Panhypopituitarism, Pediatric

Basics

Description

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])
Congenital
- Absence 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 panhypopituitarism
- Rathke cleft cyst
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
Cranial irradiation
Tumors:
- Craniopharyngioma
- Germinoma
- Glioma
- Pinealoma
- Primitive 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 history
- Infants 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 seizures
- Prolonged 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 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.
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 weight
- Patients 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 test
- Tests for adrenocorticotropic hormone or corticotropin-releasing hormone deficiency
- Must 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 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 (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 pituitary
- 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 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 steroids
- Infants 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.
Hydrocortisone
- Replacement 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 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

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 months
- T4 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