Clinical Case: Hypopituitarism in a 7-year-old boy

A 7-year-old boy, James, is brought to the pediatric endocrinology clinic by his parents due to concerns about his short stature and delayed development compared to his peers. His parents report the following:

• James has always been smaller than his classmates
• His growth has slowed significantly over the past two years
• He tires easily and often complains of feeling cold
• He has not shown signs of early puberty unlike some of his friends

Physical examination reveals:

• Height: 110 cm (<3rd percentile for age)
• Weight: 20 kg (<3rd percentile for age)
• Delayed dentition
• Childish facies with apparent central adiposity
• Tanner stage 1 for both genital development and pubic hair

Initial laboratory findings:

• Low IGF-1 levels
• Low free T4 with inappropriately normal TSH
• Low morning cortisol

MRI of the brain reveals a small anterior pituitary gland with an absent pituitary stalk and an ectopic posterior pituitary bright spot.

Based on these findings, James is diagnosed with multiple pituitary hormone deficiencies (MPHD) due to congenital hypopituitarism. He is started on hormone replacement therapy including growth hormone, levothyroxine, and hydrocortisone. His parents are counseled about the long-term management and the need for close monitoring of his growth and development.

Varieties of Clinical Presentations of Hypopituitarism in Children

1. Growth Failure and Short Stature

   Characterized by decreased growth velocity, short stature compared to genetic potential, and delayed bone age.

2. Neonatal Hypoglycemia and Prolonged Jaundice

   Severe hypoglycemia in the neonatal period, often accompanied by prolonged unconjugated hyperbilirubinemia due to cortisol and thyroid hormone deficiencies.

3. Delayed Puberty or Hypogonadism

   Lack of pubertal development by age 13 in girls or 14 in boys, or arrest of pubertal progression once initiated.

4. Central Hypothyroidism

   Symptoms of hypothyroidism including fatigue, cold intolerance, constipation, and dry skin, but with low free T4 and inappropriately normal or low TSH.

5. Central Adrenal Insufficiency

   Fatigue, weakness, poor stress response, hypoglycemia, and electrolyte imbalances due to ACTH deficiency.

6. Diabetes Insipidus

   Polyuria and polydipsia due to vasopressin deficiency, often seen in cases involving the posterior pituitary.

7. Midline Defects

   Cleft lip/palate, single central incisor, or optic nerve hypoplasia, often associated with septo-optic dysplasia.

8. Recurrent Hypoglycemia

   Due to growth hormone and cortisol deficiencies, leading to poor fasting tolerance and increased risk during illnesses.

9. Failure to Thrive in Infancy

   Poor weight gain and developmental delays in early infancy, often with feeding difficulties.

10. Visual Disturbances

    Visual field defects or decreased visual acuity due to optic nerve involvement or pituitary tumors compressing the optic chiasm.

Viva Questions and Answers on Hypopituitarism in Children

1. Q: What is hypopituitarism?

   A: Hypopituitarism is a condition characterized by decreased secretion of one or more pituitary hormones due to pituitary or hypothalamic dysfunction.

2. Q: List the major hormones produced by the anterior pituitary gland.

   A: The major hormones produced by the anterior pituitary are: Growth Hormone (GH), Adrenocorticotropic Hormone (ACTH), Thyroid-Stimulating Hormone (TSH), Follicle-Stimulating Hormone (FSH), Luteinizing Hormone (LH), and Prolactin.

3. Q: What is the most common presenting feature of hypopituitarism in children?

   A: The most common presenting feature of hypopituitarism in children is growth failure or short stature due to growth hormone deficiency.

4. Q: How does congenital hypopituitarism differ from acquired hypopituitarism in terms of clinical presentation?

   A: Congenital hypopituitarism often presents with neonatal symptoms such as hypoglycemia, prolonged jaundice, and micropenis in males. It may also be associated with midline defects. Acquired hypopituitarism typically presents later with growth failure, pubertal delay, or symptoms related to specific hormone deficiencies.

5. Q: What are the common causes of congenital hypopituitarism?

   A: Common causes of congenital hypopituitarism include genetic mutations (e.g., PROP1, POU1F1, HESX1), midline defects like septo-optic dysplasia, pituitary aplasia or hypoplasia, and congenital pituitary stalk interruption syndrome.

6. Q: How would you diagnose growth hormone deficiency in a child?

   A: Diagnosis of growth hormone deficiency involves: 1. Clinical assessment of growth (height, weight, growth velocity) 2. Bone age X-ray 3. Measurement of IGF-1 and IGFBP-3 levels 4. Growth hormone stimulation tests (e.g., insulin tolerance test, glucagon stimulation test) 5. MRI of the hypothalamic-pituitary region

7. Q: What is the significance of delayed bone age in hypopituitarism?

   A: Delayed bone age is a hallmark of hypopituitarism, particularly growth hormone deficiency. It indicates delayed skeletal maturation and can help in predicting potential for catch-up growth with treatment.

