Pseudohypoparathyroidism: Symptoms, Types, Causes and Treatment

Pseudohypoparathyroidism (PHP) is a rare, complex genetic and epigenetic disorder marked by the body's resistance to parathyroid hormone (PTH). This results in characteristic disturbances in calcium and phosphate metabolism, but the disorder is far more than just a hormonal imbalance. PHP is a multi-system condition with a broad range of symptoms, types, underlying causes, and tailored treatment approaches. This article guides you through the essentials of PHP, drawing on the latest research and clinical consensus.

Symptoms of Pseudohypoparathyroidism

Pseudohypoparathyroidism presents with a variety of symptoms, which can range from classic metabolic disturbances to less obvious physical, neurological, and developmental issues. Recognizing these symptoms early is crucial for effective management and improved quality of life.

Symptom	Description	Associated Features	Source(s)
Hypocalcemia	Low blood calcium, often causing muscle cramps/spasms	May cause seizures, tetany, paresthesia	3 4 17
Hyperphosphatemia	Elevated blood phosphate	Often with hypocalcemia	3 4 17
AHO phenotype	Albright Hereditary Osteodystrophy: round face, short stature, brachydactyly, subcutaneous ossifications	Early-onset obesity, orthopedic issues	1 3 5 13
Neurological	Cognitive impairment, intracerebral calcifications	Seizures, Fahr’s syndrome, behavioral issues	3 4 5 17
Endocrine	Multihormone resistance (PTH, TSH, GH, gonadotropins)	Hypothyroidism, growth delay, hypogonadism	1 5 13 14
Metabolic	Early onset obesity, insulin resistance, type 2 diabetes	Macrosomia, hypertension	1 2 3 5
ENT/Pulmonary	Hearing loss, sleep apnea, recurrent otitis media	Asthma-like symptoms	1

Table 1: Key Symptoms

Classic Symptoms: Metabolic and Skeletal

The core biochemical features of PHP are hypocalcemia (low calcium) and hyperphosphatemia (high phosphate), despite elevated or inappropriately normal levels of PTH. These symptoms often result in muscle cramps, tetany (involuntary muscle contractions), and in severe cases, seizures. Some patients may first present with symptoms caused by these metabolic changes, such as tingling, numbness, or even carpopedal spasms. Chronic hypocalcemia can lead to the development of intracerebral calcifications, which may manifest as neurological symptoms or be found incidentally during imaging for other reasons. These calcifications can be associated with movement disorders or cognitive decline (sometimes called Fahr’s syndrome) 3 4 17.

A significant number of patients display the Albright Hereditary Osteodystrophy (AHO) phenotype, which includes physical features such as:

• Round facies
• Short stature
• Brachydactyly (shortening of the fingers and toes)
• Subcutaneous ossifications (hard lumps under the skin)
• Early-onset obesity

In addition to these features, orthopedic complications like spinal stenosis and carpal tunnel syndrome are more common 1 3 5 13.

Neurological and Developmental Features

Many individuals with PHP experience neurological symptoms beyond those caused by hypocalcemia. These can include cognitive impairment, learning disabilities, behavioral issues, and, in severe cases, neurodevelopmental delay. Intracerebral calcifications are common, especially with delayed diagnosis and prolonged hypocalcemia 3 4 5 17. Hearing loss, both sensorineural and conductive, and decreased olfaction have also been reported 1.

Endocrine and Metabolic Disturbances

Resistance to other hormones is a hallmark of some PHP types, especially PHP1A. This can result in:

• Hypothyroidism (due to TSH resistance)
• Growth hormone (GH) deficiency (leading to short stature)
• Hypogonadism (delayed or incomplete puberty)
• Impaired glucose tolerance and increased risk of type 2 diabetes
• Early-onset obesity (sometimes with macrosomia and macrocephaly at birth) 1 2 5 13 14

ENT and Pulmonary Manifestations

Recent findings highlight frequent ENT (ear, nose, and throat) and pulmonary symptoms in PHP, such as:

• Recurrent otitis media (often requiring ear tube placement)
• Sleep apnea (notably more common in PHP1A than in other obese children)
• Asthma-like symptoms 1

Types of Pseudohypoparathyroidism

Understanding the classification of PHP is key to accurate diagnosis and management. The types are primarily based on genetic and molecular findings, but clinical features also help differentiate between them.

