metabolites such as alfacalcidol or calcitriol, and calcium supplementation.
Source: GARD Last updated on 05-01-20
PHP1B is a complex genetic disorder that may be caused by various types of changes in genes or chromosomes. While there are several different PHP1B subtypes, they all appear to somehow be associated with methylation changes involving the region of the GNAS gene.
Methylation is a chemical reaction that attaches small molecules called methyl groups to certain segments of DNA. Abnormal methylation can disrupt the normal activity of genes. For example, for genes that are only "active" when inherited from a certain parent, methylation is one way that a gene's parent of origin is "marked" during the formation of egg and sperm cells. Changes that affect the activation and deactivation of genes without any change in the underlying DNA sequence are called epigenetic changes.
Epigenetic changes involving PHP1B can be caused by a maternal deletion in the GNAS or STX16 gene, by paternal uniparental isodisomy of chromosome 20q (patUPD20q) or by undefined genetic mutations. The GNAS methylation changes are ultimately responsible for resistance to PTH signals in part of the kidneys, leading to the features of PHP1B.
Last updated on 05-01-20
The diagnosis of PHP1B is generally based on clinical features (signs, symptoms, and physical exams) and biochemical findings from a blood test for calcium-phosphate metabolism. This blood test includes measurements of calcium, phosphate, magnesium, and parathyroid hormone (PTH) in order to distinguish PHP from other conditions. PHP1B can be distinguished from other types of PHP by the absence of Albright's hereditary osteodystrophy. Molecular genetic testing can confirm the diagnosis.
Last updated on 05-01-20
PHP1B is most often sporadic (not inherited), occurring in people with no family history of PHP1B. However, sex-influenced autosomal dominant inheritance, from mother to child, has been reported. When a trait is sex- influenced, it means that the trait is expressed differently depending on whether it is inherited from a person's mother or father. This phenomenon is known as genomic imprinting.
In familial cases of PHP1B, it appears that parathyroid hormone (PTH) resistance in PHP1B develops only after maternal inheritance of the genetic change, whereas paternal inheritance is not associated with PTH resistance or other endocrine abnormalities. In several families with PHP1B, it has been reported that the disorder only occurred if the genetic change was inherited from the mother.
The genetics of PHP1B is extremely complex. The disorder may be caused by various types of genetic or epigenetic changes. Because the signs and symptoms of the sporadic and autosomal dominant forms of PHP1B are similar, identifying the specific genetic cause in each case is important for determining genetic risks to other family members.
People with personal questions or concerns about the inheritance of PHP1B, or genetic testing, are strongly encouraged to speak with a genetic counselor or other genetics professional. A genetics professional can help by:
Last updated on 05-01-20
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