5-Minute Pediatric Consult

Panhypopituitarism

Description

Deficiency of multiple pituitary hormones

Epidemiology

  • Congenital forms affect both sexes equally and are diagnosed at a young age.
  • The incidence of secondary forms depends on the underlying cause.

Basics Risk Factors Genetics
There are rare cases of autosomal recessive, autosomal dominant, and X-linked forms.

Pathophysiology

Pathology is based on specific deficiency:

  • Growth hormone (GH): Hypoglycemia in newborns and poor growth in other patients
  • Adrenocorticotropic hormone: Hypocortisolism
  • Thyroid-stimulating hormone (TSH): Hypothyroidism
  • Luteinizing hormone (LH)/follicle-stimulating hormone (FSH): Hypogonadism
  • Antidiuretic hormone: Diabetes insipidus
  • Prolactin: Hyperprolactinemia

Etiology

  • Idiopathic (some may be due to hypophysitis)
  • Congenital:
    • Absence of the pituitary (empty sella syndrome)
    • Genetic disorders due to mutations in genes or transcription factors
    • Pituitary malformations (ectopic posterior pituitary, hypoplastic infundibular stalk, hypoplastic pituitary)
    • Familial panhypopituitarism
  • Acquired:
    • Birth trauma or perinatal insult
    • Surgical resection of the gland or damage to the stalk
    • Traumatic brain injury
    • Hypophysitis
    • Child abuse
    • Iron deposition secondary to chronic transfusion therapy (e.g., β-thalassemia)
  • Infection:
    • Viral encephalitis
    • Bacterial or fungal infection
    • Tuberculosis
  • Vascular:
    • Pituitary infarction
    • Pituitary aneurysm
  • Cranial irradiation
  • Chemotherapy
  • Tumors:
    • Craniopharyngioma
    • Germinoma
    • Glioma
    • Pinealoma
    • Primitive neuroectodermal tumor (medulloblastoma)
  • Histiocytosis
  • Sarcoidosis

Associated Conditions

  • Midline defects (e.g., cleft lip/palate, hypotelorism, single central maxillary incisor)
  • Septo-optic dysplasia (de Morsier syndrome)
  • Holoprosencephaly

Signs and Symptoms

History

  • Birth history:
    • Documented or symptoms of hypoglycemia, which include poor feeding, lethargy, irritability, or seizures
    • Hypoglycemia may be secondary to hyperinsulinism (HI), but HI babies are typically large for gestational age.
    • Hypopituitary babies are not large.
    • Midline defects are associated with hypopituitarism and not HI.
  • Complications during pregnancy or delivery:
    • Birth trauma may be associated with pituitary injury.
    • Breech delivery or vacuum extraction has been associated.
  • Birth weight: Hypopituitary infants are usually normal or small for gestational age, in contrast to hyperinsulinemic infants, who are typically large.
  • History of surgeries and previous diseases: Congenital hypopituitarism is often associated with midline facial defects (e.g., single central incisor, bifid uvula, or cleft palate), which require repair.
  • Growth pattern: Plot previous heights and look for growth pattern. GH deficiency usually manifests as poor linear growth by the end of the first year of life.
  • Delayed puberty:
    • Children with delayed puberty show further growth failure in adolescence.
    • Sense of smell should be assessed to rule out Kallmann syndrome (isolated central hypogonadism and anosmia).
  • Increased thirst and urination: Children with hypothalamic disorders may present with symptoms of diabetes insipidus.
Special questions:
  • Complaints of headache: Headache can be a symptom of a brain tumor.
  • Focal neurologic symptoms are highly suggestive of CNS pathology.

Physical Exam
  • Height and weight:
    • Patients with panhypopituitarism have normal size in the newborn period.
    • Patients with HI are typically large for gestational age.
  • Prolonged conjugated hyperbilirubinemia:
    • May be 1st sign of hypothyroidism with or without hypopituitarism
    • Some state newborn screens will not detect central hypothyroidism.
    • Hypopituitarism can lead to neonatal cholestasis.
  • Micropenis in male newborns: Neonatal penis should be ≥2.5 cm in length; micropenis suggests gonadotropin and/or GH deficiency
Physical examination tricks:
  • Penile and testicular size: Measure stretched phallic length (from pubic ramus to glans) with patient lying supine and phallus at 90° to the body; use Prader beads to assess testicular volume.
  • Midline defects: Palpate for submucosal cleft palate, look for central incisor.
  • Visual field testing: Visual field defects suggest a brain tumor.

