Hypoparathyroidism in Children

Hypo-Parathyroidism Introduction Etiology Clinical Presentation Diagnosis Treatment Complications Prognosis

Introduction to Hypoparathyroidism in Children

Hypoparathyroidism is a rare endocrine disorder characterized by inadequate production or secretion of parathyroid hormone (PTH) from the parathyroid glands. This results in low serum calcium levels, elevated phosphate levels, and various clinical manifestations.

In children, hypoparathyroidism presents unique challenges due to its impact on growth, development, and long-term health outcomes. The incidence of hypoparathyroidism in the pediatric population is estimated to be around 2-3 per 100,000 person-years.

Hypoparathyroidism can be classified as:

• Primary: Due to intrinsic parathyroid gland dysfunction
• Secondary: Resulting from low magnesium levels or activating calcium-sensing receptor mutations
• Pseudohypoparathyroidism: End-organ resistance to PTH action

Understanding the underlying cause and managing the condition effectively is crucial for optimizing growth, development, and quality of life in affected children.

Etiology of Pediatric Hypoparathyroidism

The causes of hypoparathyroidism in children are diverse and can be congenital or acquired:

1. Congenital Causes:

• Genetic disorders:
  • DiGeorge syndrome (22q11.2 deletion syndrome)
  • Autoimmune polyglandular syndrome type 1 (APS-1)
  • Familial isolated hypoparathyroidism
  • HDR syndrome (Hypoparathyroidism, Deafness, Renal dysplasia)
  • Mitochondrial disorders (e.g., Kearns-Sayre syndrome)
• Congenital absence or hypoplasia of parathyroid glands

2. Acquired Causes:

• Surgical removal of parathyroid glands (e.g., during thyroidectomy or neck dissection)
• Autoimmune destruction of parathyroid glands
• Radiation-induced damage to parathyroid glands
• Infiltrative disorders (e.g., Wilson's disease, hemochromatosis)

3. Functional Hypoparathyroidism:

• Severe magnesium deficiency
• Activating mutations in the calcium-sensing receptor (CaSR) gene

4. Pseudohypoparathyroidism:

• Type 1a (Albright hereditary osteodystrophy)
• Type 1b
• Type 2

Identifying the underlying cause is crucial for appropriate management and genetic counseling when applicable.

Clinical Presentation

The clinical presentation of hypoparathyroidism in children can vary widely, depending on the severity of hypocalcemia and the age of onset. Symptoms may include:

1. Neuromuscular Symptoms:

• Muscle cramps and spasms
• Paresthesias (tingling sensations) in extremities and perioral area
• Tetany
• Seizures (particularly in neonates)
• Laryngospasm (stridor)

2. Cognitive and Behavioral Changes:

• Irritability
• Confusion
• Depression
• Anxiety

3. Cardiovascular Manifestations:

• Prolonged QT interval on ECG
• Arrhythmias
• Cardiomyopathy (in chronic cases)

4. Skeletal Manifestations:

• Reduced bone mineralization
• Increased risk of fractures
• Dental abnormalities (enamel hypoplasia, delayed tooth eruption)

5. Ocular Manifestations:

• Cataracts (in chronic hypoparathyroidism)
• Papilledema

6. Growth and Development:

• Growth retardation
• Delayed puberty

Physical examination may reveal:

• Positive Chvostek's sign (facial muscle twitching when tapping the facial nerve)
• Positive Trousseau's sign (carpopedal spasm induced by inflating a blood pressure cuff)
• Features of associated syndromes (e.g., facial dysmorphism in DiGeorge syndrome)

It's important to note that the presentation can be subtle, especially in cases of chronic, mild hypocalcemia. A high index of suspicion is needed for timely diagnosis.

Diagnosis of Pediatric Hypoparathyroidism

Diagnosis of hypoparathyroidism in children involves a combination of clinical assessment, laboratory tests, and sometimes genetic analysis:

1. Laboratory Tests:

• Serum calcium: Low total and ionized calcium
• Serum phosphate: Elevated
• Parathyroid hormone (PTH): Low or inappropriately normal
• 25-hydroxyvitamin D: To rule out vitamin D deficiency
• Serum magnesium: To exclude hypomagnesemia
• Urinary calcium excretion: Often low
• Serum albumin: For calculating corrected calcium

2. Additional Tests:

• ECG: To assess for prolonged QT interval
• Bone age X-ray: To evaluate skeletal maturation
• Dual-energy X-ray absorptiometry (DXA): To assess bone mineral density
• Brain CT or MRI: If intracranial calcifications are suspected
• Ophthalmological examination: To check for cataracts

3. Genetic Testing:

Consider genetic testing for:

• 22q11.2 deletion (DiGeorge syndrome)
• AIRE gene mutations (APS-1)
• PTH gene mutations
• GATA3 gene mutations (HDR syndrome)
• CaSR gene mutations
• GNAS gene mutations (pseudohypoparathyroidism)

4. Diagnostic Criteria:

Diagnosis is typically based on the triad of:

• Low serum calcium
• High serum phosphate
• Low or inappropriately normal PTH levels

Differential diagnosis should include other causes of hypocalcemia, such as vitamin D deficiency, chronic kidney disease, and pseudohypoparathyroidism.

