Familial vasopressin-sensitive ACTH-independent macronodular adrenal hyperplasia (VPs-AIMAH): clinical studies of three kindreds

Authors

  • Lucia Gagliardi,

    1. Endocrine and Metabolic Unit, Royal Adelaide Hospital, Adelaide, South Australia 5000, Australia,
    2. School of Medicine, University of Adelaide, South Australia 5000, Australia,
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  • Cheri Hotu,

    1. Department of Endocrinology, Greenlane Clinical Centre, Auckland District Health Board, Auckland 1051, New Zealand,
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  • Graeme Casey,

    1. Department of Molecular Pathology, SA Pathology, Adelaide, South Australia 5000, Australia,
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  • Wilton J. Braund,

    1. Department of Endocrinology, Flinders Medical Centre, Bedford Park, South Australia 5042, Australia,
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  • King-Hwa Ling,

    1. School of Medicine, University of Adelaide, South Australia 5000, Australia,
    2. Department of Molecular Pathology, SA Pathology, Adelaide, South Australia 5000, Australia,
    3. The Hanson Institute, Box 14, Rundle Mall Post Office, Adelaide, South Australia 5000, Australia,
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  • Thomas Dodd,

    1. Department of Surgical Pathology, SA Pathology, Adelaide, South Australia 5000, Australia,
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  • James Manavis,

    1. Department of Surgical Pathology, SA Pathology, Adelaide, South Australia 5000, Australia,
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  • Peter G. Devitt,

    1. Department of Surgery, Royal Adelaide Hospital, Adelaide, South Australia 5000, Australia,
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  • Richard Cutfield,

    1. Diabetes Service, North Shore Hospital, Waitemata District Health Board, Auckland 0622, New Zealand
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  • Zbigniew Rudzki,

    1. Department of Molecular Pathology, SA Pathology, Adelaide, South Australia 5000, Australia,
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  • Hamish S. Scott,

    1. School of Medicine, University of Adelaide, South Australia 5000, Australia,
    2. Department of Molecular Pathology, SA Pathology, Adelaide, South Australia 5000, Australia,
    3. The Hanson Institute, Box 14, Rundle Mall Post Office, Adelaide, South Australia 5000, Australia,
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  • David J. Torpy

    1. Endocrine and Metabolic Unit, Royal Adelaide Hospital, Adelaide, South Australia 5000, Australia,
    2. School of Medicine, University of Adelaide, South Australia 5000, Australia,
    3. The Hanson Institute, Box 14, Rundle Mall Post Office, Adelaide, South Australia 5000, Australia,
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Dr Lucia Gagliardi, Endocrine and Metabolic Unit, Royal Adelaide Hospital, North Terrace, Adelaide, South Australia 5000, Australia. Tel.: +61 8 8222 2853; Fax: +61 8 8222 5908,
E-mail: lucia.gagliardi@health.sa.gov.au

Summary

Objective  Cushing's syndrome due to familial ACTH-independent macronodular adrenal hyperplasia (AIMAH) has been reported in small kindreds. In vasopressin-sensitive AIMAH (VPs-AIMAH), VP stimulates an aberrant, ACTH-independent increase in cortisol. The aims of this study were to (i) delineate the preclinical phenotype of VPs-AIMAH in a three-generation kindred (AIMAH-01) and two smaller kindreds (AIMAH-02 and AIMAH-03) and (ii) investigate the aetiology of VP sensitivity in AIMAH-01.

Design  Clinical studies of three kindreds for adrenal tumours or early Cushing's and molecular studies of adrenal tumours (AIMAH-01).

Patients  Thirty-three individuals, from three kindreds, were screened for perturbations of the hypothalamic–pituitary–adrenal axis or adrenal tumours.

Measurements  Patients underwent clinical, biochemical and adrenal imaging investigations. Evaluation included low-dose (1 IU/70 kg) VP stimulation. Adrenal VP receptor (AVPR1A, AVPR1B, AVPR2) expression (AIMAH-01) was assessed using RT-PCR and immunohistochemistry (IHC). IHC for VP was also performed.

Results  AIMAH-01 had three siblings with Cushing's, and four individuals with suppressed ACTH/aberrant VP responses and/or adrenal nodules. In AIMAH-02, a father and son were affected. AIMAH-03 had three siblings with Cushing's.

RT-PCR showed adrenal overexpression of AVPR1A and AVPR1B. IHC detected AVPR1A. The adrenal tumour from one patient also stained weakly for VP and AVPR2.

Conclusion  Adrenal nodules, suppressed ACTH and increased VP sensitivity may represent preclinical disease, allowing early detection, and treatment, of affected individuals. In AIMAH-01, increased VP sensitivity may be due to adrenal VP receptor overexpression. In these kindreds, VPs-AIMAH is familial, and autosomal dominant inheritance is most likely.

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