Mitchell E. Geffner, MD


Cancer Control. 2002;9(3) 

In This Article

Causes of Congenital Hypopituitarism

Congenital hypopituitarism may occur as a result of birth trauma and/or asphyxia or as part of one of a number of midline anatomical defects ( Table 1 ). It may also occur secondary to a genetic mutation involving the anatomic development of the pituitary gland. The association of hypopituitarism with specific prenatal or birth trauma is sometimes difficult to prove. However, the pregnancy histories of the mothers of affected children have a higher than expected occurrence of complications late in gestation or around the time of birth, including placenta previa, abruptio placenta, and difficult deliveries.[4] A congenital basis for the hypopituitarism is strongly suggested by the presence of a transected (or interrupted) hypothalamic-pituitary stalk on MRI scan[5] (Fig 1C).

Congenital hypopituitarism may also occur as a component of one of several "midline defect syndromes." The most common disorder in this group is known as septo-optic dysplasia, or de Morsier syndrome. This disorder includes absence of the septum pellucidum (the function of which is uncertain) in 50% of cases (hence, the designation,"septo") and underdevelopment of the optic nerves, associated with variable degrees of reduced vision ranging from mild loss to complete blindness.[6] Affected children may present with "wandering" or "searching" nystagmus, an irregular jerkiness of the eyeballs, representing, in a sense, a search for vision. An ophthalmologic examination may be technically difficult in affected children if the degree of nystagmus is moderate to severe but, if the examination can be successfully performed, it will show one or both optic nerve heads to have a reduced diameter. If the involvement is subtle, fundal photography may be required for direct measurement and comparison to age-matched normative data. It should be noted that most children with optic nerve hypoplasia do not actually have associated hypopituitarism; however, for any child first ascertained to have optic nerve hypoplasia, at least a one-time referral to a pediatric endocrinologist is warranted, especially if there is any associated growth delay.

Other midline associations with hypopituitarism include the presence of a fused deciduous upper central maxillary incisor (Fig 2A),[7] cleft lip and/or palate, choanal atresia, anomalous and/or absent vascular supply to the central nervous system, and encephaloceles (either of the extrusive variety or completely internal emanating from the sphenoid sinus[8] [Fig 2B]). If there are no associated clinical, biochemical, or radiological abnormalities, the hypopituitarism is said to have an idiopathic basis.

Figure 2.

(A) MRI depiction of a fused upper central maxillary incisor (arrow) in a child with hypopituitarism. (B) Sagittal head MRI showing a transsphenoidal encephalocele (arrows) in an adolescent with hypopituitarism. (C) Lateral view cerebral angiogram showing a suprasellar arteriovenous varix at the apex of the basilar artery (arrow). Fig 2B is reproduced with permission of Springer-Verlag GmbH & Co: Kjellin IB, Kaiserman KB, Curran JG, et al. Pediatr Radiol. Aplasia of right internal carotid artery and congenital hypopituitarism. 1999;29:586-588. Fig 2C is reproduced with permission from Blackwell Science Ltd: Koral K, Geffner ME, Curran JG. Trans-sphenoidal and sphenoethmoidal encephalocele: report of two cases and review of the literature. J Australas Radiol. 2000;44:220-224.

On rare occasions, congenital hypopituitarism may have a genetic basis involving one of a series of relatively recently identified pituitary transcription factors that regulate the formation of the gland and its cellular organization.[9] One of the earliest known transcription factor genes involved in embryogenesis of the pituitary gland is Rpx (Rathke's pouch homeobox, also called HESX1), mutations of which have been found in a few cases of septo-optic dysplasia.[10] Other early transcription factor genes important in the formation of various pituitary cell populations are LHX3, LHX4, and PROP-1 (Prophet of Pit-1). Lastly, PIT-1 (also known as POU1F1) is a pituitary-specific transcription factor that is necessary for the development of somatotroph, lactotroph, and thyrotroph lineages. Inherited cases of hypopituitarism in humans have been described in conjunction with mutations of LHX3 (associated with deficiencies of all anterior pituitary hormones except corticotropin [ACTH], along with a rigid cervical spine leading to limited head rotation), PROP-1 (associated with deficiencies of growth hormone [GH], prolactin, thyroid-stimulating hormone [TSH], and sometimes gonadotropins and ACTH, along with limited elbow extensibility, blue sclerae, and, surprisingly, a large sella turcica in some affected individuals), and PIT-1 (associated with deficiencies of GH, prolactin, and TSH). Due to mutations of pituitary gene transcription factors, some cases of hypopituitarism include variability in the timing of presentation of the different hormone deficiencies. For example, GH deficiency typically manifests early in life, whereas other hormone deficiencies somewhat inexplicably present later.


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