Background

• Pseudohypoparathyroidism is a rare genetic disorder that affects the regulation of calcium and phosphate levels in the body. It falls under a group of conditions known as hypoparathyroidism disorders. To understand pseudohypoparathyroidism, let’s first review some basic concepts: 
• The parathyroid glands in the neck produce a parathyroid hormone (PTH). PTH plays a critical role in regulating calcium and phosphate levels in the blood. When calcium levels drop, PTH is released to stimulate the release of calcium from bones, increase calcium absorption from the intestines, and decrease calcium excretion by the kidneys. 

Epidemiology

Pseudohypoparathyroidism is a rare genetic disorder, and its prevalence is relatively low in the general population. The exact prevalence can vary based on the specific type of pseudohypoparathyroidism and the population being studied. Here are some general epidemiological insights: 

• Type 1a Pseudohypoparathyroidism: This subtype, also known as Albright’s hereditary osteodystrophy, is relatively rarer than type 1b. It is estimated to occur in about 1 in 20,000 to 1 in 100,000 live births. The prevalence might be slightly higher in certain ethnic groups. 
• Type 1b Pseudohypoparathyroidism: Type 1b is less common than type 1a. Its prevalence is not as well-studied or well-documented, but it is generally considered less frequent than type 1a. 

Anatomy

Pathophysiology

• The pathophysiology of pseudohypoparathyroidism involves a defect in the signaling pathway that responds to parathyroid hormone (PTH), which is produced by the parathyroid glands. This defect results in the characteristic features of the disorder, including resistance to the actions of PTH on various tissues and organs. 
• The main components of the pathophysiology of pseudohypoparathyroidism are related to the G protein-coupled receptor signaling pathway and the downstream effects of PTH on target tissues: 
• Normal PTH Signaling Pathway: When blood calcium levels decrease, the parathyroid glands release PTH. PTH then binds to its receptor on target tissues, primarily in the kidneys and bones. This binding triggers a signaling cascade that leads to various cellular responses, including increased calcium reabsorption in the kidneys and release of calcium from bones. Additionally, PTH stimulates the production of active vitamin D, which enhances calcium absorption in the intestines. 
• Defective GNAS Gene: In pseudohypoparathyroidism, there is a mutation in the GNAS gene. This gene encodes a protein that plays a crucial role in transmitting signals from various hormones, including PTH, to the interior of cells. Mutations in the GNAS gene can disrupt the normal signaling process and result in resistance to the actions of PTH. 
• Tissue-specific Effects: The effects of PTH resistance can vary depending on the tissue or organ involved. For example: 
• In the kidneys, PTH resistance leads to decreased calcium reabsorption, which can result in increased urinary excretion of calcium. This contributes to low blood calcium levels. 
• In bones, the reduced responsiveness to PTH can lead to impaired bone remodeling and mineralization, potentially causing problems with bone health and development. 
• PTH resistance can also affect other tissues in some cases, leading to the characteristic physical features seen in type 1a pseudohypoparathyroidism, such as short stature and rounded face. The exact mechanisms underlying these physical features are not fully understood. 
• Genomic Imprinting: One unique aspect of pseudohypoparathyroidism is the phenomenon of genomic imprinting. In typical cases, copies of a gene—one inherited from the mother and one from the father—are active. However, in pseudohypoparathyroidism, the defective GNAS gene is often inherited from the mother, and the paternal copy of the gene is silenced due to genomic imprinting. This leads to the condition’s characteristic pattern of inheritance and can contribute to the variable expressivity of the disorder. 

Etiology

There are two main types of pseudohypoparathyroidism, each with its underlying genetic basis: 

1. Type 1a Pseudohypoparathyroidism (PHP1a): 

• This type is also known as Albright’s hereditary osteodystrophy. 
• It is caused by mutations in the GNAS gene that result in a loss of function of the GNAS protein. 
• These mutations can affect the production or function of the GNAS protein, leading to resistance of target tissues to the actions of PTH. 
• Inheritance is often through the maternal allele, and the paternal allele is imprinted and silenced in specific tissues, contributing to the characteristic features of the disorder. 

