Laparoscopic Unilateral Adrenalectomy in Children for Isolated Primary Pigmented Nodular Adrenocortical Disease (PPNAD): Case Report and Literature Review

 

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Introduction

Primary pigmented nodular adrenocortical disease (PPNAD) is a pituitary-independent, primary adrenal form of hypercortisolism, characterized by small or normal-sized adrenal glands containing multiple cortical nodules; it is a rare syndrome and its main endocrine manifestation is adrenocorticotropic hormone-independent Cushing's syndrome. ACTH-independent adrenocortical causes of Cushing's syndrome account for up to 15% of all cases of Cushing's syndrome in children older than 7 years.

In younger children, ACTH-independent Cushing's syndrome may account for as many as half of all Cushing's syndrome cases, mostly due to adrenal tumors [1]. PPNAD may occur in an isolated form or in association with a multiple neoplasia syndrome, the Carney complex (32% of cases of PPNAD to 90% of cases, in some series).

This syndrome consists of a complex of spotty skin pigmentation (lentigines), myxomas (cardiac, cutaneous), mammary myxoid lesions, testicular tumors, pituitary adenomas, psammomatous melanotic schwannomas, and possibly other neoplasms, including adrenocortical and thyroid follicular carcinomas, testicular tumors and ovarian cysts, plus endocrine overactivity [2].

Isolated PPNAD is the result of genetic processes associated with defects of the cAMP signaling pathway. The patient is a carrier of a known inactivating mutation of the protein kinase A type R1A regulatory subunit (PRKAR1A) gene. Isolated PPNAD tissue expresses consistently high levels of phosphodiesterase 11A (PDE11A); this finding has led to the identification of PDE11A mutations as a low-penetrance predisposing factor to PPNAD. Both PRKAR1A and PDE11A gene products control the cAMP signaling pathway, which can be altered at various levels in endocrine tumors. Screening of family members is mandatory in this group of patients [3].

Primary pigmented nodular adrenocortical tumors are characterized by lipofuscin-containing, autonomously functioning, cortisol-producing nodules surrounded by mostly atrophic adrenocortical and normal adrenomedullary tissue; usually both glands are affected. Microscopically, the nodules consist of large cortical cells with eosinophilic cytoplasm and large hyperchromatic nuclei with prominent nucleoli; the cytoplasm is rich in lipofuscin pigment and, possibly, neuromelanin.

Clinically, signs of Cushing's syndrome develop in these patients: the skin is fragile and thin; purplish pink stretch marks are noted on the abdomen, thighs, buttocks, arms, and breasts; upper-body obesity, a round face, increased fat around the neck, and thin arms and legs are observed; children tend to be obese, with slowed growth rates and pubertal delay; women usually have excessive hair growth on their face, neck, chest, abdomen, and thighs.

Clinically evident Cushing's syndrome exists in 84% of patients with PPNAD, while 6% of patients with PPNAD have only biochemical evidence of adrenocortical hyperfunction, and 10% of patients may remain undiagnosed due to the paucity of symptoms.

The biochemical and radiological evaluation of patients with Cushing's syndrome caused by PPNAD reveals the ACTH-independent nature of this disorder; plasma levels of ACTH are low, normal or undetectable; adrenal steroid production is not suppressible by high-dose dexamethasone. Moreover, most patients have a paradoxical increase in UFC excretion after the administration of high-dose dexamethasone.

Computerized tomography (CT) examination of the abdomen shows adrenal glands of normal size in half of the cases. The presence of multiple small adrenal nodules with intervening segments of atrophic adrenal cortex gives a “string of beads” appearance that is characteristic of PPNAD, especially in the 12–18 years age group.

Beyond the age of 18 years, unilateral 2–3 cm adrenal macronodules are common in PPNAD, making it impossible to distinguish Cushing's syndrome due to PPNAD from the much more common ACTH-independent adrenal adenomatous hyperplasia based on radiological criteria only.

In recent years, laparoscopic bilateral adrenalectomy followed by hormone substitution has become the standard therapy for these adrenal lesions in adult patients. A few reports in the literature have also described unilateral adrenalectomy as an effective cure for primary hypercortisolism due to PPNAD.

We report the case of a young girl successfully treated at our institution by laparoscopic unilateral adrenalectomy for an isolated PPNAD.

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Correspondence

Dr. R. Guanà

Regina Margherita Children's Hospital

Division of Pediatric Surgery

Piazza Polonia 94

10100 Turin

Italy

Phone: +39 0338 770 47 16

Fax: + 39 0113 13 54 86

Email: riccardoguan@gmail.com