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Nature. 2018 Jun;558(7711):540-546. doi: 10.1038/s41586-018-0217-9. Epub 2018 Jun 13.

Targeted therapy in patients with PIK3CA-related overgrowth syndrome.

Author information

1
INSERM U1151, Institut Necker Enfants Malades, Paris, France.
2
Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
3
Service de Chirurgie Viscérale Pédiatrique, Hôpital Necker-Enfants Malades, AP-HP, Paris, France.
4
Service de Dermatologie Pédiatrique, Hôpital Necker-Enfants Malades, AP-HP, Paris, France.
5
UMR-1163 Institut Imagine, Hôpital Necker-Enfants Malades, AP-HP, Paris, France.
6
Département de Radiologie Pédiatrique, Hôpital Necker-Enfants Malades, AP-HP, Paris, France.
7
Département d'Anatomopathologie, Hôpital Necker-Enfants Malades, AP-HP, Paris, France.
8
Département de Médecine Nucléaire, Hôpital Marie Lannelongue, Le Plessis Robinsson, France.
9
Department of Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA, USA.
10
Service d'Orthopédie Pédiatrique, Hôpital Necker-Enfants Malades, AP-HP, Paris, France.
11
Service de Néphrologie Transplantation Adultes, Hôpital Necker-Enfants Malades, AP-HP, Paris, France.
12
Service de Néphrologie, Transplantation, Dialyse, Aphérèses, Centre Hospitalier Universitaire Pellegrin, Bordeaux, France.
13
UMR CNRS 5164, Immuno ConcEpT, CNRS, Bordeaux, France.
14
Service d'Imagerie Diagnostique et Interventionnelle de l'Adulte, Centre Hospitalier Universitaire Pellegrin, Bordeaux, France.
15
Service de Génétique Médicale, Hôpital Necker-Enfants Malades, AP-HP, Paris, France.
16
Service de Chirurgie Maxillo-faciale et Chirurgie Plastique, Hôpital Necker-Enfants Malades, AP-HP, Paris, France.
17
Laboratory EA 2496 Orofacial Pathologies, Imaging and Biotherapies, Montrouge, France.
18
Service de Neuropédiatrie, Hôpital de la Mère et de l'Enfant, Limoges, France.
19
Service d'Imagerie Pédiatrique, Hôpital Femme-Mère-Enfant, Bron, France.
20
Pharmacie, Hôpital Necker-Enfants Malades, AP-HP, Paris, France.
21
INSERM U1151, Institut Necker Enfants Malades, Paris, France. guillaume.canaud@inserm.fr.
22
Université Paris Descartes, Sorbonne Paris Cité, Paris, France. guillaume.canaud@inserm.fr.
23
Service de Néphrologie Transplantation Adultes, Hôpital Necker-Enfants Malades, AP-HP, Paris, France. guillaume.canaud@inserm.fr.

Abstract

CLOVES syndrome (congenital lipomatous overgrowth, vascular malformations, epidermal naevi, scoliosis/skeletal and spinal syndrome) is a genetic disorder that results from somatic, mosaic gain-of-function mutations of the PIK3CA gene, and belongs to the spectrum of PIK3CA-related overgrowth syndromes (PROS). This rare condition has no specific treatment and a poor survival rate. Here, we describe a postnatal mouse model of PROS/CLOVES that partially recapitulates the human disease, and demonstrate the efficacy of BYL719, an inhibitor of PIK3CA, in preventing and improving organ dysfunction. On the basis of these results, we used BYL719 to treat nineteen patients with PROS. The drug improved the disease symptoms in all patients. Previously intractable vascular tumours became smaller, congestive heart failure was improved, hemihypertrophy was reduced, and scoliosis was attenuated. The treatment was not associated with any substantial side effects. In conclusion, this study provides the first direct evidence supporting PIK3CA inhibition as a promising therapeutic strategy in patients with PROS.

PMID:
29899452
DOI:
10.1038/s41586-018-0217-9
[Indexed for MEDLINE]

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