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Disease Profile

Pseudohypoparathyroidism type 1B

Prevalence
Prevalence estimates on Rare Medical Network websites are calculated based on data available from numerous sources, including US and European government statistics, the NIH, Orphanet, and published epidemiologic studies. Rare disease population data is recognized to be highly variable, and based on a wide variety of source data and methodologies, so the prevalence data on this site should be assumed to be estimated and cannot be considered to be absolutely correct.

Unknown

Age of onset

Neonatal

ICD-10

E20.1

Inheritance

Autosomal dominant A pathogenic variant in only one gene copy in each cell is sufficient to cause an autosomal dominant disease

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Autosomal recessive Pathogenic variants in both copies of each gene of the chromosome are needed to cause an autosomal recessive disease and observe the mutant phenotype

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X-linked
dominant X-linked dominant inheritance, sometimes referred to as X-linked dominance, is a mode of genetic inheritance by which a dominant gene is carried on the X chromosome.

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X-linked
recessive Pathogenic variants in both copies of a gene on the X chromosome cause an X-linked recessive disorder

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Mitochondrial or multigenic Mitochondrial genetic disorders can be caused by changes (mutations) in either the mitochondrial DNA or nuclear DNA that lead to dysfunction of the mitochondria and inadequate production of energy.

Multigenic or multifactor Inheritance involving many factors, of which at least one is genetic but none is of overwhelming importance, as in the causation of a disease by multiple genetic and environmental factors.

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Not applicable

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Other names (AKA)

PHP1B

Categories

Congenital and Genetic Diseases; Endocrine Diseases; Kidney and Urinary Diseases

Summary

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.[1][2] 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.[1] Excessive growth or weight has been described in some newborns or during early infancy and childhood.[2] Some children have skeletal problems, such as reduced bone mineral density and osteitis fibrosa.[1]

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.[3] 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.[1][2]

Treatment is lifelong, aiming to normalize calcium and PTH levels with active vitamin D metabolites such as alfacalcidol or calcitriol, and calcium supplementation.[1]

Symptoms

This table lists symptoms that people with this disease may have. For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. This information comes from a database called the Human Phenotype Ontology (HPO) . The HPO collects information on symptoms that have been described in medical resources. The HPO is updated regularly. Use the HPO ID to access more in-depth information about a symptom.

Medical Terms Other Names
Learn More:
HPO ID
100% of people have these symptoms
Pseudohypoparathyroidism
0000852
80%-99% of people have these symptoms
Elevated circulating parathyroid hormone level
0003165
Hyperphosphatemia
High blood phosphate levels
0002905
Low urinary cyclic AMP response to PTH administration
0003456
30%-79% of people have these symptoms
Cataract
Clouding of the lens of the eye
Cloudy lens

[ more ]

0000518
Delayed eruption of teeth
Delayed eruption
Delayed teeth eruption
Delayed tooth eruption
Eruption, delayed
Late eruption of teeth
Late tooth eruption

[ more ]

0000684
Depressed nasal bridge
Depressed bridge of nose
Flat bridge of nose
Flat nasal bridge
Flat, nasal bridge
Flattened nasal bridge
Low nasal bridge
Low nasal root

[ more ]

0005280
Full cheeks
Apple cheeks
Big cheeks
Increased size of cheeks
Large cheeks

[ more ]

0000293
Hypoplasia of dental enamel
Underdeveloped teeth enamel
0006297
Nystagmus
Involuntary, rapid, rhythmic eye movements
0000639
Round face
Circular face
Round facial appearance
Round facial shape

[ more ]

0000311
Short neck
Decreased length of neck
0000470
Short stature
Decreased body height
Small stature

[ more ]

0004322
5%-29% of people have these symptoms
Abdominal symptom
0011458
Anxiety
Excessive, persistent worry and fear
0000739
Brachydactyly
Short fingers or toes
0001156
Chest pain
0100749
Conjunctivitis
Pink eye
0000509
Cortical subperiosteal resorption of humeral metaphyses
0003909
Depressivity
Depression
0000716
Diaphyseal sclerosis
Increased bone density in shaft of long bone
0003034
Dyskinesia
Disorder of involuntary muscle movements
0100660
Dyspnea
Trouble breathing
0002094
Hypocalcemic tetany
0003472
Hyporeflexia
Decreased reflex response
Decreased reflexes

[ more ]

0001265
Increased bone density with cystic changes
0005700
Irritability
Irritable
0000737
Laryngeal dystonia
0012049
Muscle spasm
0003394
Myoclonic spasms
0003739
Obesity
Having too much body fat
0001513
Paresthesia
Pins and needles feeling
Tingling

[ more ]