2. Type 1b Pseudohypoparathyroidism (PHP1b):

• This type is less common than type 1a. 
• It is also associated with mutations in the GNAS gene, but the specific genetic mechanisms are not fully understood. 
• Unlike type 1a, no characteristic physical features are associated with type 1b pseudohypoparathyroidism. 

Genetics

Prognostic Factors

The prognosis of individuals with pseudohypoparathyroidism can vary widely based on factors such as the specific type of pseudohypoparathyroidism (type 1a or type 1b), the severity of symptoms, the timing of diagnosis, and the management provided. Here are some factors that can influence the prognosis: 

• Type of Pseudohypoparathyroidism: 

Type 1a pseudohypoparathyroidism (Albright’s hereditary osteodystrophy) is associated with characteristic physical features, like short stature, a round face, and short fingers. These features can vary in severity and impact an individual’s quality of life. 

Type 1b pseudohypoparathyroidism generally lacks the characteristic physical features of type 1a.  

• The severity of symptoms: 

The severity of hypocalcemia (low blood calcium levels) and other symptoms can vary. Some individuals may experience mild symptoms, while others may have more pronounced complications, such as muscle cramps, seizures, and bone abnormalities. 

• Age at Diagnosis: 

Early diagnosis and intervention can portray better outcomes. Timely management can help prevent or mitigate complications associated with low calcium and phosphate levels, such as skeletal abnormalities and kidney problems. 

• Management: 

Adequate management of pseudohypoparathyroidism involves maintaining appropriate calcium and phosphate levels through supplementation and addressing associated complications. Proper management can improve an individual’s quality of life and prevent long-term complications. 

• Bone Health: 

Pseudohypoparathyroidism can affect bone health due to impaired bone remodeling and mineralization. Adequate calcium and vitamin D supplementation, along with monitoring and management of bone health, can play a role in preventing fractures and other bone-related issues. 

• Kidney Function: 

The effects of pseudohypoparathyroidism on kidney function can vary. Some individuals might experience problems with calcium excretion and kidney stones, while others might have normal kidney function. Regular monitoring of kidney function and appropriate interventions are essential. 

• Genetic Factors: 

The specific GNAS gene mutations and how they impact the signaling pathway can influence the severity and expression of the disorder. Genetic testing can provide insights into the underlying genetic factors. 

• Individual Variability: 

Pseudohypoparathyroidism can present with many symptoms and complications, even within the same family. This variability is influenced by genetic background and other unknown factors. 

Clinical History

Non-specific signs & symptoms 

• Short stature 
• Round face 
• Shortened digits 
• Obesity 
• Cognitive and behavioral changes 
• Bone and joint pain 
• Muscle weakness 
• Tetany 
• Tingling and numbness 
• Depression and anxiety 
• Cardiovascular symptoms 

    Systemic signs & symptoms 

• Hypocalcemia 
• Hypophosphatemia 
• Skeletal abnormalities 
• Renal manifestations 
• Neurological symptoms 
• Endocrine abnormalities 

Physical Examination

During a physical examination of an individual suspected of having pseudohypoparathyroidism, healthcare professionals will look for various signs and features of the disorder. While the physical exam findings can vary based on the subtype of pseudohypoparathyroidism (type 1a or type 1b) and the severity of the condition, here are some key aspects that might be assessed: 

Facial Features: 

• Individuals with type 1a pseudohypoparathyroidism might exhibit a round face and other characteristic facial features. 
• Shortened fingers and toes (brachydactyly) might also be present. 

Stature and Growth: 

• Short stature is a common feature in type 1a pseudohypoparathyroidism. Growth patterns and height will be evaluated, especially in children. 

Dental Examination: 

• Dental abnormalities, like delayed tooth eruption and enamel defects, might be assessed during a dental examination. 

Neuromuscular Examination: 

• The healthcare provider will assess muscle strength, tone, and coordination. 
• Signs of muscle cramps, spasms, and tetany might be evaluated. 