Type	Main Features	Genetic/Epigenetic Cause	Source(s)
PHP1A	Multihormone resistance, AHO phenotype	Maternal GNAS mutation	1 3 5 7 8 9 10
PHP1B	Isolated PTH (and sometimes TSH) resistance	GNAS methylation defect (epigenetic), STX16 deletion	2 3 5 7 9 10
PHP1C	Similar to 1A (AHO, hormone resistance), normal Gsα activity	Receptor-Gsα coupling defect	12 16
PPHP	AHO phenotype only, no hormone resistance	Paternal GNAS mutation	8 9
POH	Progressive osseous heteroplasia (deep tissue ossification)	GNAS mutation (paternal allele)	11

Table 2: Classification of PHP and Related Disorders

PHP Type 1A (PHP1A)

This is the classic form, featuring both multihormone resistance and the complete AHO phenotype. The resistance most often involves PTH, TSH, and sometimes gonadotropins or GH. PHP1A results from inactivating mutations in the maternal GNAS gene, which encodes the Gsα protein—a key player in hormone signaling 1 3 5 7 8 9 10.

PHP Type 1B (PHP1B)

PHP1B is characterized mainly by resistance to PTH (and sometimes TSH) without the full AHO features. However, there can be overlap, with some patients displaying mild AHO traits. PHP1B is mostly caused by epigenetic changes (methylation defects) at the GNAS locus, often linked to deletions in the STX16 gene 2 3 5 7 9 10. Notably, early-onset obesity and macrosomia can sometimes be present, especially in rare cases 2.

PHP Type 1C (PHP1C)

PHP1C is clinically similar to PHP1A, with hormone resistance and AHO phenotype, but differs at the molecular level. In PHP1C, the Gsα protein itself is functionally normal, but there is a selective defect in its coupling to hormone receptors 12 16. This subtlety can only be detected with specialized biochemical assays.

Pseudopseudohypoparathyroidism (PPHP)

PPHP presents with AHO physical features but without any hormone resistance. This form results from a paternal GNAS mutation and highlights the role of genomic imprinting in PHP 8 9.

Progressive Osseous Heteroplasia (POH)

POH is a rare, severe disorder characterized by progressive deep tissue ossification and is also linked to paternally inherited GNAS mutations. It may occur alongside or independent of AHO traits 11.

Causes of Pseudohypoparathyroidism

The root causes of PHP lie in the genetics and epigenetics of the GNAS gene locus. Understanding these mechanisms is vital for diagnosis and family counseling.

Cause Type	Mechanism	Main Impact	Source(s)
GNAS Mutation	Inactivating mutation (maternal/paternal)	Loss of Gsα function	1 3 7 8 9 10
Epigenetic Defect	Methylation abnormalities at GNAS locus	Silencing of Gsα allele	2 7 9 10 11
STX16 Deletion	Upstream regulatory gene deletion	Methylation defect at GNAS	2 7 9 10
Imprinting	Parent-of-origin-dependent gene expression	Tissue-specific hormone resistance	8 9 10

Table 3: Genetic and Epigenetic Causes of PHP

GNAS Gene Mutations

At the heart of PHP is the GNAS gene, which encodes the Gsα protein—a critical component in the signaling pathways of many hormones, including PTH. Mutations in the GNAS gene can be inherited from either parent, but the clinical outcome depends on which allele is affected due to genomic imprinting 1 3 7 8 9 10.

• Maternal GNAS mutation: Leads to PHP1A, with hormone resistance and AHO.
• Paternal GNAS mutation: Results in PPHP or, in some cases, POH, with AHO features but no hormone resistance.

Epigenetic and Regulatory Defects

Not all cases of PHP are due to changes in the DNA code itself. Many are caused by abnormal methylation patterns at the GNAS locus, silencing the gene’s activity from one parent’s allele. This is especially common in PHP1B 2 7 9 10 11. Often, the underlying cause is a deletion in the STX16 gene, which regulates methylation at the GNAS locus 2 7 9 10.

Imprinting and Tissue-Specific Expression

The GNAS gene is subject to a phenomenon called imprinting, meaning only one parental allele is active in certain tissues. For example, in the kidney, Gsα is mainly expressed from the maternal allele. This parent-of-origin effect explains the unique hormone resistance patterns in PHP and related disorders 8 9 10.

