Overview
Definition:
Hypopituitarism is a rare endocrine disorder characterized by the deficiency of one or more pituitary hormones
In pediatrics, growth hormone (GH) deficiency leads to impaired growth, while ACTH deficiency results in adrenal insufficiency, a potentially life-threatening condition.
Epidemiology:
The prevalence of pediatric hypopituitarism is estimated to be around 1 in 3,000 to 1 in 10,000 live births
GH deficiency is the most common pituitary hormone deficiency, occurring in approximately 1 in 4,000 children
ACTH deficiency is less common but more acutely dangerous.
Clinical Significance:
Undiagnosed or inadequately managed hypopituitarism can lead to severe growth failure, metabolic disturbances, and life-threatening adrenal crisis
Early diagnosis and appropriate hormone replacement are crucial for normal development, growth, and overall well-being, directly impacting patient outcomes and resident preparedness for critical care scenarios.
Clinical Presentation
Symptoms:
Growth hormone deficiency symptoms: Short stature, significantly below the 3rd percentile
Slow growth velocity (less than 5 cm/year after age 2-3)
Proportional short stature is typical
ACTH deficiency symptoms: In infants, hypoglycemia, poor feeding, vomiting, lethargy, and failure to thrive
In older children, pallor, fatigue, weight loss, abdominal pain, and recurrent infections
Signs of adrenal crisis: Hypotension, shock, fever, confusion, or coma.
Signs:
Growth hormone deficiency signs: Proportional short stature
Younger appearance than chronological age
High-pitched voice
Central obesity may be present
ACTH deficiency signs: Pale or grayish skin
Hypotension
Bradycardia (relative to fever)
Signs of dehydration
Evidence of other pituitary hormone deficiencies (e.g., hypothyroidism, hypogonadism).
Diagnostic Criteria:
Diagnosis is based on clinical suspicion, confirmed by endocrine testing
Low IGF-1 and IGFBP-3 levels in children with short stature suggest GH deficiency
Provocative testing (e.g., insulin tolerance test, glucagon stimulation test, arginine-GHRH test) is required to confirm GH deficiency
ACTH deficiency is diagnosed by low cortisol levels and unresponsiveness to ACTH stimulation testing.
Diagnostic Approach
History Taking:
Detailed birth history (macrosomia, birth asphyxia, CNS malformations)
Developmental milestones
Growth pattern assessment (serial height/weight measurements)
History of head trauma, CNS infections, radiation, or surgery
Family history of endocrine disorders or short stature
Symptoms suggestive of adrenal insufficiency: recurrent vomiting, failure to thrive, recurrent infections, hypoglycemia.
Physical Examination:
Accurate measurement of height, weight, and head circumference
Calculation of BMI and plotting on growth charts
Assessment of growth velocity
Examination for dysmorphic features suggestive of congenital syndromes
Palpation for thyromegaly
Assessment of pubertal development
Evaluation for signs of dehydration, pallor, or hypotension.
Investigations:
Initial investigations: Complete blood count (CBC), electrolytes, blood urea nitrogen (BUN), creatinine, calcium, phosphate, glucose
Thyroid function tests (TSH, free T4)
Liver function tests
Insulin-like growth factor-1 (IGF-1) and IGF-binding protein-3 (IGFBP-3) levels
Provocative testing for GH deficiency (e.g., ITT, glucagon test, GHRH-arginine test), aiming for a peak GH < 10 ng/mL
ACTH stimulation test (e.g., cosyntropin stimulation test): Measure baseline cortisol and 30/60-minute cortisol after synthetic ACTH 1-24 administration
A peak cortisol < 18-20 mcg/dL (500-550 nmol/L) confirms adrenal insufficiency
Pituitary MRI: To identify structural abnormalities (tumors, cysts, congenital malformations) or absence of the pituitary gland.
Differential Diagnosis:
For short stature: Familial short stature, constitutional delay of growth and puberty, nutritional deficiencies, chronic illnesses (renal, cardiac, GI), skeletal dysplasias, hypothyroidism, Cushing’s syndrome, psychosocial dwarfism
For ACTH deficiency: Other causes of adrenal insufficiency (e.g., congenital adrenal hyperplasia, autoimmune adrenalitis), severe sepsis, dehydration, hypovolemic shock.
Management
Initial Management:
For adrenal crisis: Immediate intravenous fluid resuscitation with normal saline, intravenous hydrocortisone (100 mg/m² as bolus, then continuous infusion or repeated boluses), and correction of hypoglycemia with dextrose
Prompt transfer to ICU if unstable
Once stabilized, determine the etiology of hypopituitarism
For GH deficiency: Hormone replacement should only be initiated after other life-threatening deficiencies (especially ACTH) have been addressed.
