Pseudohypoparathyroidism in Children

Pseudo-Hypoparathyroidism Introduction Etiology Clinical Presentation Diagnosis Treatment Complications Prognosis

Introduction to Pseudohypoparathyroidism in Children

Pseudohypoparathyroidism (PHP) is a rare, heterogeneous group of disorders characterized by end-organ resistance to parathyroid hormone (PTH). This results in hypocalcemia, hyperphosphatemia, and elevated PTH levels, mimicking hypoparathyroidism despite normal or elevated PTH production.

PHP is primarily caused by genetic defects affecting the GNAS gene complex, which encodes the alpha subunit of the stimulatory G protein (Gsα). This protein is crucial for PTH signal transduction in target tissues, particularly the kidneys and bones.

The incidence of PHP is estimated to be around 0.79 per 100,000 births.

PHP is classified into several subtypes:

• Type 1a (PHP1A): Classic form with Albright Hereditary Osteodystrophy (AHO) phenotype
• Type 1b (PHP1B): PTH resistance without AHO features
• Type 1c (PHP1C): Similar to PHP1A but with normal Gsα activity
• Type 2 (PHP2): Rare form with normal cAMP generation but impaired phosphaturic response to PTH
• Pseudopseudohypoparathyroidism (PPHP): AHO features without hormonal resistance

Understanding the specific subtype is crucial for appropriate management and genetic counseling.

Etiology of Pediatric Pseudohypoparathyroidism

The etiology of pseudohypoparathyroidism is primarily genetic, with various mutations affecting the GNAS gene complex:

1. Genetic Causes:

• PHP1A:
  • Heterozygous inactivating mutations in the maternal GNAS gene
  • Leads to reduced Gsα protein expression and function
• PHP1B:
  • Epigenetic alterations (mostly methylation defects) in the GNAS locus
  • Can be sporadic or familial (autosomal dominant)
• PHP1C:
  • Specific mutations in GNAS affecting receptor coupling but not Gsα activity
• PHP2:
  • Exact genetic cause often unclear
  • May represent a variant of PHP1B in some cases
• PPHP:
  • Paternal inheritance of GNAS mutations (as opposed to maternal in PHP1A)

2. Inheritance Patterns:

• PHP1A and PHP1C: Autosomal dominant, maternal transmission
• PHP1B: Sporadic or autosomal dominant
• PPHP: Autosomal dominant, paternal transmission

3. Imprinting Effects:

The GNAS locus is subject to genomic imprinting, leading to parent-of-origin effects on phenotype expression. This explains why maternal transmission leads to hormone resistance (PHP1A), while paternal transmission results in PPHP.

Understanding the genetic basis is crucial for accurate diagnosis, prediction of associated features, and genetic counseling for affected families.

Clinical Presentation

The clinical presentation of pseudohypoparathyroidism in children can vary widely depending on the subtype and age of onset. Key features include:

1. Common Features Across Subtypes:

• Hypocalcemia: Ranging from asymptomatic to severe symptoms
• Hyperphosphatemia
• Elevated PTH levels
• Normal or low 1,25-dihydroxyvitamin D levels

2. Subtype-Specific Features:

• PHP1A and PHP1C (with Albright Hereditary Osteodystrophy):
  • Short stature
  • Obesity
  • Round facies
  • Brachydactyly (especially 4th and 5th metacarpals)
  • Subcutaneous ossifications
  • Developmental delay or cognitive impairment
  • Resistance to other hormones (TSH, GHRH, gonadotropins)
• PHP1B:
  • Typically no AHO features
  • PTH resistance may be isolated or associated with mild TSH resistance
• PHP2:
  • Similar to PHP1B, but with normal cAMP response to PTH
• PPHP:
  • AHO features without hormonal resistance
  • Normal calcium, phosphate, and PTH levels

3. Symptoms of Hypocalcemia:

• Neuromuscular irritability (tetany, muscle cramps)
• Paresthesias
• Seizures
• Laryngospasm
• Cognitive symptoms (irritability, confusion)

4. Additional Endocrine Manifestations:

• Hypothyroidism (due to TSH resistance)
• Growth hormone deficiency
• Hypogonadism

The age of onset and severity of symptoms can vary significantly, with some children diagnosed in infancy due to hypocalcemic seizures, while others may be identified later in childhood or adolescence during evaluation for short stature or other AHO features.