8. Q: How does central hypothyroidism differ from primary hypothyroidism in terms of laboratory findings?

   A: In central hypothyroidism, free T4 is low but TSH is inappropriately normal or low. In primary hypothyroidism, free T4 is low and TSH is elevated.

9. Q: What is the treatment for multiple pituitary hormone deficiency (MPHD) in children?

   A: Treatment for MPHD involves hormone replacement therapy: 1. Growth hormone injections 2. Levothyroxine for central hypothyroidism 3. Hydrocortisone for adrenal insufficiency 4. Sex hormone replacement at appropriate age for hypogonadism 5. Desmopressin for diabetes insipidus, if present

10. Q: What is septo-optic dysplasia and how is it related to hypopituitarism?

    A: Septo-optic dysplasia is a congenital disorder characterized by optic nerve hypoplasia, midline brain defects, and pituitary hypoplasia. It is a common cause of congenital hypopituitarism, often presenting with multiple hormone deficiencies.

11. Q: How would you manage a neonate suspected of having congenital hypopituitarism?

    A: Management of a neonate with suspected congenital hypopituitarism includes: 1. Immediate treatment of hypoglycemia 2. Evaluation of all pituitary hormone axes 3. Initiation of hydrocortisone replacement 4. Thyroid hormone replacement if central hypothyroidism is confirmed 5. Consideration of growth hormone therapy after the neonatal period 6. MRI of the brain to evaluate pituitary anatomy 7. Genetic testing as appropriate

12. Q: What are the potential long-term consequences of untreated hypopituitarism in children?

    A: Long-term consequences may include: 1. Severe short stature 2. Delayed or absent puberty 3. Osteoporosis 4. Increased cardiovascular risk 5. Cognitive and developmental delays 6. Adrenal crisis (if ACTH deficient) 7. Infertility

13. Q: How does hypopituitarism affect pubertal development?

    A: Hypopituitarism can cause delayed or absent puberty due to gonadotropin (FSH and LH) deficiency. This results in lack of secondary sexual characteristics, delayed growth spurt, and potential infertility if untreated.

14. Q: What is the role of MRI in the evaluation of hypopituitarism?

    A: MRI is crucial in evaluating hypopituitarism to: 1. Assess pituitary size and structure 2. Identify congenital anomalies (e.g., pituitary stalk interruption) 3. Detect tumors or other lesions 4. Evaluate the hypothalamus and surrounding structures 5. Look for associated midline defects

15. Q: How do you monitor the effectiveness of growth hormone therapy in children?

    A: Monitoring of growth hormone therapy includes: 1. Regular height and weight measurements 2. Calculation of growth velocity 3. Periodic bone age X-rays 4. IGF-1 level measurements 5. Assessment of pubertal development 6. Monitoring for potential side effects

16. Q: What is panhypopituitarism and how does it differ from partial hypopituitarism?

    A: Panhypopituitarism refers to deficiency of all or most pituitary hormones. Partial hypopituitarism involves deficiency of one or more, but not all, pituitary hormones. Panhypopituitarism typically requires more comprehensive hormone replacement and may have a more severe clinical presentation.

17. Q: How does central adrenal insufficiency differ from primary adrenal insufficiency in terms of management?

    A: In central adrenal insufficiency: 1. Only glucocorticoid replacement is needed (hydrocortisone) 2. Mineralocorticoid replacement is not required 3. Lower doses of hydrocortisone are typically sufficient 4. ACTH levels are low or inappropriately normal In primary adrenal insufficiency, both glucocorticoid and mineralocorticoid replacement are usually necessary, and ACTH levels are high.

18. Q: What is the significance of hyperprolactinemia in a child with suspected hypopituitarism?

    A: Hyperprolactinemia in the context of hypopituitarism may indicate: 1. A prolactin-secreting pituitary adenoma 2. Pituitary stalk compression (interrupting dopamine inhibition) 3. Hypothalamic dysfunction It's important to evaluate further with MRI and to consider the impact on other pituitary functions, particularly gonadotropins.

19. Q: How would you manage a child with hypopituitarism during an acute illness or surgery?

    A: Management during acute illness or surgery includes: 1. Increasing hydrocortisone dose (typically 2-3 times maintenance) 2. Administering hydrocortisone parenterally if oral intake is compromised 3. Monitoring fluid and electrolyte balance closely 4. Adjusting other hormone replacements as needed 5. Educating parents and patients about stress dosing of hydrocortisone

20. Q: What genetic tests would you consider in a child with congenital hypopituitarism?

    A: Genetic tests to consider include: 1. PROP1 gene mutations (most common cause of MPHD) 2. POU1F1 (PIT1) gene mutations 3. HESX1 gene mutations (associated with septo-optic dysplasia) 4. LHX3 and LHX4 gene mutations 5. GH1 and GHRHR mutations for isolated GH deficiency 6. Whole exome sequencing in complex cases

21. Q: How does hypopituitarism affect bone health in children?

    A: Hypopituitarism can negatively impact bone health due to: 1. Growth hormone deficiency reducing bone formation 2. Gonadotropin deficiency leading to lack of sex steroids essential for bone mineralization 3. Central hypothyroidism affecting bone turnover 4. Potential overtreatment with glucocorticoids These factors can lead to reduced bone mineral density and increased fracture risk.

