Pseudohypoparathyroidism type 1A (PHP1A) – 67 Symptoms, Signs and Prognosis

What is Pseudohypoparathyroidism type 1A (PHP1A)

• Pseudohypoparathyroidism type 1A (PHP1a) is a rare hormonal disorder.
• Pseudohypoparathyroidism type 1A is a type of pseudohypoparathyroidism.
• Pseudohypoparathyroidism occurs when your body is unable to respond to parathyroid hormone, a hormone that controls the levels of calcium, phosphorous, and vitamin D in the blood.

What is the prevalence?

• The prevalence of Pseudohypoparathyroidism type 1A is not well understood.
• A recent article from Denmark reported a PHP1A prevalence of 1.1 per 100,000 inhabitants.
• A lower prevalence of 3.4 per million inhabitants was reported in Japan

Synonyms

• AHO-PHP syndrome 1a
• Albright hereditary osteodystrophy-PHP syndrome 1a
• PHP1A
• Albright hereditary osteodystrophy with multiple hormone resistance

What causes this condition?

• A mutation in the GNAS gene is the cause of pseudohypoparathyroidism type 1A.
A malfunction in the guanine nucleotide-binding protein could potentially be the cause of certain types of pseudohypoparathyroidism.
• There is an autosomal dominant pattern of inheritance for this illness.
A genetic condition known as pseudohypoparathyroidism is inherited either by autosomal dominant genes or X-linked dominant genes.
• It is known that heterozygous Gsα-inactivating pathogenic mutations produce PHP1A and PPHP.
• It was later demonstrated that the disease phenotype linked to the polymorphism is dependent on the inheritance of the changes from the mother (PHP1A) or father (PPHP)/POH.
• The GNAS locus yields a number of sense and antisense transcripts that use different first exons and promoters in addition to the mRNA encoding Gsα.
• These include exon XL, which permits the production of an extra-large Gsα variation (XLαs), and exon A/B, which results in a splice variant that appears to encode an amino-terminally shortened form of Gsα.
• The GNAS gene is also the source of the 55-kDa neuroendocrine secretory protein (NESP55) and a non-coding antisense transcript (AS).
• In PHP1A, most studies have not identified a correlation between genotype and phenotype; individuals with molecular deficiencies ranging from point mutations to epigenetic errors at GNAS can exhibit the AHO phenotype.
• A recent study found that patients with truncating mutations were more likely than missense mutations to have subcutaneous ossifications.

• Pseudohypoparathyroidism type 1A (PHP1A) is a rare genetic disorder that is caused by mutations in the GNAS gene. The GNAS gene provides instructions for making a protein called Gs alpha, which plays a critical role in signaling pathways that regulate the activity of certain hormones, including parathyroid hormone (PTH) and other hormones that affect bone and mineral metabolism.
• In PHP1A, the mutations in the GNAS gene lead to a defect in Gs alpha protein function, resulting in resistance to the action of PTH and other hormones that normally stimulate the release of calcium from bones and increase calcium levels in the blood. As a result, individuals with PHP1A have low levels of calcium in the blood (hypocalcemia) and high levels of phosphate (hyperphosphatemia), even though the parathyroid glands may produce and release PTH normally or at higher-than-normal levels.

Symptoms and Signs of Pseudohypoparathyroidism type 1A

• The symptoms are very similar to hypoparathyroidism, a condition that occurs parathyroid hormone levels are too low. 
• In contrast to hypoparathyroidism, in which the synthesis or secretion of parathyroid hormone (PTH) is impaired or absent, in pseudohypoparathyroidism, target tissues are unresponsiveness to the actions of PTH.
• Chronic hypocalcemia in this disorder leads to hyperplastic parathyroid glands and increased levels of PTH.
• The etiology of this condition is due to renal resistance to a hormone in the body called parathyroid hormone (PTH).
• This process results in hypocalcemia, hyperphosphatemia, and elevated PTH.
• There are also other features such as resistance to other hormones including thydroid stimulating hormone (TSH), growth-hormone-releasing hormone (GHRH) and gonadotropins
• Pseudohypoparathyroidism type 1A (PHP1a) also termed as Albright hereditary osteodystrophy due to the constellation of clinical features.

A review of contemporary literature demonstrates the Non-classic features of pseudohypoparathyroidism type 1A.

Along with the Albright Hereditary Osteodystrophy phenotype and hormone resistance, patients with Pseudohypoparathyroidism type 1A may have the below additional complications

• skeletal complications
• metabolic complications
• ear nose throat related complications
• pulmonary complications

The clinical care of the patients affected with PHP1A can be greatly improved by understanding the above non classic features of this condition

100% present Symptoms and Signs

• Pseudohypoparathyroidism

Very Common Symptoms and Signs (80%-98% present)

• Elevated circulating parathyroid hormone (PTH) levels
• Hyperphosphatemia
• Hypocalcemia 
• Low urinary cyclic AMP response to PTH administration 
• Pituitary resistance to thyroid hormone 
• Round face 
• Short stature 

Common Symptoms and Signs (30%-79% present)

• Basal ganglia calcification 
• Brachydactyly – Possibly due to the brachydactyly, the majorities of children with PHP1A have difficulty with fine motor skills, such as handwriting.
• Broad 1st metacarpal 
• Cataract 
• Choroid plexus calcification 
• Constrictive median neuropathy 
• Delayed eruption of teeth 
• Depressed nasal bridge 
• Ectopic ossification 
• Full cheeks 
• Growth hormone deficiency 
• Hypoplasia of dental enamel 
• Increased bone mineral density 
• Intellectual disability 
• Nystagmus 
• Obesity – Obesity is typically recognized in the first 2-years of life
• Polyphagia 
• Short 4th metacarpal 
• Short 5th metacarpal 
• Short fifth metatarsal 
• Short metacarpal 
• Short metatarsal 
• Short neck 
• Thickened calvaria

