Chapter 551 Hypopituitarism
Hypopituitarism denotes underproduction of growth hormone (GH) alone or in combination with deficiencies of other pituitary hormones. Affected children have postnatal growth impairment that is specifically corrected by replacement of GH. The incidence of congenital hypopituitarism is thought to be between 1 in 4,000 and 1 in 10,000 live births. With expanding knowledge of the genes that direct pituitary development or hormone production, an increasing proportion of cases can be attributed to specific genetic disorders. Mutations in 7 candidate genes account for 13% of isolated growth hormone deficiency (IGHD) and 20% of multiple pituitary hormone deficiency (MPHD) cases. The likelihood of finding mutations is increased by positive family histories and decreased in cases with adrenocorticotropin hormone (ACTH) deficiency. The genes, hormonal phenotypes, associated abnormalities and modes of transmission for such established genetic disorders are shown in Tables 551-1 and 551-2. Acquired hypopituitarism usually has a later onset and different causes (Table 551-3).
Table 551-1 ETIOLOGIC CLASSIFICATION OF MULTIPLE PITUITARY HORMONE DEFICIENCY
| GENE OR LOCATION | PHENOTYPE | INHERITANCE |
|---|---|---|
| GENETIC FORMS | ||
| POU1F1 (PIT1) | GH, TSH, PRL | R, D |
| PROP1 | GH, TSH, PRL, LH, FSH, ±ACTH, variable AP | R |
| LHX3 | GH, TSH, PRL, LH, FSH, variable AP, ±short neck | R |
| LHX4 | GH, TSH, ACTH, small AP, EPP, ±Arnold Chiari | D |
| TPIT | ACTH, severe neonatal form | R |
| HESX1 | GH, variable for others, small AP, EPP | R, D |
| SOX3 | Variable deficiencies, ±MR, EPP, small AP and stalk | XL |
| PTX2 | Rieger syndrome | D |
| GLI2 | Holoprosencephaly, midline defects | D |
| GLI3 | Hall-Pallister syndrome | D |
| SHH (Sonic hedgehog) | GH deficiency with single central incisor | D |
| ACQUIRED FORMS | ||
| Idiopathic | ||
| Irradiation | GH deficiency precedes other deficiencies | |
| Inflammation | Histiocytosis, sarcoidosis | |
| Autoimmune | Hypophysitis | |
| Post-surgical | Stalk section, vascular compromise | |
| Tumor | Craniopharyngioma, glioma, pinealoma | |
| Trauma | Battering, shaken baby, vehicular | |
| UNCERTAIN ETIOLOGY | ||
| Idiopathic | ||
| Congenital absence of pituitary | ||
| Septo-optic dysplasia | ||
| Birth trauma | ||
ACTH, adrenocorticotropic hormine; AP, anterior pituitary; D, dominant; EPP, ectopic posterior pituitary; FSH, follicle-stimulating hormone; GH, growth hormone; LH, luteinizing hormone; MR, mental retardation; PRL, prolactin; R, recessive; TSH, thyroid-stimulating hormone; XL, X-linked.
Table 551-3 CAUSES OF ACQUIRED HYPOPITUITARISM
NON-PITUITARY TUMORS
INFECTION
INFARCTION
AUTOIMMUNE DISORDER
OTHER
* Pituitary tumors are classically the most common cause of hypopituitarism. However, new findings imply that causes related to brain damage might outnumber pituitary adenomas in causing hypopituitarism.
From Schneider HJ, Aimaretti G, Kreitschmann-Andermahr I, et al: Hypopituitarism, Lancet 369:1461–1470, 2007.
Multiple Pituitary Hormone Deficiency
Genetic Forms
Sequentially expressed transcriptional activation factors direct the differentiation and proliferation of anterior pituitary cell types. These proteins are members of a large family of DNA-binding proteins resembling homeobox genes. Mutations produce different forms of multiple pituitary hormone deficiency. PROP1 and POU1F1 genes are expressed fairly late in pituitary development and are expressed only in cells of the anterior pituitary. Mutations produce hypopituitarism without anomalies of other organ systems. The HESX1, LHX3, LHX4, and PTX2 genes are expressed at earlier stages. They are also expressed in other organs. Mutations in these genes tend to produce phenotypes that extend beyond hypopituitarism to include abnormalities in other organs.
PROP1
PROP1 is found in the nuclei of somatotropes, lactotropes, and thyrotropes. Its roles include turning on POU1F1 expression, hence its name prophet of PIT1. Mutations of PROP1 are the most common explanation for recessive MPHD and are 10 times as common as the combined total of mutations in other pituitary transcription factor genes. Deletions of 1 or 2 base pairs in exon 2 are most common, followed by missense, nonsense, and splice-site mutations. Anterior pituitary hormone deficiencies are seldom evident in the neonatal period. Growth in the 1st yr of life is considerably better than with POU1F1 defects. The median age at diagnosis of GH deficiency is around 6 yr. Recognition of thyroid-stimulating hormone (TSH) deficiency is delayed relative to recognition of GH deficiency. Basal and thyrotropin-releasing hormone (TRH)-stimulated prolactin (PRL) levels tend to be higher than in POU1F1 mutations.
