Vol.2, No.8, 454-456 (2013) Case Reports in Clinical Medicine
http://dx.doi.org/10.4236/crcm.2013.28119
Familial primary pigmented nodular adrenocortical
disease without Carney complex (CNC): A case
report and review of literature
Vaibhav Pandey1*, Vivek Srivastava2, Anand kumar2, Mumtaz Ansari2, S. K. Singh3
1Department of Paediatric Surgery, Institute of Medical Sciences, Banaras Hindu University, Varanasi, India;
*Corresponding Author: sunny.imsbhu@g mail.com
2Department of General Surgery, Institute of Medical Sciences, Banaras Hindu University, Varanasi, India
3Department of Endocrinology, Institute of Medical Sciences, Banaras Hindu University, Varanasi, India
Received 23 July 2013; revised 20 August 2013; accepted 19 September 2013
Copyright © 2013 Vaibhav Pandey et al. This is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
ABSTRACT
Primary pigmented nodular adrenocortical dis-
ease (PPNAD) is a rare cause of familial Cush-
ing's syndrome. It is characterized by bilateral
adrenocortical hyperplasia with small to nor-
mal-sized adrenal glands containing multiple
small adrenal cortical pigmented nodules [1,2].
PPNAD may occur in an isolated form or as fa-
milial PPNAD. Familial cases of PPNAD are
usually associated with Carney complex in
which Cushing’s syndrome is the most common
endocrine manifestation [3]. Familial cases of
PPNAD without associated Carney complex are
very rare. Only a few cases of familial isolated
PPNAD have been reported in the literature,
mostly in females [4]. Isolated familial PPNAD
has got a better prognosis than familial PPNAD
associated with Carney Complex. This observa-
tion has important consequences for clinical
management, follow-up and genetic counselling
of such patients. Familial cases of PPNAD are
rare and mostly present in females with associ-
ated Carney complex. W e herein repo rt a cas e of
familial Cushing’s syndrome in male siblings
due to PPNAD without associated Carney com-
plex.
Keywords: PPNAD; Carney Complex;
Familial Cushing’s Syndrome
1. INTRODUCTION
Primary pigmented nodular adrenocortical disease
(PPNAD) is a form of bilateral adrenocortical hyperpla-
sia that is often associated with corticotrophin (ACTH)-
independent Cushing’s syndrome (CS) and is character-
ized by small to normal-sized adrenal glands containing
multiple small cortical pigmented nodules [1 ,2]. PPNAD
may occur in an isolated form or be associated with the
multiple neoplasia syndrome, a complex of spotty skin
pigmentation, myxomas, and endocrine overactivity, or
Carney complex, in which Cushing’s syndrome is the
most common endocrine manifestation [3]. Although rare,
familial cases of isolated PPNAD have been reported,
most commonly in females [4]. We herein report a case
of familial Cushing’s syndrome in male siblings due to
PPNAD without associated Carney complex.
2. CASE REPORT
A 13 years old male presen ted with complaints of p ro-
gressive increase in body weight from the last 5 years,
easy bruisability and recurrent infections. Further ques-
tioning revealed significant central abdominal weight
gain over the preceding 6 months with proximal muscle
weakness. On examination features suggestive of Cush-
ing’s syndrome were present like centripetal fat distribu-
tion with abdominal striae, proximal myopathy and skin
atrophy with spontaneous bruises Figure 1. Blood pres-
sure readings were mildly elevated. There was no visual
field defect. He had normal secondary sexual character-
istics and was clinically euthyroid. The baseline cortisol
level was 22 µg/dl [8 AM] and there was failure of sup-
-pression with the 1 mg overnight dexamethasone sup-
pression test, with a post- suppression cortisol level of 42
µg/dl. The baseline adrenocorticotrophic hormone
(ACTH) level was 24.3 pg/ml. Endocrine evaluation for
other secondary causes of osteoporosis revealed normal
calcium profiles, thyroid function and testosterone level.

V. Pandey et al. / Case Reports in Clinical Medicine 2 (2013) 454-4 56 455
Figure 1. Siblings with features of Cushing’s Syndrome.
