Pseudohypoparathyroidism

Overview

Pseudohypoparathyroidism represents a group of heterogeneous disorders caused by impaired responsiveness to parathyroid hormone at the level of its target organs, primarily the kidneys and bones. Unlike true hypoparathyroidism where PTH production is deficient, in PHP the parathyroid glands produce normal or even elevated amounts of PTH, but the body's tissues cannot respond appropriately to the hormone's signal. This results in a unique clinical scenario where despite adequate hormone production, the physiological effects of PTH are absent or diminished.

The condition is classified into several types based on clinical features, biochemical findings, and molecular defects. Type 1a PHP, also known as Albright hereditary osteodystrophy (AHO), is the most common and well-characterized form. It results from mutations in the GNAS gene, which encodes the alpha subunit of the stimulatory G protein (Gsα). This protein is crucial for PTH receptor signaling, and its dysfunction leads to resistance not only to PTH but often to other hormones that use similar signaling pathways, including thyroid-stimulating hormone (TSH), gonadotropins, and growth hormone-releasing hormone (GHRH).

The clinical presentation of PHP is highly variable, ranging from mild biochemical abnormalities detected incidentally to severe symptoms including seizures from hypocalcemia, developmental delays, and distinctive physical features. The complexity of this condition extends beyond endocrine manifestations, as patients may experience skeletal abnormalities, soft tissue calcifications, and neurocognitive challenges. Understanding the multisystem nature of PHP is essential for comprehensive patient care and long-term management.

Symptoms

The symptoms of pseudohypoparathyroidism vary significantly depending on the type and severity of the condition. While some individuals may have minimal symptoms, others experience a wide range of manifestations affecting multiple organ systems.

Metabolic Symptoms

• Muscle cramps and tetany (involuntary muscle contractions)
• Paresthesias (tingling sensations) in fingers, toes, and around the mouth
• Seizures, particularly in untreated hypocalcemia
• Fatigue and weakness
• Mental fog or difficulty concentrating

Musculoskeletal Symptoms

• Leg pain - often related to muscle cramps or bone abnormalities
• Knee pain - may occur due to skeletal abnormalities
• Wrist pain - can result from brachydactyly or calcium deposits
• Elbow weakness - related to muscle dysfunction
• Short stature (adult height often below 5 feet)
• Brachydactyly (shortened fingers and toes, especially 4th and 5th)

Physical Features (Albright Hereditary Osteodystrophy)

• Round face with full cheeks
• Short neck
• Obesity, particularly truncal
• Shortened metacarpals and metatarsals
• Dimpling over knuckles when making a fist
• Dental abnormalities (delayed eruption, enamel hypoplasia)

Neurological Symptoms

• Developmental delays in children
• Intellectual disability (variable severity)
• Basal ganglia calcifications
• Movement disorders
• Increased intracranial pressure (rare)

Endocrine-Related Symptoms

• Hypothyroidism symptoms (fatigue, cold intolerance, weight gain)
• Hypogonadism (delayed puberty, infertility)
• Growth hormone deficiency
• Irregular menstrual periods in females
• Decreased libido

Causes

Pseudohypoparathyroidism is caused by genetic defects that impair the body's ability to respond to parathyroid hormone. The underlying molecular mechanisms vary among the different types of PHP, but all result in end-organ resistance to PTH.

Genetic Mutations

GNAS Gene Mutations (PHP Type 1a and 1c)

• Most common cause of PHP
• Located on chromosome 20q13
• Encodes the alpha subunit of stimulatory G protein (Gsα)
• Inherited in an autosomal dominant pattern
• Subject to genomic imprinting (maternal inheritance causes PHP1a)

PRKAR1A Gene Mutations (PHP Type 1c)

• Rare cause of PHP
• Affects protein kinase A signaling
• Results in hormone resistance without AHO features

Molecular Mechanisms

The pathophysiology involves disrupted signal transduction:

• G-protein dysfunction: Impaired coupling between PTH receptor and adenylyl cyclase
• Reduced cAMP production: Decreased intracellular signaling
• Target organ resistance: Kidneys cannot respond to PTH signals
• Multi-hormone resistance: Affects other G-protein coupled receptors

Imprinting and Inheritance

• Maternal inheritance: GNAS mutations from mother cause PHP1a
• Paternal inheritance: Same mutations cause pseudopseudohypoparathyroidism (PPHP)
• Tissue-specific imprinting: Explains variable hormone resistance
• Sporadic cases: De novo mutations account for 20-30% of cases

Environmental Factors

While PHP is genetic, certain factors can influence severity:

• Dietary calcium and vitamin D intake
• Compliance with medication
• Concurrent illnesses affecting calcium metabolism
• Pregnancy and lactation (increased calcium demands)

Risk Factors

As a genetic disorder, the primary risk factors for pseudohypoparathyroidism relate to inheritance patterns and family history. Understanding these factors is crucial for genetic counseling and early diagnosis.