Neurological Assessment: 

• The presence of numbness, tingling, or other sensory abnormalities might be evaluated. 
• Neurological reflexes and responses will be checked. 

Cardiovascular Evaluation: 

• Heart rate and rhythm will be assessed. 
• The healthcare provider might check for prolonged QT interval on an electrocardiogram (ECG), which can be associated with hypocalcemia. 

Skeletal Examination: 

• Bone abnormalities might be observed, such as short stature or brachydactyly. 
• The healthcare provider might evaluate joint mobility and any signs of bone pain. 

Age group

Associated comorbidity

• Osteoporosis and fractures 
• Kidney stones 
• Nephrocalcinosis 
• Hypothyroidism 
• Hypogonadism 
• Dental abnormalities 
• Neurological and cognitive impairments 
• Cardiovascular risks 
• Reproductive challenges 
• Growth & development
• Physical activity  
• Lifestyle 

Associated activity

Acuity of presentation

The acuity of presentation for pseudohypoparathyroidism can vary widely based on factors like the severity of the disorder, the specific type (type 1a or type 1b), the age at which symptoms develop, and the individual’s genetic makeup. Here are different ways in which the condition can present acutely:: 

Neonatal or Infantile Onset: 

• In some cases, particularly with type 1a pseudohypoparathyroidism, symptoms might become apparent shortly after birth or in infancy. 
• Newborns with the disorder might exhibit features such as a round face, short stature, and brachydactyly. 
• Hypocalcemia-related symptoms, such as muscle cramps and tetany, can manifest early in life. 

Childhood and Adolescence: 

• Children and adolescents might present with delayed growth and developmental delays due to the effects of pseudohypoparathyroidism on bone health and hormonal imbalances. 
• Dental problems, such as delayed tooth eruption and enamel defects, might become noticeable during this period. 

Adolescent and Young Adult Years: 

• Hormonal imbalances associated with pseudohypoparathyroidism can impact growth, development, and reproductive functions, leading to hypothyroidism and hypogonadism. 
• Skeletal abnormalities, including short stature and brachydactyly, might become more pronounced during adolescence. 

Adulthood: 

• Adults with pseudohypoparathyroidism can experience a range of symptoms, including hypocalcemia-related manifestations like muscle cramps, numbness, and tetany. 
• Bone health issues, such as osteoporosis and an increased risk of fractures, might become more prominent. 

Acute Hypocalcemia: 

• In some cases, individuals with pseudohypoparathyroidism, particularly type 1a, might experience acute episodes of severe hypocalcemia. 
• Acute hypocalcemia can lead to symptoms such as muscle twitching, seizures, and arrhythmias. 

Differential Diagnoses

• True hypoparathyroidism 
• Vitamin D deficiency 
• Worsening of CKD chronic kidney disease 

Laboratory Studies

Imaging Studies

Procedures

Histologic Findings

Staging

Treatment Paradigm

The treatment paradigm for pseudohypoparathyroidism aims to manage the imbalances in calcium, phosphate, and vitamin D, as well as address associated symptoms and complications. As always, consult a healthcare professional for personalized medical advice. Here’s a general overview: 

