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Panhypopituitarism, Pediatric

Basics

Description

- Acquired - Birth trauma or perinatal insult - Surgical resection of the gland or damage to the stalk - Traumatic brain injury - Hypophysitis - Iron deposition secondary to chronic transfusion therapy (e.g., ²-thalassemia)

- Infection - Viral encephalitis - Bacterial or fungal infection - Tuberculosis

- Vascular - Pituitary infarction - Pituitary aneurysm

- Duration: long-term therapy: monitored by a pediatric endocrinologist - rhGH: in children and adolescents: until growth velocity drops to 2.5 cm/year; puberty is complete. - GH-deficient adults may benefit from lifelong rhGH because of the GH impact on body composition, lipid profile, and cardiac function. - Patient should again undergo GH provocative testing of rhGH therapy to determine if adult treatment is necessary. - DDAVP: for life, as needed to control symptoms of polyuria/polydipsia - Sex steroids: Begin around age 12 years; may be continued for lifetime - Levothyroxine for life - Hydrocortisone: replacement dose based on individual 's need; stress dose coverage for life

Technically, "panhypopituitarism " (pan meaning "all " ) requires deficiency of all 8 pituitary hormones; however, the term generally is used for deficiencies of >1 pituitary hormone.

Epidemiology

  • Congenital forms affect both sexes equally and are diagnosed early in childhood.
  • The epidemiology of acquired or secondary forms depends on the underlying cause.

Risk Factors

Genetics

Most cases are not thought to be genetic; however, there are rare autosomal recessive, autosomal dominant, and X-linked forms.

Pathophysiology

  • Pathology is based on specific deficiency or deficiencies.
  • Growth hormone (GH): hypoglycemia in newborns and poor growth in patients older than 6 " 12 months
  • Adrenocorticotropic hormone: hypocortisolism
  • Thyroid-stimulating hormone (TSH): hypothyroidism
  • Luteinizing hormone (LH)/follicle-stimulating hormone (FSH): hypogonadism
  • Antidiuretic hormone: diabetes insipidus
  • Prolactin: Hyperprolactinemia can accompany hypothalamic causes of hypopituitarism.

Etiology

  • Idiopathic (some may be due to hypophysitis, [inflammation of the pituitary gland])
  • CongenitalAbsence of the pituitary (empty sella syndrome is a risk)Pituitary malformations (ectopic posterior pituitary, hypoplastic infundibular stalk, hypoplastic pituitary)Genetic disorders due to mutations in genes or transcription factors (POUF1, HESX1, LHX3, LHX4, OTX2, SOX2, SOX3, PTX2, PROP1, etc.)Familial panhypopituitarismRathke cleft cyst
  • AcquiredBirth trauma or perinatal insultSurgical resection of the gland or damage to the stalkTraumatic brain injuryHypophysitisIron deposition secondary to chronic transfusion therapy (e.g., ²-thalassemia)
  • InfectionViral encephalitisBacterial or fungal infectionTuberculosis
  • VascularPituitary infarctionPituitary aneurysm
  • Cranial irradiation
  • Tumors:CraniopharyngiomaGerminomaGliomaPinealomaPrimitive neuroectodermal tumor (medulloblastoma)
  • Histiocytosis
  • Sarcoidosis

Commonly Associated Conditions

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

Diagnosis

History

  • Birth historyInfants with hypopituitarism are usually normal or small for gestational age, in contrast to hyperinsulinemic infants, who are typically large for gestational age.Documented or symptoms of hypoglycemia, which include poor feeding, lethargy, irritability, or seizuresProlonged hyperbilirubinemia: may be first sign of hypothyroidism and/or hypopituitarism
  • Complications during pregnancy or delivery:Birth trauma may be associated with pituitary injury.Breech delivery or vacuum extraction has been associated.
  • History of surgeries and previous diseases: Congenital hypopituitarism is often associated with midline facial defects, such as a single central incisor, bifid uvula, or cleft palate, which require repair.
  • Growth pattern: Plot previous lengths/heights and look for growth pattern. GH deficiency usually manifests as poor linear growth by the end of the 1st year of life.
  • Delayed pubertyChildren 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.
  • Complaints of headache and/or a visual defect: can be symptoms of a brain tumor. Focal neurologic symptoms are highly suggestive of CNS pathology.