Genetic Risk Factors

• Family history: 50% risk if parent carries mutation
• Maternal inheritance: Higher risk of PHP1a phenotype
• Consanguinity: Increased risk in related parents
• Ethnic background: No specific ethnic predilection identified

Factors Affecting Severity

• Age: Symptoms often manifest in childhood
• Gender: Some features more prominent in females
• Nutritional status: Poor diet worsens symptoms
• Kidney function: Renal disease exacerbates condition
• Compliance: Poor medication adherence increases complications

Complication Risk Factors

• Untreated hypocalcemia
• Poor monitoring of calcium and phosphate levels
• Concurrent endocrinopathies
• Pregnancy without proper management
• Surgical procedures without preparation

Diagnosis

Diagnosing pseudohypoparathyroidism requires a combination of clinical evaluation, biochemical testing, imaging studies, and genetic analysis. The complexity of the condition often necessitates a multidisciplinary approach.

Clinical Evaluation

• Medical history: Family history, growth patterns, developmental milestones
• Physical examination: AHO features, short stature, brachydactyly
• Symptom assessment: Tetany, seizures, paresthesias
• Chvostek's sign: Facial twitching when tapping facial nerve
• Trousseau's sign: Carpopedal spasm with blood pressure cuff

Laboratory Testing

Essential Tests

• Serum calcium: Low or low-normal (ionized calcium more accurate)
• Serum phosphate: Elevated
• PTH levels: Elevated (key distinguishing feature)
• 25-hydroxyvitamin D: Often low
• 1,25-dihydroxyvitamin D: Low or inappropriately normal
• Alkaline phosphatase: May be elevated

Additional Endocrine Testing

• Thyroid function tests: TSH often elevated
• Growth hormone testing: May show deficiency
• Gonadotropins: LH/FSH resistance assessment
• Cortisol levels: Usually normal

Imaging Studies

• Hand X-rays: Shortened metacarpals, especially 4th and 5th
• Skull X-ray/CT: Basal ganglia calcifications
• Bone density scan: May show increased density
• Renal ultrasound: Check for nephrocalcinosis

Genetic Testing

• GNAS gene sequencing: Identifies mutations in 70-80% of PHP1a
• Methylation analysis: For PHP1b diagnosis
• Chromosomal microarray: Detects deletions/duplications
• Family testing: Cascade screening for at-risk relatives

Functional Tests

• PTH infusion test: Blunted urinary cAMP response
• Ellsworth-Howard test: Historic test, rarely used now
• Calcium loading test: Assesses renal calcium handling

Treatment Options

Treatment of pseudohypoparathyroidism focuses on correcting metabolic abnormalities, managing symptoms, and preventing complications. The approach must be individualized based on the specific type of PHP, severity of symptoms, and presence of associated hormone resistances.

Calcium and Vitamin D Management

Calcium Supplementation

• Calcium carbonate: 1-3 grams elemental calcium daily in divided doses
• Calcium citrate: Better absorbed, especially with achlorhydria
• Target levels: Maintain serum calcium in low-normal range (8-8.5 mg/dL)
• Monitoring: Regular calcium levels to avoid hypercalciuria

Vitamin D Therapy

• Calcitriol (1,25-dihydroxyvitamin D): 0.25-2 mcg daily
• Alfacalcidol: Alternative active vitamin D analog
• Cholecalciferol: May supplement if 25-OH vitamin D low
• Dose adjustment: Based on calcium and phosphate levels

Phosphate Management

• Dietary phosphate restriction: Limit high-phosphate foods
• Phosphate binders: Calcium carbonate with meals
• Sevelamer: Non-calcium binder for severe hyperphosphatemia
• Goal: Maintain phosphate <5.5 mg/dL