• Diagnosis and Genetic Testing: Accurate diagnosis is essential. Genetic testing can identify mutations in genes like GNAS, which are associated with pseudohypoparathyroidism. Differentiating between subtypes is crucial for tailored treatment. 
• Calcium and Vitamin D Supplementation: Individuals with pseudohypoparathyroidism often have low calcium levels due to the lack of response to PTH. Calcium and active vitamin D (calcitriol) supplements may be prescribed to maintain proper calcium levels in the blood and bone health. 
• Phosphate Control: Some forms of pseudohypoparathyroidism can lead to elevated phosphate levels in the blood. Dietary phosphate restriction and phosphate-binding medications may be used to manage this. 
• Monitoring and Adjustments: Regular monitoring of calcium, phosphate, and PTH levels is important to guide treatment adjustments and maintain optimal mineral balance. 
• Treat Associated Conditions: Pseudohypoparathyroidism can be associated with other hormonal imbalances, such as thyroid disorders. Managing these conditions is important for overall health. 
• Bone Health: Since calcium and phosphate play a crucial role in bone health, individuals with pseudohypoparathyroidism may be at an increased risk of bone problems. Regular bone density assessments and potentially other interventions may be recommended to prevent fractures and maintain bone strength. 
• Symptomatic Relief: Managing symptoms associated with low calcium levels, such as muscle cramps, tetany, and seizures, is important. In severe cases, intravenous calcium may be needed to rapidly correct low calcium levels. 
• Long-term Follow-up: Regular follow-up appointments with healthcare providers who are familiar with the condition are necessary to monitor treatment effectiveness, adjust medications, and address any new developments. 
• Patient Education: Education about the condition, dietary considerations (such as managing calcium and phosphate intake), and potential complications is essential for effective self-management. 
• Psychosocial Support: Living with a rare condition can be challenging. Connecting with support groups or mental health professionals can provide emotional support and coping strategies. 

by Stage

by Modality

Chemotherapy

Radiation Therapy

Surgical Interventions

Hormone Therapy

Immunotherapy

Hyperthermia

Photodynamic Therapy

Stem Cell Transplant

Targeted Therapy

Palliative Care

providing-a-healthy-environment-to-manage-pseudohypoparathyroidism

• Dietary Choices: 

A vitamin D and calcium diet can help support bone health and maintain proper mineral levels. 

Foods sufficient in calcium include dairy products, fortified plant-based milk, leafy greens, and certain fish. 

Vitamin D is received from sunlight exposure and dietary sources like fatty fish and fortified foods. 

• Hydration: 

Staying well-hydrated is important to prevent kidney stone formation, especially for individuals prone to hypercalciuria (increased urinary calcium excretion). 

Adequate fluid intake can help dilute urine and reduce the risk of kidney stones. 

• Physical Activity: 

Regular physical activity, particularly weight-bearing exercises like walking or strength training, can help maintain bone health and muscle strength. 

Exercise can also help manage weight and support overall well-being. 

• Home Safety: 

Individuals with pseudohypoparathyroidism, especially those prone to muscle cramps and weakness, should ensure a safe living environment to prevent falls and injuries. 

Removing tripping hazards and having proper lighting can reduce the risk of accidents. 

• Stress Management: 

Chronic stress can exacerbate symptoms like muscle tension and pain. 

Stress management techniques such as mindfulness, meditation, and relaxation exercises can be beneficial. 

• Regular Medical Follow-Up: 

Maintaining regular appointments with healthcare providers for check-ups, blood tests, and adjustments to treatment plans is essential. 

• Travel Considerations: 

Travelers should plan to ensure access to necessary medications and supplements. 

Adequate hydration and prevention of urinary stasis can be vital during travel to reduce the risk of kidney stones. 

• Emotional Support: 

Building a strong support network of family, friends, and support groups can help individuals manage the emotional aspects of living with a chronic condition. 

• Education: 

Educating family members and caregivers about the condition, its symptoms, and treatment requirements can help create a supportive environment. 

Use of calcium salts in the treatment of pseudohypoparathyroidism

• Calcium chloride 

Calcium chloride is a form of calcium salt that contains a higher concentration of elemental calcium compared to other calcium supplements. It is sometimes used as a treatment option for managing low blood calcium levels in conditions like hypocalcemia, including in cases of pseudohypoparathyroidism. 

• Calcium gluconate 

Calcium gluconate is another form of calcium salt that is commonly used to treat low blood calcium levels (hypocalcemia) in various medical conditions, including pseudohypoparathyroidism. Like other calcium supplements, its use should be under the guidance of healthcare professionals, and its effectiveness and safety depend on the specific situation and the individual’s needs. 

• Calcium carbonate 

Calcium carbonate is a commonly used calcium supplement often prescribed to treat low blood calcium levels (hypocalcemia) in various medical conditions, including pseudohypoparathyroidism. It is available as an oral supplement and is widely used for short-term and long-term management of calcium imbalances. 

