Inherited Adrenal Hypoplasia: Not Just for Kids!

Lin Lin; John C. Achermann

Disclosures

Clin Endocrinol. 2004;60(5) 

In This Article

Combined Pituitary Hormone Deficiency

The corticotrope cell lineage is one of the first to differentiate from progenitor cells in the pituitary gland (Fig. 2). Consequently, mutations in factors that affect early pituitary development (e.g. HESX1, LHX4) will result in ACTH deficiency as part of a combined pituitary hormone deficiency (CPHD) in early childhood (Cohen & Radovick, 2002; Scully & Rosenfeld, 2002; Dattani, 2003). Patients with milder forms of these conditions, or mutations in other transcription factors (e.g. PROP1), may develop more limited forms of pituitary hormone deficiency, and ACTH deficiency may only occur with time. Therefore, careful vigilance of patients with pituitary dysfunction may be needed long into adult life.

Overview of pituitary development. Mutations in several genes can cause panhypopituitarism (e.g. HESX1, LHX4) or isolated ACTH deficiency (e.g. Tpit, TBX19). Several patients with PROP1 mutations have also developed ACTH deficiency with time. It is unclear whether this is a direct phenomenon or secondary to the transient pituitary enlargement seen in some of these patients (adapted with permission from Achermann & Jameson, 1999).

HESX1 is a homeodomain transcription factor that is expressed during the early stages of forebrain and pituitary development (Dattani et al., 1998). HESX1 is a functional repressor of putative targets within forebrain and pituitary development, and severe loss-of-function mutations in HESX1 have been described in several patients with variants of septo-optic dysplasia (optic nerve hypoplasia, absent corpus callosum, thin septum pellicidum) and panhypopituitarism (Dattani et al., 1998; Brickman et al., 2001; Tajima et al., 2003; OMIM 601802). Milder loss of function mutations in HESX1 have also been identified. These patients have panhypopituitarism or even isolated GH deficiency in the absence of optic nerve hypoplasia (Thomas et al., 2001; Carvalho et al., 2003).

Mutations in the Lim-domain factor, LHX4, have been described in a kindred with panhypopituitarism (including ACTH deficiency), but apparently spared gonadotrope function (Machinis et al., 2001; OMIM 602146). These patients have posterior pituitary ectopia and abnormal cerebellar tonsils on MRI scanning. To date, corticotrope function appears to be preserved in families with pituitary dysfunction due to the related Lim-domain factor, LHX3 (Netchine et al., 2000).

Mutations in PROP1 have been described in over 100 patients with multiple pituitary hormone deficiency (Wu et al., 1998; OMIM 601538). These individuals usually present in childhood with GH and TSH insufficiency. Gonadotropin deficiency may be apparent in early childhood (e.g. micropenis, undescended testes), or may not present until adolescence or even early adulthood (Deladoey et al., 1999). Although most data show that PROP1 is not expressed in the corticotrope cell line, it is emerging that a significant proportion of patients with PROP1 gene mutations actually develop ACTH insufficiency with time (Mendonca et al., 1999; Vallette-Kasic et al., 2001). It remains to be seen whether this is due to a hitherto unknown effect of PROP1 on corticotrope function, or following damage to the corticotrope cell population secondary to the pituitary enlargement seen in some patients (Riepe et al., 2001; Vallette-Kasic et al., 2001).

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