Occasional Symptoms and Signs (5%-29% present)

• Abdominal symptom 
• Abnormal platelet function 
• Anxiety 
• Band keratopathy 
• Broad distal phalanx of the thumb 
• Calcinosis 
• Cerebral calcification
• Chest pain 
• Choreoathetosis 
• Confusion 
• Conjunctivitis 
• Depressivity 
• Dyspnea 
• Hypergonadotropic hypogonadism 
• Hyperostosis frontalis interna 
• Hypertension 
• Hypocalcemic tetany 
• Hyporeflexia 
• Involuntary movements 
• Irritability 
• Laryngeal dystonia 
• Muscle spasm 
• Myoclonic spasms 
• Oligomenorrhea 
• Osteoma cutis 
• Paresthesia 
• Prolonged QT interval 
• Reduced bone mineral density 
• Sensorineural hearing impairment 
• Short 3rd metacarpal 
• Spinal cord compression 
• Strabismus

Rare Symptoms and Signs (4%-1%)

• Elevated calcitonin 
• Hypocalcemic seizures 
• Prolactin deficiency – Reduced circulating prolactin concentration

Metabolic Complications

• The most common Metabolic Complications of Pseudohypoparathyroidism type 1A is Obesity
• Obesity is typically recognized in the first 2-years of life, but it is not part of the AHO spectrum as it was shown in 2007 to be a feature specific for PHP1A, but not for PPHP.
• Interestingly, early-onset obesity can be observed also in PHP1B, as recently documented for a patient with PHP1B due to the frequently encountered 3-kb deletion in STX16, the gene encoding syntaxin 16.
• Although increased food-intake through central mechanisms may contribute to weight gain in some children with PHP1A, a reduction in resting energy expenditure is likely the primary mechanism leading to obesity.
• A reduction in resting energy expenditure of 346.4 kcals/day (95% CI −585.5 to −106.9) is found in children with PHP1A compared with obese controls, which was recently confirmed by Roizen et al., who observed a similar reduction of 273.9 kcals/day (SE 60.0 kcals/day).
• Patients with PHP1A can have increased interest in food, especially in the first two years of life, but older patients do not report increased hunger compared with obese controls.
• These findings are supported by previous studies in murine models of PHP1A; for example, mice with a brain-specific maternal Gnas exon 1-ablation had increased feed efficiency but normal food intake when the Gnas mutation was paternally inherited.
• In humans affected by PHP1A, obesity occurs despite early and adequate treatment of TSH resistance and growth hormone deficiency.

Prognosis of Pseudohypoparathyroidism type 1A – Pseudohypoparathyroidism life expectancy

Here is the prognosis of the Pseudohypoparathyroidism type 1A

• With the appropriate and timely treatment, ideally there is a good Prognosis for this condition
• Due to the features of this disorder such as severe short stature, obesity and subcutaneous ossifications, the Quality of life is considerably affected
• If the endocrine diseases associated with this condition are correctly treated, than the Life expectancy is pretty normal

PHP-I patients should be monitored annually for both blood biochemical profile (PTH, calcium, phosphate, TSH) and urinary calcium excretion.

Active vitamin D metabolites, preferentially calcitriol, with or without oral calcium supplementation, are the treatment of choice, and the dose should be titrated to maintain normocalcemia.

Patients with PHP-I should also be screened and treated for associated endocrinopathies, particularly hypothyroidism and hypogonadism.

Summary

Pseudohypoparathyroidism type 1A (PHP1A) is a rare genetic disorder that affects the body’s response to parathyroid hormone (PTH) and other hormones. It is primarily caused by mutations in the GNAS gene, which is involved in the signaling pathways of several hormones, including PTH.

Here are some key features and characteristics of Pseudohypoparathyroidism type 1A:

1. Hormonal resistance: Individuals with PHP1A have resistance to the action of PTH, leading to impaired regulation of calcium and phosphorus levels in the body. Despite having normal or elevated levels of PTH, the body fails to respond appropriately, resulting in low levels of calcium and high levels of phosphorus in the blood.
2. Skeletal abnormalities: PHP1A can cause certain skeletal abnormalities, such as short stature, a rounded face, short neck, and shortening of the bones in the hands and feet. These skeletal features may be similar to those seen in Albright’s hereditary osteodystrophy (AHO), which can occur in individuals with PHP1A.
3. Neurological and developmental issues: Some individuals with PHP1A may experience neurological symptoms, including intellectual disability, developmental delays, and behavioral problems. These symptoms can vary in severity and are not present in all cases.
4. Endocrine disturbances: Besides the parathyroid hormone resistance, PHP1A can also affect the response to other hormones regulated by the GNAS gene, such as thyroid-stimulating hormone (TSH), gonadotropins, and growth hormone-releasing hormone (GHRH). This can lead to additional endocrine abnormalities, including hypothyroidism, delayed or absent sexual development, and growth hormone deficiency.
5. Other features: PHP1A may be associated with other clinical features, such as obesity, insulin resistance, and skin abnormalities.

The diagnosis of Pseudohypoparathyroidism type 1A is typically confirmed through genetic testing to identify mutations in the GNAS gene. Management and treatment of PHP1A involve addressing the specific symptoms and complications associated with the condition.

This may include supplementation with calcium and vitamin D to maintain adequate levels, managing endocrine dysfunctions, addressing developmental and behavioral issues, and providing appropriate supportive care.

It’s important to consult with a healthcare professional, such as a geneticist or endocrinologist, for a comprehensive evaluation, diagnosis, and ongoing management of Pseudohypoparathyroidism type 1A.

They can provide personalized guidance and recommendations based on an individual’s specific needs and symptoms.