Pigmented Nodular Adrenocortical Disease, Primary, 1

A number sign (#) is used with this entry because primary pigmented nodular adrenocortical disease-1 (PPNAD1) is caused by heterozygous mutation in the protein kinase A regulatory subunit 1-alpha gene (PRKAR1A; 188830) on chromosome 17q.

Description

Primary pigmented micronodular adrenocortical disease 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 Micronodular 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).

Clinical Features

Arce et al. (1978) reported 4 sibs with 'familial Cushing syndrome.' Three sibs had onset around adolescence of moon facies, obesity, hypertrichosis, purple striae, and osteoporosis. Skull radiographs showed no enlargement of the sella turcica, and dexamethasone suppression resulted in no change of circulating steroid levels. Measurement of serum ACTH was not available. Functional studies showed adrenal autonomy. Adrenalectomy resulted in complete remission in 3 sibs; the fourth died from a presumed virilizing adrenal carcinoma. Histology of the 3 sibs demonstrated enlarged adrenal glands containing numerous yellow cortical nodules ranging in size from 0.3 to 1.5 cm. Lipochromic pigment was reported. Although data were lacking, this family may have had PPNAD.

Donaldson et al. (1981) described a brother and sister with bilateral micronodular adrenal hyperplasia manifesting at birth. Both had clinical features of adrenal Cushing syndrome, including hypertension, increased serum cortisol, and decreased serum ACTH.

Shenoy et al. (1984) reported 4 patients, aged 12 to 21 years, with Cushing syndrome due to autonomously functioning bilateral adrenocortical neoplasms. All underwent curative adrenalectomy. Pathologic findings included decreased, normal, or slightly increased total gland weight, multiple small (less than 4 mm) black, brown, dark-green, red, or yellow nodules, and cortical atrophy and disorganization of the normal zonation between the nodules. Lipofuscin was present within most of the enlarged cortical cells. Shenoy et al. (1984) suggested the term 'primary pigmented nodular adrenocortical disease' to describe the disease entity.

Hodge and Froesch (1988) described 2 sisters with primary micronodular adrenocortical dysplasia leading to Cushing syndrome. Bilateral adrenalectomy was performed at ages 14 and 30 years, respectively. The disease appeared to be characterized by autonomous overactivity of nests of abnormal adrenal cells with suppression of endogenous corticotropin.

Teding van Berkhout et al. (1989) described Cushing syndrome due to pigmented nodular adrenocortical dysplasia in 2 sisters. The disorder was successfully treated by complete adrenalectomy. No evidence of associated disorders suggesting Carney syndrome was found in the 2 sisters or their first-degree relatives. However, the serum of both girls and their mother contained immunoglobulins capable of stimulating adrenal cortisol production in vitro. The results were interpreted as indicating that the disorder is an inherited disease of immunologic origin (Wulffraat et al., 1988).

Diagnosis

Stratakis et al. (1999) found that 9 (70%) of 13 patients with PPNAD demonstrated a paradoxical increase in urinary free cortisol on day 6 of the dexamethasone suppression test, a finding that distinguished patients with PPNAD from those with ACTH-independent macronodular adrenocortical hyperplasia (AIMAH; 219080).

Molecular Genetics

Groussin et al. (2002) identified mutations in the PRKAR1A gene (see, e.g., 188830.0009) in 5 unrelated patients with isolated PPNAD who had no clinical signs or symptoms of Carney complex. All of the mutations were predicted to result in truncation of the protein. The authors concluded that mutations in the PRKAR1A gene can result in isolated cases of PPNAD.