22. Q: What is the approach to diagnosing diabetes insipidus in a child with hypopituitarism?

    A: Diagnosis of diabetes insipidus involves: 1. Assessment of fluid intake and urine output 2. Measurement of serum and urine osmolality 3. Water deprivation test (if necessary) 4. Assessment of response to desmopressin 5. MRI to evaluate posterior pituitary bright spot and pituitary stalk 6. Differentiation between central and nephrogenic diabetes insipidus

23. Q: How does the treatment of growth hormone deficiency differ in a child with a history of malignancy?

    A: In a child with a history of malignancy: 1. Growth hormone therapy is typically delayed for 2 years after completion of cancer treatment 2. Close monitoring for tumor recurrence is essential 3. The decision to start GH should involve an oncologist 4. Lower doses of GH may be considered initially 5. Increased vigilance for secondary malignancies is necessary 6. The risk-benefit ratio should be carefully discussed with the family

24. Q: What are the potential side effects of growth hormone therapy in children?

    A: Potential side effects include: 1. Benign intracranial hypertension (pseudotumor cerebri) 2. Slipped capital femoral epiphysis 3. Scoliosis progression 4. Edema 5. Arthralgia and myalgia 6. Insulin resistance and impaired glucose tolerance 7. Pancreatitis (rare) 8. Potential increased risk of secondary neoplasms in cancer survivors (controversial)

25. Q: How would you approach the transition of care for an adolescent with hypopituitarism to adult endocrinology services?

    A: Transition of care should involve: 1. Gradual introduction to adult services starting in early adolescence 2. Education about the condition and self-management 3. Assessment of understanding of hormone replacement needs 4. Discussion about fertility and long-term health implications 5. Ensuring continuity of hormone replacement 6. Addressing psychosocial aspects of chronic disease management 7. Coordinated transfer of medical records 8. Joint pediatric-adult clinic visits when possible

26. Q: What is the significance of an ectopic posterior pituitary bright spot on MRI?

    A: An ectopic posterior pituitary bright spot on MRI: 1. Is a hallmark of congenital hypopituitarism 2. Often associated with pituitary stalk interruption syndrome 3. Indicates abnormal embryological development of the pituitary gland 4. Is frequently associated with multiple pituitary hormone deficiencies 5. May be accompanied by anterior pituitary hypoplasia 6. Can help in differentiating congenital from acquired causes of hypopituitarism

27. Q: How does hypopituitarism affect growth velocity at different stages of childhood?

    A: The impact on growth velocity varies: 1. Infancy: May have normal growth due to nutrition-dependent growth 2. Early childhood: Growth velocity typically declines, leading to height deviations 3. Mid-childhood: Continued slow growth with increasing height deficit 4. Puberty: Absent pubertal growth spurt if untreated 5. The degree of growth impairment depends on the severity of GH deficiency and the presence of other hormone deficiencies

28. Q: What is the role of IGF-1 and IGFBP-3 measurements in diagnosing and monitoring growth hormone deficiency?

    A: IGF-1 and IGFBP-3 measurements: 1. Serve as surrogate markers for GH action 2. Are used in initial screening for GH deficiency 3. Help in monitoring compliance and adequacy of GH replacement 4. Are less invasive than GH stimulation tests 5. Must be interpreted in the context of age, pubertal stage, and nutritional status 6. May be low in conditions other than GH deficiency (e.g., malnutrition, hypothyroidism)

29. Q: How would you manage precocious puberty in a child with treated hypopituitarism?

    A: Management of precocious puberty in this context involves: 1. Confirming the diagnosis with hormonal tests and imaging 2. Investigating for potential causes (e.g., GH treatment effects, hydrocephalus) 3. Considering GnRH analog therapy to halt pubertal progression 4. Adjusting GH dosage if necessary 5. Monitoring growth velocity and bone age advancement 6. Balancing the goals of height optimization and age-appropriate pubertal development 7. Regular reassessment of the treatment plan

30. Q: What are the implications of PROP1 gene mutations in congenital hypopituitarism?

    A: PROP1 gene mutations: 1. Are the most common genetic cause of combined pituitary hormone deficiency 2. Typically result in deficiencies of GH, TSH, PRL, and gonadotropins 3. May lead to evolving ACTH deficiency over time 4. Can be associated with pituitary enlargement in childhood, which often resolves spontaneously 5. Usually present with growth failure and hypothyroidism in early childhood 6. Require lifelong monitoring for the development of additional hormone deficiencies