Management of Associated Endocrinopathies

Hypothyroidism

• Levothyroxine replacement therapy
• Monitor TSH and free T4 levels
• Adjust dose based on clinical response

Growth Hormone Deficiency

• Growth hormone therapy in children with proven deficiency
• Monitor growth velocity and IGF-1 levels
• Continue until final height achieved

Hypogonadism

• Sex hormone replacement when indicated
• Fertility counseling and treatment
• Monitor for complications

Symptom Management

• Acute hypocalcemia: IV calcium gluconate
• Seizures: Anticonvulsants if recurrent despite calcium control
• Muscle cramps: Magnesium supplementation may help
• Pain management: For leg pain and joint discomfort

Monitoring and Follow-up

• Laboratory monitoring:
  • Calcium, phosphate, PTH every 3-6 months
  • 24-hour urine calcium annually
  • Renal function and vitamin D levels
• Imaging surveillance:
  • Renal ultrasound for nephrocalcinosis
  • Bone density monitoring
  • Ophthalmologic exams for cataracts

Prevention

While pseudohypoparathyroidism cannot be prevented due to its genetic nature, many complications can be avoided through proper management and early intervention. Prevention strategies focus on genetic counseling, early diagnosis, and preventing metabolic complications.

Genetic Counseling

• Counseling for affected individuals and family members
• Discussion of inheritance patterns and recurrence risks
• Prenatal testing options for at-risk pregnancies
• Preimplantation genetic diagnosis availability
• Family planning considerations

Early Detection

• Newborn screening in families with PHP
• Regular monitoring of at-risk family members
• Biochemical screening before symptoms develop
• Growth monitoring in children
• Developmental assessments

Complication Prevention

• Nephrocalcinosis prevention: Avoid hypercalciuria
• Cataract prevention: Maintain stable calcium levels
• Seizure prevention: Consistent calcium management
• Dental care: Regular checkups, fluoride treatment
• Bone health: Weight-bearing exercise, fall prevention

Lifestyle Modifications

• Dietary calcium and vitamin D optimization
• Low-phosphate diet education
• Regular exercise for bone health
• Stress management to prevent symptom exacerbation
• Medical alert identification

When to See a Doctor

Seek immediate medical attention for:

• Seizures or convulsions
• Severe muscle cramps or tetany
• Difficulty breathing due to laryngospasm
• Chest pain or irregular heartbeat
• Confusion or altered mental status
• Severe leg pain or muscle weakness

Schedule an appointment if experiencing:

• Persistent muscle cramps or twitching
• Tingling around mouth or in fingers/toes
• Unexplained fatigue or weakness
• Growth delays in children
• Recurrent knee pain or joint problems
• Family history of PHP or similar conditions

Regular monitoring needed for:

• Known PHP patients (every 3-6 months)
• Medication adjustments
• Pregnancy planning or management
• Pre-surgical evaluation
• Growth and development concerns

Related Conditions

• Hypoparathyroidism
• Vitamin D Deficiency
• Chronic Kidney Disease
• Hypothyroidism
• Osteomalacia
• Rickets
• Multiple Endocrine Neoplasia

References

1. Mantovani G, Bastepe M, Monk D, et al. Diagnosis and management of pseudohypoparathyroidism and related disorders: first international Consensus Statement. Nat Rev Endocrinol. 2018;14(8):476-500.
2. Hanna P, Grybek V, Perez de Nanclares G, et al. Genetic and Epigenetic Defects at the GNAS Locus Lead to Distinct Patterns of Skeletal Growth but Similar Early-Onset Obesity. J Bone Miner Res. 2018;33(8):1480-1488.
3. Underbjerg L, Sikjaer T, Mosekilde L, Rejnmark L. Pseudohypoparathyroidism - epidemiology, mortality and risk of complications. Clin Endocrinol (Oxf). 2016;84(6):904-911.
4. Thiele S, Mantovani G, Barlier A, et al. From pseudohypoparathyroidism to inactivating PTH/PTHrP signalling disorder (iPPSD), a novel classification proposed by the European EuroPHP network. Eur J Endocrinol. 2016;175(6):P1-P17.
5. Elli FM, Linglart A, Garin I, et al. The Prevalence of GNAS Deficiency-Related Diseases in a Large Cohort of Patients Characterized by the EuroPHP Network. J Clin Endocrinol Metab. 2016;101(10):3657-3668.