Physical Exam

  • Height and weightPatients with panhypopituitarism have normal to small size in the newborn period.May have poor linear growth after 6 " 12 months of life
  • Micropenis in male newborns: Neonatal penis should be ≥2.5 cm in length; micropenis suggests gonadotropin and/or GH deficiency.
  • Delayed puberty if no breast development by 13 years of age in girls, and no testicular enlargement by 14 years of age in boys.
  • May have other anatomic midline defects
  • Physical exam pearls:Penile and testicular size: Measure stretched phallic length (from pubic ramus to glans) with patient lying supine and phallus at 90 degrees to the body; use Prader beads to assess testicular volume.Midline defects: Palpate for submucosal cleft palate and look for single central incisor.Visual field testing: Visual field defects suggest a brain tumor.

Diagnostic Tests & Interpretation

Lab

  • Liver function tests (LFTs): LFTs in newborns with congenital hypopituitarism are often elevated and accompanied by conjugated hyperbilirubinemia, as opposed to simple congenital hypothyroidism, in which unconjugated hyperbilirubinemia exists.
  • Thyroid function tests: Total and free T4 will be low, but TSH may be low, normal, or elevated.
  • Serum insulin-like growth factor-1 (IGF-1) and insulin-like 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 due to poor nutrition.
  • GH stimulation tests: should be performed by a pediatric endocrinologist
  • Basal serum cortisol: Draw at 8 a.m. in children with a normal diurnal rhythm.
  • 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 testTests for adrenocorticotropic hormone or corticotropin-releasing hormone deficiencyMust be performed by a pediatric endocrinologist
  • Estradiol, testosterone, ultrasensitive LH and FSH: Measure concentrations in first 6 months of life and again after age 11 years. Best measured in the morning
  • Water deprivation testDefinitive 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 (prolactin, 8-a.m. cortisol, T4, free T4, IGF-1, IGFBP-3, serum and urine osmolality, testosterone, estradiol, ultrasensitive LH and FSH) can all be done in a nonfasting state.Stimulation tests must be performed by a pediatric endocrinologist.

Imaging

  • Bone age: typically significantly delayed in GH deficiency and/or hypothyroidism
  • MRI with contrast of brain with fine cuts through the hypothalamus and pituitaryLook 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 of any etiology, although can be present in normal infants.Ectopic pituitary consistent with GH deficiency and other anterior pituitary deficiencies.

Alert

  • If adrenocorticotropic hormone deficient, stress dosing of glucocorticoids is necessary.
  • Replacing thyroid hormone in a child with untreated adrenal insufficiency can precipitate adrenal crisis.
  • A patient with diabetes insipidus who does not have an intact thirst mechanism and access to free water is at high risk for acute hypernatremia.