0003401
Prolonged QT interval
0001657
Short metacarpal
Shortened long bone of hand
0010049
1%-4% of people have these symptoms
Growth hormone deficiency
0000824
Hypocalcemic seizures
Low calcium seizures
0002199
Pituitary resistance to thyroid hormone
0008227
Percent of people who have these symptoms is not available through HPO
Autosomal dominant inheritance
0000006
Hypocalcemia
Low blood calcium levels
0002901
Sporadic
No previous family history
0003745

Cause

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.[4]

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.[5] Changes that affect the activation and deactivation of genes without any change in the underlying DNA sequence are called epigenetic changes.[6]

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.[4]

Diagnosis

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.[8] PHP1B can be distinguished from other types of PHP by the absence of Albright's hereditary osteodystrophy.[8][1] Molecular genetic testing can confirm the diagnosis.[1]

Testing Resources

  • The Genetic Testing Registry (GTR) provides information about the genetic tests for this condition. The intended audience for the GTR is health care providers and researchers. Patients and consumers with specific questions about a genetic test should contact a health care provider or a genetics professional.

    Organizations

    Support and advocacy groups can help you connect with other patients and families, and they can provide valuable services. Many develop patient-centered information and are the driving force behind research for better treatments and possible cures. They can direct you to research, resources, and services. Many organizations also have experts who serve as medical advisors or provide lists of doctors/clinics. Visit the group’s website or contact them to learn about the services they offer. Inclusion on this list is not an endorsement by GARD.

    Organizations Supporting this Disease

      Social Networking Websites

        Learn more

        These resources provide more information about this condition or associated symptoms. The in-depth resources contain medical and scientific language that may be hard to understand. You may want to review these resources with a medical professional.

        Where to Start

        • MedlinePlus was designed by the National Library of Medicine to help you research your health questions, and it provides more information about this topic.
        • The National Organization for Rare Disorders (NORD) has a report for patients and families about this condition. NORD is a patient advocacy organization for individuals with rare diseases and the organizations that serve them.

          In-Depth Information

          • GeneReviews provides current, expert-authored, peer-reviewed, full-text articles describing the application of genetic testing to the diagnosis, management, and genetic counseling of patients with specific inherited conditions.
          • Medscape Reference provides information on this topic. You may need to register to view the medical textbook, but registration is free.
          • The Monarch Initiative brings together data about this condition from humans and other species to help physicians and biomedical researchers. Monarch’s tools are designed to make it easier to compare the signs and symptoms (phenotypes) of different diseases and discover common features. This initiative is a collaboration between several academic institutions across the world and is funded by the National Institutes of Health. Visit the website to explore the biology of this condition.
          • Online Mendelian Inheritance in Man (OMIM) is a catalog of human genes and genetic disorders. Each entry has a summary of related medical articles. It is meant for health care professionals and researchers. OMIM is maintained by Johns Hopkins University School of Medicine. 
          • Orphanet is a European reference portal for information on rare diseases and orphan drugs. Access to this database is free of charge.
          • PubMed is a searchable database of medical literature and lists journal articles that discuss Pseudohypoparathyroidism type 1B. Click on the link to view a sample search on this topic.

            References

            1. Giovanna Mantovani. Pseudohypoparathyroidism type 1B. Orphanet. October, 2014; https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=94089.
            2. Haldeman-Englert CR, Hurst ACE, Levine MA. Disorders of GNAS Inactivation. GeneReviews. October 26, 2017; https://www.ncbi.nlm.nih.gov/books/NBK459117/.
            3. Cassandra L. Kniffin. PSEUDOHYPOPARATHYROIDISM, TYPE IB; PHP1B. OMIM. June 2010; https://omim.org/entry/603233.
            4. Poradosu S, Bravenboer B, Takatani R, Jüppner H. Pseudohypoparathyroidism type 1B caused by methylation changes at the GNAS complex locus. BMJ Case Rep. May 11, 2016; 2016:
            5. Beckwith-Wiedeman syndrome. Genetics Home Reference. June, 2015; https://ghr.nlm.nih.gov/condition/beckwith-wiedemann-syndrome#genes.
            6. Epigenetics. NHGRI Talking Glossary. https://www.genome.gov/glossary/index.cfm?id=528.
            7. HM LUK, IFM LO, TMF TONG, KKS LAI, STS LAM. Pseudohypoparathyroidism Type 1b: First Case Report in Chinese and Literature Review. HK J Paediatr. 2015; 20:32-36.
            8. Valentina Donghi, Stefano Mora, Ilaria Zamproni, Giuseppe Chiumello and Giovanna Weber. Pseudohypoparathyroidism, an often delayed diagnosis: a case series. Cases Journal. 2009; https://www.casesjournal.com/content/2/1/6734.

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