Congenital panhypopituitarism, or the deficiency of more than one pituitary hormone, is caused by gross malformation and histologic or molecular abnormalities of the hypothalamic–pituitary unit. Gross hypothalamic–pituitary malformation may be associated with other midline brain malformations, including holoprosencephaly and anencephaly. Holoprosencephaly, characterized by ventral midline fusion of forebrain structures, is the most frequent brain malformation in humans. Because induction of hypothalamic development is intimately involved in forebrain midline signaling
during embryogenesis, mild cases of holoprosencephaly may present clinically with only hypothalamic/pituitary dysfunction. Four genes have been shown to cause holoprosencephaly in humans when mutated, including sonic hedgehog (SHH). Septooptic dysplasia, or de Morsier syndrome, describes the association of optic nerve hypoplasia with septum pellucidum agenesis; additional associations may be schizencephaly or callosal absence, and a case of septooptic dysplasia with cerebrocortical dysplasia has been reported. Septooptic dysplasia occurs with variable degrees of neuroendocrine dysfunction, primarily hypothalamic involvement and GH deficiency. Septooptic dysplasia has been associated with mutations of the HESX1 homeobox gene. Thus, mutations in transcription factors active during early hypothalamic–pituitary development frequently result in gross abnormalities that may be visualized with brain imaging. Mutations in factors active later during cellular differentiation and function (such as Pit1 or PROP1) may result in histologic and functional changes, but not radiologically apparent abnormalities. Nonetheless, the clinical characteristics are similar.

Common clinical findings in the newborn with panhypopituitarism include hypoglycemia and jaundice and, in boys, micropenis. Newborn screening for hypothyroidism may detect a low thyroxine level (T₄) with a normal TSH level. In infants with gross malformations, there may be midline defects (such as cleft palate), neurologic signs, and visual defects (especially nystagmus). In the older child, there may be a single central incisor or, most commonly, growth failure. Treatment consists of replacing the identified deficient hormones and addressing the underlying cause.

Isolated GH deficiency (GHD) occurs as a spectrum of clinical diseases, all sharing growth failure as the main phenotypic trait. The familial forms include autosomal recessive and autosomal dominant patterns of inheritance. Complete or classic GHD is not difficult to diagnose. However, partial GHD or insufficiency is often more difficult to confirm biochemically because of the hormone’s circadian rhythm. Indirect means of measuring GH function have therefore been devised, including random growth factor (insulinlike growth factor-1 [IGF-1] and IGF-binding protein [IGFBP]-3) levels, provocative GH testing, and overnight serum GH sampling. Because all of these tests have questionable specificity, interassay differences, or, in the case of GH, paucity of published age-, gender-, or pubertal-specific normal ranges, diagnosis of GHD cannot rely on any single parameter. The combination of subnormal growth velocity, delayed bone age, and two provocative stimulation tests with failing results is accepted as adequate indication of GHD. Provocative GH testing falsely passes children with neurosecretory GHD; the pharmacologic stimulus bypasses the defect and prompts release of normal levels of GH by the unaffected pituitary gland, whereas spontaneous GH secretion in these children is blunted because of the defect in the hypothalamic or higher brain centers’ triggering of GH release. Clinical concern based upon the knowledge that neurosecretory GHD exists, especially after cranial irradiation, can be diagnosed by overnight GH sampling. The various neuromodulators of GH secretion are listed in Table 377.3. Children with GH insufficiency, including neurosecretory GHD, achieve improvements in final height with GH therapy, as do children with classic GHD but not children with non-GHD short stature.

Isolated gonadotropin deficiency actually may be more common than GHD. However, most patients present to reproductive endocrinologists with
the chief complaint of infertility. More complete deficiency of gonadotropins presents as inadequate adolescent sexual development. Distinguishing idiopathic hypogonadotropic hypogonadism from constitutional delay of growth and development as well as from psychological dysfunction (depression or anorexia nervosa) can be difficult. Gonadotropin-releasing hormone (GnRH) testing, evaluating the gonadotropin response to an administered GnRH bolus, may be misleading, because the latter conditions also do not demonstrate a gonadotropin response to GnRH. Partial gonadotropin deficiency, conversely, may proceed slowly through puberty and a GnRH bolus testing will cause release of gonadotropins. Patients with Kallmann syndrome (clinically manifested by delayed puberty associated with anosmia) are often easier to diagnose because of the anosmia. This is a familial syndrome, and genetic analysis often detects a mutation in the X chromosome KAL locus that encodes a developmental chemoattractant for both GnRH-secreting and olfactory neuron migration.