Use of fat-soluble vitamins in the treatment of pseudohypoparathyroidism

• Calcitriol 

Calcitriol, also known as 1,25-dihydroxyvitamin D3, is the active form of vitamin D. It treats various conditions, including pseudohypoparathyroidism, to help manage calcium and phosphate imbalances. 

use-of-intervention-with-a-procedure-in-treating-pseudohypoparathyroidism

• Parathyroid Surgery: 

In cases where pseudohypoparathyroidism is associated with parathyroid adenomas (tumors), surgical removal of the affected parathyroid gland(s) might be considered to correct hyperparathyroidism. 

Parathyroidectomy can help normalize calcium and phosphate levels and alleviate related symptoms. 

• Kidney Stone Removal: 

If an individual with pseudohypoparathyroidism develops kidney stones (renal calculi), extracorporeal shock wave lithotripsy (ESWL) or ureteroscopy might be used to break down and remove the stones. 

These procedures aim to relieve urinary obstruction and prevent complications. 

• Bone Health Procedures: 

Individuals with pseudohypoparathyroidism are at an increased risk of osteoporosis and fractures. Bone density scans (DEXA scans) can assess bone health and guide management. 

Depending on the severity of bone loss, treatments such as bisphosphonates might be considered to strengthen bones and reduce fracture risk. 

• Electrolyte Management: 

In severe electrolyte imbalances, intravenous administration of electrolyte solutions might be needed to restore balance rapidly. 

Intravenous administration might also be necessary for severe cases of hypocalcemia. 

• Catheter-based Procedures: 

Catheter-based procedures might be considered to address urinary abnormalities and prevent stone recurrence for cases of severe hypercalciuria (excessive urinary calcium excretion) that lead to kidney stone formation. 

• Genetic Testing and Counseling: 

Genetic testing can be considered to identify specific mutations associated with pseudohypoparathyroidism and to provide valuable information for family planning and risk assessment. 

use-of-phases-in-managing-the-pseudohypoparathyroidism

• Diagnosis and Initial Treatment Phase: 

This phase involves the initial evaluation, diagnosis, and commencement of treatment after pseudohypoparathyroidism is diagnosed. 

The focus is stabilizing blood calcium levels and addressing acute symptoms such as muscle cramps and tetany. 

Calcium and vitamin D supplementation are commonly initiated to maintain calcium balance and improve bone health. 

• Childhood and Adolescent Growth Phase: 

In pediatric cases, managing growth and development is a critical consideration. 

Children might need specialized care to address growth delays, skeletal abnormalities, and developmental challenges. 

Regular bone health and hormonal imbalances monitoring is essential during this phase. 

• Adolescent and Young Adult Phase: 

Hormonal imbalances can impact reproductive health and bone density. 

Particular attention might be given to managing hypothyroidism, hypogonadism, and maintaining bone health. 

Education about long-term management and potential complications is essential as individuals transition to adulthood. 

• Adulthood and Long-Term Management Phase: 

This phase involves maintaining calcium and phosphate levels, preventing bone loss, and monitoring for complications. 

Managing bone health, preventing fractures, and addressing the risk of kidney stones are key aspects. 

Regular medical follow-up appointments and blood tests to monitor mineral levels are essential. 

• Complication Management Phase: 

Individuals who develop complications like kidney stones or fractures might enter a phase focused on managing these issues. 

Procedures, medications, and lifestyle adjustments might be needed to address complications and prevent recurrence. 

• Elderly and Aging Phase: 

In older individuals, maintaining bone health and preventing fractures become particularly important. 

Closely monitoring mineral levels, bone density, and overall health is essential as individuals age. 

• Genetic Counseling and Family Planning Phase: 

This phase involves providing genetic counseling to individuals and families to discuss inheritance patterns, risk assessment, and family planning options. 

Medication

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References

• https://www.ncbi.nlm.nih.gov/books/NBK547709/