ACTH-independent macronodular adrenal hyperplasia (AIMAH) is an endogenous form of adrenal Cushing syndrome characterized by multiple bilateral adrenocortical nodules that cause a striking enlargement of the adrenal glands. Although some familial cases have been reported, the vast majority of AIMAH cases are sporadic. Patients typically present in the fifth or sixth decade of life, approximately 10 years later than most patients with other causes of Cushing syndrome (Swain et al., 1998; Christopoulos et al., 2005). Approximately 10 to 15% of adrenal Cushing syndrome is due to primary bilateral ACTH-independent adrenocortical pathology. The 2 main subtypes are AIMAH and primary pigmented nodular adrenocortical disease (PPNAD; see 610489), which is often a component of the Carney complex (160980) and associated with mutations in the PRKAR1A gene (188830). AIMAH is rare, representing less than 1% of endogenous causes of Cushing syndrome (Swain et al., 1998; Christopoulos et al., 2005). See also ACTH-independent Cushing syndrome (615830) due to somatic mutation in the PRKACA gene (601639). Cushing 'disease' (219090) is an ACTH-dependent disorder caused in most cases by pituitary adenomas that secrete excessive ACTH. Genetic Heterogeneity of ACTH-Independent Macronodular Adrenal Hyperplasia AIMAH2 (615954) is caused by germline mutation on 1 allele of the ARMC5 gene (615549) coupled with a somatic mutation in the other allele. AIMAH3 (620990) is caused by germline mutation on 1 allele of the KDM1A gene (609132) coupled with a somatic mutation in the other allele.

Primary pigmented nodular adrenocortical disease (PPNAD) is a form of ACTH-independent adrenal hyperplasia resulting in Cushing syndrome. It is usually seen as a manifestation of the Carney complex (CNC1; 160980), a multiple neoplasia syndrome. However, PPNAD can also occur in isolation (Groussin et al., 2002). Genetic Heterogeneity of Primary Pigmented Nodular Adrenocortical Disease See also PPNAD2 (610475), caused by mutation in the PDE11A gene (604961) on chromosome 2q31; PPNAD3 (614190), caused by mutation in the PDE8B gene (603390) on chromosome 5q13; and PPNAD4 (615830), caused by a duplication on chromosome 19p13 that includes the PRKACA gene (601639).

Any primary pigmented nodular adrenocortical disease in which the cause of the disease is a mutation in the PDE11A gene.

Any combined pituitary hormone deficiencies, genetic form in which the cause of the disease is a mutation in the OTX2 gene.

ACTH-independent macronodular adrenal hyperplasia-2 is an autosomal dominant tumor susceptibility with syndromic incomplete penetrance, as a second hit to the ARMC5 gene is required to develop macronodular hyperplasia (Assie et al., 2013).

Combined pituitary hormone deficiency-8 (CPHD8) is an autosomal dominant disorder characterized by deficiency of one or more of the pituitary hormones. Affected individuals have short stature due to growth hormone (GH; 139250) deficiency with variable deficiencies of other pituitary hormones, including TSH (see 188540), ACTH, and LH/FSH (see 118850). Posterior pituitary deficiency leading to central diabetes insipidus is rare (Bashamboo et al., 2017). Many patients are diagnosed with 'pituitary stalk interruption syndrome' (PSIS), which is characterized by a thin or absent pituitary stalk, absent or ectopic posterior pituitary, and hypoplasia of the anterior pituitary demonstrated on brain imaging, although this classic triad may be incomplete. Brauner et al. (2020) noted the complex phenotypic and genetic heterogeneity of PSIS, and concluded that it is a feature of genetic disorders or syndromes rather than a specific clinical entity. For a discussion of genetic heterogeneity of combined pituitary hormone deficiency, see CPHD1 (613038).

Neurooculorenal syndrome (NORS) is an autosomal recessive developmental disorder with highly variable clinical manifestations involving several organ systems. Some affected individuals present in utero with renal agenesis and structural brain abnormalities incompatible with life, whereas others present in infancy with a neurodevelopmental disorder characterized by global developmental delay and dysmorphic facial features that may be associated with congenital anomalies of the kidney and urinary tract (CAKUT). Additional more variable features may include ocular anomalies, most commonly strabismus, congenital heart defects, and pituitary hormone deficiency. Brain imaging usually shows structural midline defects, including dysgenesis of the corpus callosum and hindbrain. There is variation in the severity, manifestations, and expressivity of the phenotype, even within families (Rasmussen et al., 2018; Munch et al., 2022).