Most children with PROP1 mutations develop deficiencies of luteinizing hormone (LH) and follicle-stimulating hormone (FSH). Some enter puberty spontaneously and then retreat from it. Girls experience secondary amenorrhea and boys show regression of testicular size and secondary sexual characteristics. Partial deficiency of ACTH develops over time in about 30% of patients with PROP1 defects. Anterior pituitary size is small in most patients, but in others there is progressive enlargement of the pituitary. A central mass originates within the sella turcica but might extend above it. The cellular content of the mass during the active phase of enlargement is not known. With time, the contents of the mass appear to degenerate, with multiple cystic areas. The mass might persist as a nonenhancing structure or might disappear completely, leaving an empty sella turcica. At different stages, MRI findings can suggest a macroadenoma, microadenoma, craniopharyngioma, or a Rathke pouch cyst.
POU1F1 (PIT1)
POU1F1 (formerly PIT1) was identified as a nuclear protein that binds to the GH and PRL promoters. It is necessary for emergence and mature function of somatotropes, lactotropes, and thyrotropes. Dominant and recessive mutations in POU1F1 are responsible for complete deficiencies of GH and PRL and variable TSH deficiency. Affected patients exhibit nearly normal fetal growth but experience severe growth failure in the 1st yr of life. With normal production of LH and FSH, puberty develops spontaneously, though at a later than normal age. These patients are not at risk for development of ACTH deficiency. Anterior pituitary size is normal to small.
HESX1
The HESX1 gene is expressed in precursors of all 5 cell types of the anterior pituitary early in embryologic development. Mutations result in a complex phenotype with defects in development of the optic nerve. Heterozygotes for loss-of-function mutations show the combinations of isolated GH deficiency and optic nerve hypoplasia. Homozygotes can have full expression of septo-optic dysplasia (SOD). This condition combines incomplete development of the septum pellucidum with optic nerve hypoplasia and other midline abnormalities. Clinical observation of nystagmus and visual impairment in infancy leads to the discovery of optic nerve and brain abnormalities. SOD is associated with anterior and/or posterior pituitary hormone deficiencies in about 25% of the cases. These patients often show the triad of a small anterior pituitary gland, an attenuated pituitary stalk, and an ectopic posterior pituitary bright spot. The great majority of patients with SOD do not have HESX1 mutations. The etiology might involve mutations in another gene or a nongenetic explanation (Chapters 585 and 623).
LHX3
LHX3 activates the α-glycoprotein subunit (α-GSU) promoter and acts synergistically with POU1F1 to increase transcription from the PRL, β-TSH, and POU1F1 promoters. The hormonal phenotype produced by recessive loss-of-function mutations in this gene resembles that produced by PROP1 mutations. There are deficiencies of GH, PRL, TSH, LH, and FSH but not ACTH. It is not clear whether the deficiencies are present from birth or whether they appear later in childhood. Some affected persons show enlargement of the anterior pituitary. The 1st patients to be described had the unusual findings of a short neck and a rigid cervical spine. They were only able to rotate their necks about 90 degrees compared with the normal rotation of 150 to 180 degrees.
LHX4
Dominantly inherited mutations in the LHX4 gene consistently produce GH deficiency, with the variable presence of TSH and ACTH deficiencies. Additional findings can include a very small V-shaped pituitary fossa, Chiari I malformation, and an ectopic posterior pituitary.
PTX2
Rieger syndrome is a complex phenotype caused by mutations in the PTX2 transcription factor gene. This gene is also referred to as RIEG1. It is expressed in multiple tissues, including the anterior pituitary gland. In addition to variable degrees of anterior pituitary hormone deficiency, children with Rieger syndrome have colobomas of the iris and abnormal development of the kidneys, gastrointestinal tract, and umbilicus.
Other Congenital Forms
Severe, early-onset MPHD including deficiency of ACTH is often associated with the triad of anterior pituitary hypoplasia, absence or attenuation of the pituitary stalk, and an ectopic posterior pituitary bright spot on MRI. Most cases are sporadic and there is a male predominance. Some are due to abnormalities of the SOX3 gene, located on the X chromosome. As with septo-optic dysplasia, the majority of cases have not been explained at the genetic level.
Pituitary hypoplasia can occur as an isolated phenomenon or in association with more extensive developmental abnormalities such as anencephaly or holoprosencephaly. Midfacial anomalies (cleft lip, palate; Chapter 302) or the finding of a solitary maxillary central incisor indicate a high likelihood of GH or other anterior or posterior hormone deficiency. At least 12 genes have been implicated in the complex genetic etiology of holoprosencephaly (Chapter 585.7). In the Hall-Pallister syndrome, absence of the pituitary gland is associated with hypothalamic hamartoblastoma, postaxial polydactyly, nail dysplasia, bifid epiglottis, imperforate anus, and anomalies of the heart, lungs, and kidneys. The combination of anophthalmia and hypopituitarism has been associated with mutations in the SIX6, SOX2, and OTX2 genes.
Acquired Forms
Any lesion that damages the hypothalamus, pituitary stalk, or anterior pituitary can cause pituitary hormone deficiency (see Table 551-3). Because such lesions are not selective, multiple hormonal deficiencies are usually observed. The most common lesion is the craniopharyngioma (Chapter 491). Central nervous system germinoma, eosinophilic granuloma (histiocytosis), tuberculosis, sarcoidosis, toxoplasmosis, meningitis, and aneurysms can also cause hypothalamic-hypophyseal destruction. Trauma, including shaken child syndrome (Chapter 37), motor vehicle accidents, traction at delivery, anoxia, and hemorrhagic infarction, can also damage the pituitary, its stalk, or the hypothalamus.
Isolated Growth Hormone Deficiency and Insensitivity
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