Other Contributing Factors

While GNAS mutations and epigenetic defects are the primary causes, ongoing research is identifying additional genetic contributors to disorders with overlapping features, such as progressive osseous heteroplasia and other rare syndromes 5 11.

Treatment of Pseudohypoparathyroidism

The management of PHP is multifaceted and should be personalized, with input from endocrinology, genetics, orthopedics, neurology, and other specialties. Early, coordinated, and lifelong care is the gold standard.

Treatment	Purpose/Target	Notes/Monitoring	Source(s)
Calcium/Vit D	Correct hypocalcemia	Monitor serum Ca, phosphate, PTH	4 13 14 17
Active Vit D	Enhance calcium absorption	Calcitriol or alfacalcidol	4 13 14 17
Hormone Replacement	Manage TSH, GH, or gonadotropin resistance	Thyroid, GH, sex hormones	5 13 14 15
Metabolic Care	Address obesity, glucose intolerance	Diet, exercise, diabetes screening	1 2 5 13
Orthopedic	Manage skeletal deformities	Surgery/physical therapy as needed	1 5 14
Neurocognitive	Support cognitive/behavioral issues	Educational, psychological support	1 5 13 14
Monitoring	Prevent complications, adjust therapy	Regular labs, imaging, specialist follow-up	13 14 15

Table 4: Treatment and Management Strategies

Correcting Biochemical Abnormalities

• Calcium and active vitamin D supplementation: The cornerstone of treatment is to correct hypocalcemia using oral calcium and active vitamin D analogs (such as calcitriol or alfacalcidol), since the body’s ability to respond to PTH is impaired 4 13 14 17.
• Regular monitoring: It’s crucial to watch for hypercalcemia, hypercalciuria, and kidney stones, even though PHP is not typically associated with increased renal calcifications 3 4 17.

Managing Hormone Resistance

• Thyroid hormone replacement: For those with TSH resistance and hypothyroidism.
• Growth hormone therapy: In selected patients with GH deficiency and poor growth 5 13 14 15.
• Sex hormone replacement: For hypogonadism or delayed puberty 5 13 14.

Addressing Obesity and Metabolic Risks

• Lifestyle interventions: Early engagement with nutritionists and physical therapists is essential, as obesity often begins in childhood.
• Monitoring for metabolic syndrome: Regular screening for type 2 diabetes, hypertension, and lipid abnormalities is recommended 1 2 5 13.

Orthopedic and Dental Care

• Surgical/orthopedic interventions: May be needed for severe skeletal deformities, brachydactyly, or carpal tunnel syndrome.
• Regular dental assessments: To address dental abnormalities seen in some patients 1 5 13 14.

Neurocognitive and Psychological Support

• Developmental assessment and intervention: Early and ongoing support for cognitive or behavioral difficulties can greatly enhance quality of life 1 5 13 14.

Multidisciplinary, Lifelong Care

• Coordinated care: The first international consensus recommends a lifelong, multidisciplinary approach, starting in early infancy and continuing into adulthood, with structured transition from pediatric to adult services 13 14 15.
• Genetic counseling: Essential for families, given the inheritance patterns and implications for future pregnancies 13 14.

Conclusion

Pseudohypoparathyroidism is a complex, multi-system disorder requiring careful attention to symptoms, type, cause, and management. Early recognition and coordinated care can significantly improve outcomes.

Key Takeaways:

• PHP presents with a combination of biochemical, physical, neurological, and metabolic symptoms, which may evolve over time 1 3 5.
• It is classified into several subtypes based on clinical features and underlying genetic/epigenetic changes, most notably involving the GNAS gene 2 3 7 8 9 10.
• Causes include DNA mutations, methylation defects, and imprinting abnormalities, with parent-of-origin effects playing a major role 2 7 8 9 10 11.
• Treatment focuses on correcting hypocalcemia, managing hormone resistance, addressing obesity and skeletal issues, and providing neurocognitive support, always within a multidisciplinary, lifelong framework 4 5 13 14 15 17.

With advances in molecular genetics and international consensus guidelines, the outlook for people with PHP is better than ever—especially when care begins early and is tailored to the unique needs of each individual.