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 PHP1A 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
- AHO-PHP syndrome 1a
- Albright hereditary osteodystrophy-PHP syndrome 1a
- Albright hereditary osteodystrophy with multiple hormone resistance
What causes this condition?
Pseudohypoparathyroidism type 1A is caused by a genetic variation (mutation) in the GNAS gene.
A defect in the the guanine nucleotide-binding protein may be responsible for some forms of Pseudohypoparathyroidism
This disease is inherited in an autosomal dominant pattern.
Pseudohypoparathyroidism is a hereditary disorder inherited either through X- linked dominant genes or through autosomal dominant genes.
PHP1A and PPHP have been known to be caused by heterozygous Gsα-inactivating pathogenic variants.
It was subsequently shown that the disease phenotype associated with the variant depends on the alterations’ maternal (PHP1A) or paternal (PPHP)/POH inheritance.
Besides the mRNA encoding Gsα, several additional sense and antisense transcripts are derived from the GNAS locus that utilize alternative first exons and promoters.
These include exon A/B that gives rise to a splice variant that appears to encode an amino-terminally truncated form of Gsα, while exon XL allows generation of an extra-large Gsα variant (XLαs).
In addition, a non-coding antisense transcript (AS) and the 55-kDa neuroendocrine secretory protein (NESP55) are derived from the GNAS locus.
Most studies have not found a genotype/phenotype relationship in PHP1A, and the AHO phenotype can be seen in patients with molecular defects ranging from point mutations to epigenetic defects at GNAS.
One recent study reported that subcutaneous ossifications were more common in patients harboring truncating versus missense mutations
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 PHP1A 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
Very Common Symptoms and Signs (80%-98% present)
- Elevated circulating parathyroid hormone (PTH) levels
- 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
- 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
- Obesity – Obesity is typically recognized in the first 2-years of life
- 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
- Band keratopathy
- Broad distal phalanx of the thumb
- Cerebral calcification
- Chest pain
- Hypergonadotropic hypogonadism
- Hyperostosis frontalis interna
- Hypocalcemic tetany
- Involuntary movements
- Laryngeal dystonia
- Muscle spasm
- Myoclonic spasms
- Osteoma cutis
- Prolonged QT interval
- Reduced bone mineral density
- Sensorineural hearing impairment
- Short 3rd metacarpal
- Spinal cord compression
Rare Symptoms and Signs (4%-1%)
- Elevated calcitonin
- Hypocalcemic seizures
- Prolactin deficiency – Reduced circulating prolactin concentration
The most common Metabolic Complications 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.