The patient had similar clinical & laboratory finding as
his elder brother who wa s diag no sed as a case of PPNAD
and was cured following bilateral adrenalectomy Figure
2. So on the basis of the clinical and laboratory data in
the background of a significant family history of the di-
agnosis of hypercortisolism due to familial PPNAD was
made.
The patient underwent bilateral adren alectomy th rough
a bilateral subcostal approach. The diagnosis was then
confirmed histopathologically Figure 3. Patient was dis-
charged on oral steroids 10 - 15 mg/day and Calcium and
Vitamin D3 supplimentation. In the 6 months following
adrenalectomy, there was resolution in his clinical fea-
tures with less facial rounding and plethora. His weight
decreased from 37 to 33 kg within 2 months and the cen-
tral adiposity decreased. Features of CNC were absent in
both the cases on subsequent regular follow up over a
period of ten years.
3. DISCUSSION
Cushing syndrome is a symptom complex that reflects
excessive tissue exposure to cortisol. It may be adreno-
corticotrophic hormone (ACTH) dependent or inde-
pendent. ACTH-independent processes account for ap-
proximately 15% to 20% of cases in adults and 15% in
children >7 years old. Of these ACTH-independent
causes, almost all are due to adrenal adenoma or carci-
noma [5]. Micronodular adrenal hyperplasia (MAH), and
its pigmented variant, primary pigmented nodular
adrenocortical disease (PPNAD) are rare [6]. Our pa tient
had clinically evident features of Cushing’s syndrome,
which exists in abou t 84% of patients with PPNAD. Ap-
proximately 10% have a paucity of symptoms and are
diagnosed late; this group represents latent PPNAD. The
Figure 2. Elder brother in follow up after bilateral adrenalec-
tomy.
Figure 3. H& E×400 Micronodules of size 2 - 4 mm and atro-
phic internodular area with brown/black pigmentation.
remaining 6% of patients have only biochemical evi-
dence of Cushing’s syndrome [7]. ACTH levels are usu-
ally low, normal or undetectable and adrenal glucocorti-
coid production is not suppressed by high-dose dexa-
methasone [8]. PPNAD forms part of a wider clinical
spectrum of an autosomal dominant multiple endocrine
neoplasia syndrome known as Carney complex charac-
terised by complex of myxomas, spotty pigmentation and
endocrine overactivity [9]. Half of PPNAD patients ap-
pear to be sporadic cases and the other half are familial,
mostly associated with Carney complex (CNC) [2]. Fa-
milial cases of isolated PPNAD have also been reported
and usually no other clinical features associated with
CNC are seen in these families. A polypyrimidine tract
mutation of the PRKAR1A gene has been described
leading to a mild phenotype, almost exclusively CS due
to PPNAD without any other associated features of CNC.
The low penetrance of this genetic defect could explain
the rarity of familial isolated PPNAD [4 ]. In PPN AD on e

V. Pandey et al. / Case Reports in Clinical Medicine 2 (2013) 454-4 56
456
or more macronodules (>1 cm in diameter) can be pre-
sent unilaterally or bilaterally, making the differential
diagnosis from ACTH independent macronodular adrenal
hyperplasia (AIMAH) very difficult [10]. In patients with
PPNAD there is delayed paradoxical increase of urinary
free cortisol by 100% or more using the sequential
LDDST and HDDST which forms the basis of Liddle’s
test, differentiating PPNAD from AIMNH [11]. In
PPNAD, the characteristic macroscopic findings usually
described include small brown-black nodules separated
by an atrophic adrenal cortex. The cut surface is yellow,
often with small brown foci. Histologically, the nodules
consist of clear lipid-laden zona-fasciculata-type cells
corresponding to the yellow areas on gross examination,
while the brown foci consist of compact lipid-sparse
zona-reticularis type cells [12]. Bilateral adrenalectomy
is the treatment of choice for CS due to PPNAD. The
laparoscopic approach is associated with a lower mor-
bidity rate compared with the open technique, less post-
operative pain, shorter hospitalization time and lower
overall cost.
4. CONCLUSION
Isolated familial PPNAD is a rare entity and has got a
better prognosis than familial PPNAD associated with
Carney Complex. This observation has important conse-
quences for clinical management, follow-up and genetic
counselling of such patients.