Tests

Laboratory

  • Liver function tests: Typically elevated liver enzymes in the newborn period
  • Thyroid function tests including free thyroxine (T4): TSH may be normal, but free T4 will be low.
  • Thyrotropin-releasing hormone stimulation test: Delayed, normal, or exaggerated TSH response is consistent with a hypothalamic lesion.
  • Serum insulinlike growth factor-I (IGF-I) and insulinlike growth factor binding protein-3 (IGFBP-3): May be low, but normal growth factors do not exclude GH deficiency in children with brain tumors. IGF-1 may be low secondary to poor nutritional status.
  • Free T4 by equilibrium dialysis: Must measure, not calculate, the free T4 concentration in serum
  • GH stimulation tests: Should be performed by a pediatric endocrinologist
  • Cortrosyn stimulation test: More helpful in the diagnosis of primary adrenal insufficiency than secondary (adrenocorticotropic hormone) or tertiary (corticotropin-releasing hormone) deficiency
  • Metyrapone or corticotropin-releasing hormone stimulation test:
    • Definitive tests for adrenocorticotropic hormone or corticotropin-releasing hormone deficiency
    • Metyrapone not currently available in the US
    • Must be performed by a pediatric endocrinologist
  • Estradiol, testosterone, ultrasensitive LH and FSH: Delayed puberty if no breast development by 13 years in girls, and no testicular enlargement by 14 years in boys
  • Water deprivation test:
    • Definitive test for antidiuretic hormone deficiency (diabetes insipidus)
    • Should be performed by a pediatric endocrinologist
Comments on testing:
  • Measurement of water intake and urine output over 24 hours at home can help diagnosis of diabetes insipidus.
  • Baseline serum tests can all be done in a nonfasting state.
  • Stimulation tests need to be performed by a pediatric endocrinologist.

Imaging
  • Bone age: Typically significantly delayed in GH deficiency or hypothyroidism
  • MRI with contrast of brain with fine cuts through the pituitary hypothalamus:
    • Look for tumors but also size of pituitary, infundibulum, and presence of normal bright spot in posterior pituitary.
    • Absence of the bright spot is highly associated with central diabetes insipidus.
    • Ectopic pituitary consistent with GH deficiency and other anterior pituitary deficiencies

ALERT:
  • If adrenocorticotropic hormone deficient, stress dosing of glucocorticoids is necessary.
  • A patient with diabetes insipidus who does not have an infact thirst mechanism and access to free water is at high risk for acute hypernatremia.

Differential Diagnosis

  • HI in newborns
  • Isolated hormone deficiency, such as GH
  • Constitutional growth delay

Medication (Drugs)

  • Recombinant human GH (rhGH) by SC injection daily: 0.3 mg/kg/wk
  • Desmopressin acetate (DDAVP): Available in oral and intranasal formulations. Dose is variable.
  • Estrogen/Testosterone: Initiated at time of puberty at low doses and slowly increased over 1–2 years to mimic endogenous secretion of sex steroids.
  • Estrogen given as oral form to girls while testosterone given as injection to boys every month
  • Levo-thyroxine (Levo-T) PO: 25–200 levo-T4 mcg daily, based on weight, age, and free T4 levels
  • TSH levels will not be useful in monitoring therapy, even after treatment is initiated.
  • Hydrocortisone:
    • Replacement doses if needed: 8–15 mg/m2/day PO, divided q8h (or t.i.d.)
    • In stress circumstances such as fever or illness, dose increased to 25–100 mg/m2/day PO
    • For surgery, major illness, vomiting: Loading dose of 50–100 mg/m2 IM or IV followed by 50–100 mg/m2 divided q4h; oral stress doses should be divided q8h.
    • To calculate hydrocortisone dose, estimate body surface area (BSA) using a nomogram or the following formula: BSA (m2) = square root of (height [cm] × weight [kg]/3600)
Duration:
  • Long-term therapy: Monitored by a pediatric endocrinologist
  • rhGH:
    • In children and adolescents: Until growth velocity drops to 2.5 cm/yr; once puberty is complete
    • GH-deficient adults may benefit from lifelong rhGH therapy because of the impact of GH on body composition, lipid profile, and cardiac function.
    • Patient should again undergo GH provocative testing off rhGH therapy to determine if adult treatment is necessary.
  • DDAVP: For life as needed to control symptoms of polyuria/polydipsia
  • Acute hypernatremia may be managed with DDAVP, intravenous vasopressin, or fluids alone.
  • Sex steroids: Around age 12, may be continued for lifetime
  • Levo-thyroxine for life
  • Hydrocortisone:
    • Replacement dose based on individual’s need
    • Stress dose coverage for life
  • Possible conflicts with other treatments:
    • There is a theoretical risk that GH might stimulate tumor growth because of its mitogenic effect. Current data argue against GH as a tumor stimulant.

