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Lucas Bouys and Jerome Bertherat

Described for the first time in 1985, Carney complex (CNC) is a rare dominantly inherited multiple neoplasia syndrome with almost full penetrance, and characterized by both endocrine – primary pigmented nodular adrenocortical disease with Cushing’s syndrome, acromegaly and thyroid tumors – and non-endocrine manifestations such as cardiac, cutaneous and mucosal myxomas, pigmented cutaneous lesions, psammomatous melanotic schwannoma, osteochondromyxoma and a wide range of other tumors with potential malignancy. The pathophysiology of CNC is a model of dysregulation of the cAMP-PKA signalling in human diseases: as described twenty years ago, inactivating heterozygous mutations of PRKAR1A formerly known as CNC1, encoding the regulatory subunit 1α of protein kinase A are identified in more than 70% of the index cases, while inactivating mutations of genes encoding phosphodiesterases are found in rare and particular forms of the complex. There is at present no medical specific treatment for CNC, every confirmed or suspected CNC patient should be managed by a multidisciplinary team according to each manifestation of the disease and offered a long-term follow-up and genetic counselling. The better knowledge that we have now of this fascinating rare disease and its genetics will help to improve patients outcome.

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Jacques Young, Jérôme Bertherat, Marie Christine Vantyghem, Olivier Chabre, Salima Senoussi, Rita Chadarevian, Frédéric Castinetti, and the Compassionalte use Programme

Objective

Ketoconazole (KTZ) is one of few available treatments for Cushing’s syndrome (CS). Although KTZ has been associated with severe hepatotoxicity, little information is available about hepatic safety in CS. The aim of this study was to document changes in liver function in patients with CS treated with KTZ.

Design

An observational prospective French cohort study (Compassionate Use Programme (CUP)).

Methods

Enrolled patients were stratified into a KTZ-naive cohort and a cohort already treated by another formulation of ketoconazole (KTZ-switch cohort). Liver function markers (alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase, γ-glutamyltransferase and bilirubin) were monitored at regular intervals. Patients with ALT > 3 × ULN (upper limit of normal), total bilirubin > 2 × ULN or both ALP > 2 × ULN and ALT > ULN were considered to have liver injury.

Results

Overall, 108 patients were analysed (47 KTZ-naïve; 61 KTZ-switch). The median KTZ dose was 600 mg/day. Most abnormalities observed were asymptomatic mild increases of liver enzymes. Four patients in the KTZ-naïve cohort (8.5%) and two in the KTZ-switch cohort (3.3%) developed liver injury, considered related to KTZ in three cases (all KTZ-naïve in the first month of treatment). Five patients had mild liver function abnormalities at baseline and two had proven liver metastases. Two patients recovered on discontinuation of KTZ and the remaining patient died of unrelated causes.

Conclusions

These findings highlight the need for close monitoring of liver enzymes especially during the first six months of treatment. Liver enzyme abnormalities usually occurred within four weeks were asymptomatic and could be reversed on timely discontinuation of KTZ.