Diagnosis of Pediatric Pseudohypoparathyroidism

Diagnosis of pseudohypoparathyroidism involves a combination of clinical assessment, biochemical testing, radiological evaluation, and genetic analysis:

1. Laboratory Tests:

• Serum calcium: Low
• Serum phosphate: Elevated
• Parathyroid hormone (PTH): Elevated
• 25-hydroxyvitamin D: Normal
• 1,25-dihydroxyvitamin D: Low or inappropriately normal
• Serum magnesium: Normal
• Thyroid function tests (TSH, free T4)
• Urinary cAMP and phosphate excretion in response to exogenous PTH (Ellsworth-Howard test)

2. Radiological Evaluation:

• Hand X-rays: To assess for brachydactyly and bone age
• Skull X-ray: For basal ganglia calcifications
• Renal ultrasound: To check for nephrocalcinosis
• Bone densitometry (DXA scan): To assess bone mineral density

3. Genetic Testing:

• GNAS gene sequencing and deletion/duplication analysis
• Methylation analysis of the GNAS locus
• STX16 gene testing (for some familial PHP1B cases)

4. Additional Assessments:

• Neuropsychological evaluation: For developmental delay or cognitive impairment
• Endocrine evaluations: Growth hormone stimulation test, gonadotropin levels
• Ophthalmological examination: For cataracts

5. Diagnostic Criteria:

Diagnosis is typically based on:

• Presence of hypocalcemia and hyperphosphatemia
• Elevated PTH levels
• Evidence of PTH resistance (e.g., blunted phosphaturic response to PTH)
• Presence of AHO features (for PHP1A and PHP1C)
• Genetic or epigenetic alterations in the GNAS locus

Differential diagnosis should include other causes of hypocalcemia, such as vitamin D deficiency, hypoparathyroidism, and calcium-sensing receptor mutations.

Treatment of Pediatric Pseudohypoparathyroidism

Treatment of pseudohypoparathyroidism in children aims to normalize serum calcium and phosphate levels, manage associated endocrine abnormalities, and address complications. The approach includes:

1. Management of Hypocalcemia:

• Calcium supplementation:
  • Oral calcium salts (e.g., calcium carbonate, calcium citrate)
  • Dose: 30-50 mg/kg/day of elemental calcium, divided into 2-4 doses
• Active vitamin D analogs:
  • Calcitriol (1,25-dihydroxyvitamin D3): 20-60 ng/kg/day in 2-3 divided doses
  • Alfacalcidol (1α-hydroxyvitamin D3): Alternative in some countries
• Goal: Maintain serum calcium in the low-normal range and reduce PTH levels

2. Management of Hyperphosphatemia:

• Dietary phosphate restriction
• Phosphate binders (in some cases)

3. Treatment of Associated Endocrinopathies:

• Levothyroxine for hypothyroidism
• Growth hormone therapy for growth hormone deficiency
• Sex hormone replacement for hypogonadism

4. Management of AHO Features:

• Multidisciplinary approach involving endocrinology, orthopedics, and developmental specialists
• Physical therapy and occupational therapy as needed
• Obesity management: Dietary counseling and lifestyle interventions

5. Monitoring and Dose Adjustments:

• Regular monitoring of serum calcium, phosphate, PTH, and urinary calcium excretion
• Adjust doses to maintain serum calcium in the low-normal range and reduce PTH levels
• Monitor for complications (e.g., nephrocalcinosis, cataracts)

6. Genetic Counseling:

• Provide information about inheritance patterns and recurrence risks
• Discuss implications for family planning

7. Supportive Care:

• Educational support for children with developmental delays
• Psychological support for patients and families

Treatment should be individualized based on the specific subtype of PHP, severity of symptoms, and associated features. Close collaboration between pediatric endocrinologists and other specialists is crucial for optimal management.