Treatment of Pediatric Hypoparathyroidism

The treatment of hypoparathyroidism in children aims to normalize serum calcium levels, manage symptoms, and prevent complications. The approach includes:

1. Acute Management of Severe Hypocalcemia:

• Intravenous calcium gluconate: For symptomatic hypocalcemia or severe hypocalcemia
• Close monitoring of serum calcium levels
• ECG monitoring during calcium administration

2. Chronic Management:

• Oral Calcium Supplementation:
  • Elemental calcium: 30-50 mg/kg/day divided into 3-4 doses
  • Various calcium salts can be used (carbonate, citrate)
• 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
• Thiazide Diuretics:
  • To reduce urinary calcium excretion
  • Hydrochlorothiazide: 1-2 mg/kg/day
• Magnesium Supplementation:
  • If hypomagnesemia is present
• Low Phosphate Diet:
  • To help manage hyperphosphatemia

3. Monitoring and Dose Adjustments:

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

4. Emerging Therapies:

• Recombinant human PTH (1-84): Approved for adults, under investigation for pediatric use
• PTH analogs: Potential future treatments

5. Management of Underlying Causes:

• Treatment of associated conditions in syndromic cases
• Genetic counseling for familial cases

Treatment should be individualized based on the child's age, severity of hypocalcemia, and underlying cause. Close collaboration between pediatric endocrinologists, nephrologists, and other specialists is often necessary for optimal management.

Complications of Pediatric Hypoparathyroidism

Untreated or poorly managed hypoparathyroidism in children can lead to several complications:

1. Acute Complications:

• Seizures
• Laryngospasm
• Cardiac arrhythmias
• Tetany

2. Chronic Complications:

• Neurological:
  • Basal ganglia calcifications
  • Cognitive impairment
  • Extrapyramidal disorders
• Renal:
  • Nephrocalcinosis
  • Nephrolithiasis
  • Chronic kidney disease
• Skeletal:
  • Reduced bone mineral density
  • Increased fracture risk
  • Dental abnormalities
• Ocular:
  • Cataracts
  • Calcifications of the lens and cornea
• Cardiovascular:
  • Prolonged QT interval
  • Cardiomyopathy
• Growth and Development:
  • Growth retardation
  • Delayed puberty
• Psychological:
  • Depression
  • Anxiety
  • Cognitive dysfunction

3. Treatment-Related Complications:

• Hypercalciuria (due to calcium and vitamin D supplementation)
• Nephrocalcinosis
• Hyperphosphatemia
• Soft tissue calcifications

Regular monitoring and appropriate management are crucial to prevent these complications and ensure optimal growth and development in affected children.

Prognosis of Pediatric Hypoparathyroidism

The prognosis for children with hypoparathyroidism depends on several factors, including the underlying cause, age at diagnosis, severity of hypocalcemia, and adequacy of treatment:

1. Overall Prognosis:

• With proper management, most children with hypoparathyroidism can lead relatively normal lives
• Early diagnosis and treatment are crucial for preventing complications and ensuring normal growth and development
• Life-long treatment and monitoring are typically required
• Quality of life can be significantly impacted, particularly in cases of poor control or late diagnosis

2. Factors Affecting Prognosis:

• Etiology:
  • Genetic causes may have associated comorbidities affecting overall prognosis
  • Acquired causes (e.g., post-surgical) may have a more predictable course
• Age at diagnosis:
  • Early diagnosis and treatment generally lead to better outcomes
  • Neonatal hypocalcemia can have significant neurological consequences if not promptly treated
• Adherence to treatment:
  • Consistent medication adherence is crucial for maintaining stable calcium levels
  • Poor adherence can lead to recurrent symptoms and complications
• Severity of hypocalcemia:
  • Severe or prolonged hypocalcemia episodes may lead to long-term complications

3. Long-term Outcomes:

• Growth and Development:
  • With adequate treatment, normal growth can often be achieved
  • Some children may experience mild developmental delays
• Bone Health:
  • Risk of reduced bone mineral density persists despite treatment
  • Regular monitoring and appropriate management can minimize fracture risk
• Renal Function:
  • Long-term risk of nephrocalcinosis and chronic kidney disease necessitates ongoing renal monitoring
• Neurological Outcomes:
  • Risk of basal ganglia calcifications increases with duration of disease
  • Cognitive function is generally preserved with adequate treatment
• Endocrine Function:
  • Some patients may develop other endocrine abnormalities, especially in cases of autoimmune polyendocrine syndromes

4. Transition to Adult Care:

• Successful transition to adult endocrine care is crucial for long-term management
• Education about the condition and self-management skills should be emphasized during adolescence
• Ongoing monitoring for long-term complications is necessary throughout adulthood

5. Future Perspectives:

• Emerging therapies, such as PTH replacement, may improve long-term outcomes and quality of life
• Advances in genetic testing and personalized medicine may allow for more targeted treatments in the future

In summary, while hypoparathyroidism in children is a chronic condition requiring lifelong management, many affected individuals can achieve good outcomes with appropriate treatment and follow-up. Regular monitoring, adherence to treatment, and a multidisciplinary approach to care are key to optimizing long-term prognosis and quality of life.

External Resources

• Hypoparathyroidism in Children: An Update - Comprehensive review article from the Journal of Clinical Research in Pediatric Endocrinology
• Treatment of Hypoparathyroidism: A 2020 SBE Consensus - Guidelines from the Brazilian Society of Endocrinology and Metabolism
• UpToDate: Hypoparathyroidism - Regularly updated clinical resource (subscription required)
• Endocrine Society Clinical Practice Guidelines for Hypoparathyroidism - Comprehensive guidelines for diagnosis and management