Medical Management:
Growth hormone replacement: Recombinant human growth hormone (rhGH) administered subcutaneously, typically once daily
Dosing is usually 0.025-0.05 mg/kg/day (0.06-0.12 IU/kg/day), adjusted based on growth response and biochemical markers
Adrenal replacement: Hydrocortisone is the drug of choice for cortisol replacement in children
Dosing is typically 8-10 mg/m²/day, divided into 2-3 doses, with the largest dose in the morning
Stress dosing is crucial during illness or injury
Fludrocortisone may be needed if mineralocorticoid deficiency is present.
Surgical Management:
Surgical intervention is indicated for pituitary tumors (e.g., craniopharyngioma, adenoma) or other structural lesions causing hypopituitarism
Transsphenoidal surgery is the preferred approach for most pituitary adenomas
Craniopharyngiomas may require transfrontal or transsphenoidal approaches
Surgery aims to remove the tumor and decompress the optic pathways, but may also lead to further pituitary damage
Radiotherapy may be considered for residual tumor or unresectable lesions.
Supportive Care:
Regular monitoring of growth parameters, IGF-1 levels, and bone age
Close monitoring for signs of adrenal insufficiency, especially during illness
Education of parents and patient regarding stress dosing of hydrocortisone and emergency preparedness
Nutritional assessment and support
Psychosocial support for the child and family
Regular follow-up with pediatric endocrinology team.
Complications
Early Complications:
Adrenal crisis, which can be fatal if not recognized and treated promptly
Electrolyte imbalances (hyponatremia, hyperkalemia) due to ACTH deficiency
Severe hypoglycemia due to ACTH or GH deficiency
Severe dehydration.
Late Complications:
Failure to achieve adequate adult height despite GH replacement
Development of other pituitary hormone deficiencies (hypogonadism, hypothyroidism, diabetes insipidus) over time
Impaired bone density and increased fracture risk
Psychological issues related to short stature or chronic illness
Increased risk of cardiovascular disease in untreated GH deficiency
Complications related to pituitary surgery or radiotherapy (e.g., visual impairment, new hormone deficiencies, recurrence of tumor).
Prevention Strategies:
Strict adherence to hormone replacement therapy schedules
Thorough education of patients and families on stress dosing protocols for hydrocortisone and recognition of adrenal crisis symptoms
Regular medical follow-ups to monitor growth, hormone levels, and overall health
Prompt management of intercurrent illnesses
Screening for other pituitary hormone deficiencies
Careful surgical planning and post-operative care for pituitary tumors.
Prognosis
Factors Affecting Prognosis:
The underlying etiology of hypopituitarism
The extent of pituitary hormone deficiencies
The age at diagnosis and initiation of treatment
Adherence to treatment regimens
The presence and management of complications such as adrenal crisis
Success of surgical intervention for pituitary tumors.
Outcomes:
With appropriate GH replacement, children can achieve significant improvements in growth velocity and final adult height, though typically not reaching the mid-parental target height
Adequate glucocorticoid replacement is life-saving
Patients with isolated GH deficiency generally have a good prognosis for growth
Patients with multiple pituitary hormone deficiencies require lifelong hormone replacement and vigilant monitoring
Prognosis for pituitary tumors depends on the tumor type, size, and extent of resection.
Follow Up:
Lifelong follow-up with an endocrinologist is essential
GH replacement therapy is typically continued through adolescence and sometimes into adulthood if GH deficiency persists
Regular assessments of growth, puberty, bone health, and psychosocial adjustment
Monitoring for new pituitary hormone deficiencies and the potential recurrence of pituitary tumors
Education regarding the need for medical alert bracelets and carrying emergency hydrocortisone.
Key Points
Exam Focus:
Recognize the signs and symptoms of GH and ACTH deficiency in pediatric patients
Understand the indications and interpretation of provocative endocrine tests for GH and ACTH
Be proficient in the medical management of adrenal crisis and chronic adrenal insufficiency (stress dosing)
Grasp the principles of GH replacement therapy (dosing, monitoring)
Differentiate hypopituitarism from other causes of short stature and adrenal insufficiency.
Clinical Pearls:
Always rule out ACTH deficiency first in a child with suspected hypopituitarism, as it is a medical emergency
Infants with unexplained hypoglycemia, vomiting, and poor weight gain should be screened for adrenal insufficiency
Growth hormone therapy is indicated for confirmed GH deficiency with a growth failure
it is NOT for short stature of other etiologies without GH deficiency
Patients on hydrocortisone must be educated about stress dosing: double the dose for mild illness, triple for moderate, and IV hydrocortisone for severe illness/vomiting.
Common Mistakes:
Initiating GH therapy before ruling out and treating ACTH deficiency
Underestimating the severity of adrenal crisis or failing to initiate prompt treatment
Inadequate stress dosing of hydrocortisone during illness
Relying solely on IGF-1 levels without provocative testing for GH deficiency diagnosis
Failure to consider structural lesions (tumors) as a cause of hypopituitarism, especially in older children or those with other neurological signs.