Differential Diagnosis

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

Treatment

Medication

  • Recombinant human GH (rhGH) by SC injection daily: 0.15 " 0.3 mg/kg/week
  • Desmopressin acetate (DDAVP): available in oral and intranasal formulations. Rarely given subcutaneously. Dose is variable.Acute hypernatremia may be managed with DDAVP, IV vasopressin, or fluids alone.Some infants with diabetes insipidus can be managed initially with thiazide diuretics.
  • Estrogen/testosterone: started at puberty at low doses and slowly increased over ’ Ό2 years to mimic endogenous secretion of sex steroidsInfants with micropenis may be given monthly testosterone for 3 doses to aid penile enlargement.
  • Estrogen given as topical or oral forms to girls, whereas testosterone initially given as injection to boys every month
  • Levothyroxine PO: 25 " 200 mcg daily, based on weight, age, and free T4 levels
  • TSH levels may not be useful in monitoring therapy for central hypothyroidism, even after treatment is initiated.
  • HydrocortisoneReplacement doses if needed: 8 " 15 mg/m2/24 h PO, divided b.i.d. or t.i.d.In stress circumstances such as fever, severe illness, vomiting, or surgery, doses increased to 50 " 100 mg/m2/24 h PO.If dosed IV, provide a loading dose of 50 " 100 mg/m2 IM or IV followed by 50 " 100 mg/m2/24 h 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]/3,600).
  • Duration: long-term therapy: monitored by a pediatric endocrinologistrhGH: in children and adolescents: until growth velocity drops to 2.5 cm/year; puberty is complete.GH-deficient adults may benefit from lifelong rhGH because of the GH impact on body composition, lipid profile, and cardiac function.Patient should again undergo GH provocative testing of rhGH therapy to determine if adult treatment is necessary.DDAVP: for life, as needed to control symptoms of polyuria/polydipsiaSex steroids: Begin around age 12 years; may be continued for lifetimeLevothyroxine for lifeHydrocortisone: replacement dose based on individual 's need; stress dose coverage for life

Ongoing Care

Follow-up Recommendations

  • Initially, every 3 months by a pediatric endocrinologist
  • When pituitary hormones are replaced, expect the following:GH: immediate resolution of hypoglycemia; and improved growth velocity within 3 " 6 monthsT4 levels should normalize within 4 " 6 weeks.Side effects of GH therapy: headache, vision problems, seizures, changes in activity level, limp, knee or hip pain

Prognosis

  • For congenital forms, the prognosis is excellent with endocrine replacement.
  • Diabetes insipidus in infants can be challenging to manage.
  • For secondary forms, the overall prognosis depends on the primary disease.

Complications

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

Alert

  • rhGH therapy can be associated with idiopathic intracranial hypertension (pseudotumor cerebri).
  • rhGH deficiency/therapy can also be associated with slipped capital femoral epiphysis (SCFE). Carefully evaluate any limp or knee, or hip pain in patients on rhGH therapy. SCFE mandates orthopedic consultation.
  • Diagnosis of panhypopituitarism must be considered in patients with hypoglycemic seizures.
  • The family and the patient must understand the importance of taking stress doses of steroid appropriately (e.g., with surgery, vomiting, or febrile illnesses).
  • 20% of normal children will fail a single GH provocative test.
  • TSH levels are 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.

Additional Reading

  • Ascoli P, Cavagnini F. Hypopituitarism. Pituitary. 2006;9(4):335 " 342. [View Abstract]
  • Di Iorgi N, Napoli F, Maghnie M, et al. Diabetes insipidus " diagnosis and management. Horm Res Paediatr. 2012;77(2):69 " 84. [View Abstract]
  • Grossman AB. Clinical review: the diagnosis and management of central hypoadrenalism. J Clin Endocrinol Metab. 2012;95(11):4855 " 4863. [View Abstract]
  • Jenkins PJ, Mukherjee A, Shalet SM. Does growth hormone cause cancer? Clin Endocrinol. 2006;64(2):115 " 121. [View Abstract]
  • Nandagopal R, Laverdiere C, Meacham L, et al. Endocrine late effects of childhood cancer therapy: a report from the children 's oncology group. Horm Res. 2008;69(2):65 " 74. [View Abstract]

Codes

ICD09

ICD10

SNOMED

  • 32390006 Panhypopituitarism (disorder)
  • 190470005 idiopathic panhypopituitarism (disorder)

FAQ

  • Q: When do I give stress doses 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: Is it acceptable to replace thyroid hormone while the evaluation of other pituitary hormones is pending?
  • A: You must ensure the patient is adrenally sufficient; if not, glucocorticoids must be initiated prior to thyroid hormone replacement.
  • Q: Do all state newborn screens detect central hypothyroidism?
  • A: No. Many states initially screen for elevated TSH levels.