  • GH: Immediate resolution of hypoglycemia, if present, and improved growth velocity within 3–6 months
  • T4 levels should normalize within 4–6 weeks.

Prognosis

  • Endocrine prognosis for congenital forms is excellent.
  • Prognosis for secondary forms depends on the primary disease.

Complications

  • Hypoglycemia in the newborn period
  • Short stature
  • Adrenal crisis
  • Dehydration/Hypernatremia

ALERT:
  • rhGH therapy is associated with idiopathic intracranial hypertension (pseudotumor cerebri), which typically improves whether or not medication is stopped.
  • rhGH deficiency/therapy is associated with slipped capital femoral epiphysis. Carefully evaluate any limp or knee or hip pain in patients on rhGH therapy. Slipped capital femoral epiphysis mandates orthopedic consultation.
  • GH is a mitogenic factor, so there has been a theoretical potential for increasing the incidence of leukemia. Clinical studies have not confirmed this hypothesis.
  • The family and the patient must understand the importance of taking stress doses of steroid appropriately (e.g., with surgery, vomiting, or febrile illnesses).
  • You must consider the diagnosis of panhypopituitarism in patients with hypoglycemic seizures.
  • Normal children can fail to respond to GH provocative testing.
  • Ordering a TSH level is generally not helpful when evaluating pituitary/hypothalamic causes of hypothyroidism. The unbound free T4 level (by equilibrium dialysis) is the most useful test both to establish the diagnosis and to monitor L-thyroxine replacement therapy.

ICD9

  • 253.2 Panhypopituitarism

FAQ

  • Q: When do I give the stress dose of steroid and for how long?
    • A: Whenever the patient has fever, vomiting, serious illness, or surgery. Continue until 24 hours after stress resolves (e.g., the day after fever breaks or vomiting stops).
  • Q: What are the chances of cretinism if hypopituitarism is congenital?
    • A: Minimal, if medication is taken properly.

BIBLIOGRAPHY

  1. De Vries L, Lazar L, Phillip M. Craniopharyngioma: Presentation and endocrine sequelae in 36 children. J Endocr Metab. 2003;16:703–710.
  2. Jenkins PJ, Mukherjee A, Shalet SM. Does growth hormone cause cancer? Clin Endocrinol (Oxf). 2006;64(2):115–121.  [PMID:16430706]
  3. Maghnie M. Diabetes insipidus. Horm Res. 2003;59(Suppl 1):42–54.  [PMID:12566720]
  4. McGauley G, Cuneo R, Salomon F Growth hormone deficiency and quality of life. Horm Res. 1996;45:34–37.  [PMID:8742116]
  5. Parks JS, Brown MR, Hurley DL Heritable disorders of pituitary development. J Clin Endocrinol Metab. 1999;84:4362–4370.  [PMID:10599689]
  6. Reynaud R, Gueydan M, Saveanu A Genetic screening of combined pituitary hormone deficiency: Experience in 195 patients. J Clin Endocrinol Metab. 2006;91(9):3329–3336.  [PMID:16735499]
  7. Sklar CA, Constine LS. Chronic neuroendocrinological sequelae of radiation therapy. Int J Radiat Oncol Biol Phys. 1995;31:1113–1121.  [PMID:7713777]

AUTHORS

Vaneeta Bamba, MDCraig A. Alter, MD (4th Edition)

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