Pseudohypoparathyroidism type 1B

Other Names: PHP1B

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.

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. 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.

Inheritance

Autosomal dominant pattern, a 50/50 chance.

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.

Signs and symptoms

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.

For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed.

100% of people have these symptoms

• Pseudohypoparathyroidism

80%-99% of people have these symptoms

• Elevated circulating parathyroid hormone level
• Hyperphosphatemia(High blood phosphate levels)
• Low urinary cyclic AMP response to PTH administration

30%-79% of people have these symptoms

• Cataract(Clouding of the lens of the eye)
• Delayed eruption of teeth(Delayed eruption)
• Depressed nasal bridge(Depressed bridge of nose)
• Full cheeks(Apple cheeks)
• Hypoplasia of dental enamel(Underdeveloped teeth enamel)
• Nystagmus(Involuntary, rapid, rhythmic eye movements)
• Round face(Circular face)
• Short neck(Decreased length of neck)
• Short stature(Decreased body height)

5%-29% of people have these symptoms

• Abdominal symptom
• Anxiety(Excessive, persistent worry and fear)
• Brachydactyly(Short fingers or toes)
• Chest pain
• Conjunctivitis(Pink eye)
• Cortical subperiosteal resorption of humeral metaphyses
• Depressivity(Depression)
• Diaphyseal sclerosis(Increased bone density in shaft of long bone)
• Dyskinesia(Disorder of involuntary muscle movements)
• Dyspnea(Trouble breathing)
• Hypocalcemic tetany
• Hyporeflexia(Decreased reflex response)
• Increased bone density with cystic changes
• Irritability(Irritable)
• Laryngeal dystonia
• Muscle spasm
• Myoclonic spasms
• Obesity(Having too much body fat)
• Paresthesia(Pins and needles feeling)
• Prolonged QT interval
• Short metacarpal(Shortened long bone of hand)

1%-4% of people have these symptoms

• Growth hormone deficiency
• Hypocalcemic seizures(Low calcium seizures)
• Pituitary resistance to thyroid hormone

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.

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

Treatment

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

NIH genetic and rare disease info

• NIH info on Pseudohypoparathyroidism type 1B

Pseudohypoparathyroidism type 1B is a rare disease.

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