Complications of Pediatric Pseudohypoparathyroidism

Pseudohypoparathyroidism can lead to various complications, both due to the underlying disorder and its treatment:

1. Hypocalcemia-Related Complications:

• Seizures
• Laryngospasm
• Cardiac arrhythmias
• Cognitive impairment
• Basal ganglia calcifications

2. Hyperphosphatemia-Related Complications:

• Soft tissue calcifications
• Vascular calcifications

3. Skeletal Complications:

• Reduced bone mineral density
• Increased fracture risk
• Skeletal deformities (related to AHO features)

4. Renal Complications:

• Nephrocalcinosis
• Nephrolithiasis
• Chronic kidney disease

5. Endocrine Complications:

• Growth retardation
• Hypothyroidism
• Hypogonadism
• Obesity and metabolic syndrome

6. Neurological and Developmental Complications:

• Developmental delay
• Cognitive impairment
• Seizure disorders

7. Ocular Complications:

• Cataracts
• Optic nerve edema (rare)

8. Dental Complications:

• Enamel hypoplasia
• Delayed tooth eruption
• Increased risk of dental caries

9. Psychological Complications:

• Depression and anxiety
• Low self-esteem (related to physical features of AHO)
• Social adjustment difficulties

10. Treatment-Related Complications:

• Hypercalciuria (due to calcium and vitamin D supplementation)
• Iatrogenic hypercalcemia
• Gastrointestinal side effects from calcium supplements

Early recognition and appropriate management of these complications are crucial for optimizing long-term outcomes in children with pseudohypoparathyroidism. Regular multidisciplinary follow-up is essential to monitor for and address these potential complications.

Prognosis of Pediatric Pseudohypoparathyroidism

The prognosis for children with pseudohypoparathyroidism varies depending on the subtype, severity of symptoms, associated features, and quality of management. Here are key aspects of prognosis:

1. Overall Prognosis:

• With appropriate treatment, most patients can achieve a good quality of life
• Life expectancy is generally normal, but can be affected by associated complications
• Long-term management is required throughout life

2. Factors Affecting Prognosis:

• Subtype of PHP:
  • PHP1A and PHP1C may have more complex management due to multiple hormone resistances
  • PHP1B typically has a more focused management of calcium homeostasis
• Age at diagnosis and initiation of treatment:
  • Early diagnosis and treatment generally lead to better outcomes
  • Delayed diagnosis may result in more severe complications
• Adherence to treatment:
  • Consistent adherence to calcium and vitamin D supplementation is crucial
  • Regular follow-up and monitoring improve long-term outcomes
• Severity of AHO features (in relevant subtypes):
  • Can impact physical abilities and psychosocial well-being

3. Long-term Outcomes:

• Growth and Development:
  • Final adult height may be reduced, especially in PHP1A
  • Cognitive outcomes vary, with some patients experiencing mild to moderate intellectual disability
• Bone Health:
  • Risk of reduced bone mineral density persists
  • Fracture risk may be elevated throughout life
• Renal Function:
  • Long-term risk of nephrocalcinosis and chronic kidney disease necessitates ongoing renal monitoring
• Endocrine Function:
  • Ongoing management of multiple endocrine abnormalities may be necessary
  • Fertility may be affected in some patients
• Metabolic Health:
  • Increased risk of obesity and metabolic syndrome

4. Quality of Life:

• Many patients achieve good quality of life with appropriate management
• Psychosocial support may be beneficial, especially for those with AHO features
• Educational and vocational achievements can be variable

5. Transition to Adult Care:

• Successful transition to adult endocrine care is crucial for long-term management
• Patient education about self-management is important during adolescence

In summary, while pseudohypoparathyroidism is a lifelong condition requiring ongoing management, many affected individuals can achieve good outcomes with appropriate care. Regular monitoring, adherence to treatment, and a multidisciplinary approach are key to optimizing long-term prognosis and quality of life. Advances in genetic understanding and potential future therapies may further improve outcomes for these patients.

External Resources

• GeneReviews: Pseudohypoparathyroidism - Comprehensive review of genetic aspects and clinical management
• Diagnosis and Management of Pseudohypoparathyroidism and Related Disorders: First International Consensus Statement - Consensus guidelines from international experts
• Endocrine Society Clinical Practice Guidelines for Pseudohypoparathyroidism - Clinical practice recommendations
• Orphanet: Pseudohypoparathyroidism - Information portal for rare diseases, including pseudohypoparathyroidism