REFERENCES
[1] Carney, J.A. and Young, W.F. (1992) Primary pigmented
nodular adrenocortical disease and its associated condi-
tions. Endocrinologist, 2, 6-21.
http://dx.doi.org/10.1097/00019616-199201000-00003
[2] Stratakis, C.A. and Kirschner, L.S. (1998) Clinical and
genetic analysis of primary bilateral adrenal diseases (mi-
cro- and macronodular disease) leading to Cushing syn-
drome. Hormone and Metabolic Research, 30, 456-63.
http://dx.doi.org/10.1055/s-2007-978914
[3] Stratakis, C.A., Kirschner, L.S. and Carney, J.A. (2001)
Clinical and molecular features of the Carney complex:
Diagnostic criteria and recommendations for patient evalu-
ation. The Journal of Clinical Endocrinology & Meta-
bolism, 86, 4041-4046.
http://dx.doi.org/10.1210/jc.86.9.4041
[4] Groussin, L., Horvath, A., Jullian, E., Boikos, S., Rene-
Corail, F., Lefebvre, H., et al. (2006) A PRKAR1A muta-
tion associated with primary pigmented nodular adreno-
cortical disease in 12 kindreds. The Journal of Clinical
Endocrinology & Metabolism, 91, 1943-1949.
http://dx.doi.org/10.1210/jc.2005-2708
[5] Arnaldi, G., Angeli, A., Atkinson, A.B., et al. (2003) Di-
agnosis and complications of Cushing’s sy ndrome: A
consensus statement. The Journal of Clinical Endocri-
nology & Metabolism, 88, 5593-5602.
http://dx.doi.org/10.1210/jc.2003-030871
[6] Stratakis, C.A. (2007) Adrenocortical tumors, primary
pigmented adrenocortical disease (PPNAD)/Carney com-
plex, and other bilateral hyperplasias: The NIH studies.
Hormone and Metabolic Research, 39, 467-473.
http://dx.doi.org/10.1055/s-2007-981477
[7] Carney, J.A., Gordon, H., Carpenter, P.C., Shenoy, B.V.
and Go, V.L. (1985) The complex of myxomas, spotty
pigmentation, and endocrine overactivity. Medicine, 64,
270-283.
http://dx.doi.org/10.1097/00005792-198507000-00007
[8] Sarlis, N.J., Chrousos, G.P., Doppman, J.L., Carney, J.A.
and Stratakis, C.A. (1997) Primary pigmented nodular
adrenocortical disease: Reevaluation of a patient with
Carney complex 27 years after unilateral adrenalectomy.
The Journal of Clinical Endocrinology & Metabolism, 82,
1274-1278. http://dx.doi.org/10.1210/jc.82.4.1274
[9] Groussin, L., Jullian, E., Perlemoine, K., Louvel, A., Le-
heup, B., Luton, J.P., et al. (2002) Mutations of the
PRKAR1A gene in Cushing’s syndrome due to sporadic
primary pigmented adrenocortical disease. The Journal of
Clinical Endocrinology & Metabolism, 87, 4324-4329.
http://dx.doi.org/10.1210/jc.2002-020592
[10] Doppman, J.L., Travis, W.D., Nieman, L., Chrousos, G.P.,
Gomez, M.T., Cutler, G.B., et al. (1989) Cushing syn-
drome due to primary pigmented nodular adrenocortical
disease: Findings at CT and MR imaging. Radiology, 172,
415-420.
[11] Stratakis, C.A., Sarlis, N., Kirschner, L.S., Carney, J.A.,
Doppman, J.L., Nieman, L.K., Chrousos, G.P. and Pa-
panicolaou, D.A. (1999) Paradoxical response to dexa-
methasone in the diagnosis of primary pigmented nodular
adrenocortical disease. Annals of Internal Medicine, 131,
585-591.
http://dx.doi.org/10.7326/0003-4819-131-8-199910190-0
0006
[12] Neville, A.M., McGee, J.O’D., Isaacson, P.G. and Wright,
N.A. (1992) Oxford Textbook of pathology. Vol. 2b. In:
Pathology of systems. Oxford medical publications. Ox-
ford University Press, New York, 1968-1986.