Idiopathic splenomegaly in childhood and the spectrum of RAS-associated lymphoproliferative disease: a case report.
Case report
KRAS
RAS-associated lymphoproliferative disease
Splenomegaly
Journal
BMC pediatrics
ISSN: 1471-2431
Titre abrégé: BMC Pediatr
Pays: England
ID NLM: 100967804
Informations de publication
Date de publication:
21 01 2021
21 01 2021
Historique:
received:
05
09
2020
accepted:
14
01
2021
entrez:
21
1
2021
pubmed:
22
1
2021
medline:
28
5
2021
Statut:
epublish
Résumé
KRAS (KRAS proto-oncogene, GTPase; OMIM: 190,070) encodes one of three small guanosine triphosphatase proteins belonging to the RAS family. This group of proteins is responsible for cell proliferation, differentiation and inhibition of apoptosis. Gain-of-function variants in KRAS are commonly found in human cancers. Non-malignant somatic KRAS variants underlie a subset of RAS-associated autoimmune leukoproliferative disorders (RALD). RALD is characterized by splenomegaly, persistent monocytosis, hypergammaglobulinemia and cytopenia, but can also include autoimmune features and lymphadenopathy. In this report, we describe a non-malignant somatic variant in KRAS with prominent clinical features of massive splenomegaly, thrombocytopenia and lymphopenia. A now-11-year-old girl presented in early childhood with easy bruising and bleeding, but had an otherwise unremarkable medical history. After consulting for the first time at 5 years of age, she was discovered to have massive splenomegaly. Clinical follow-up revealed thrombocytopenia, lymphopenia and increased polyclonal immunoglobulins and C-reactive protein. The patient had an unremarkable bone marrow biopsy, flow cytometry showed no indication of expanded double negative T-cells, while malignancy and storage disorders were also excluded. When the patient was 8 years old, whole exome sequencing performed on DNA derived from whole blood revealed a heterozygous gain-of-function variant in KRAS (NM_004985.5:c.37G > T; (p.G13C)). The variant was absent from DNA derived from a buccal swab and was thus determined to be somatic. This case of idiopathic splenomegaly in childhood due to a somatic variant in KRAS expands our understanding of the clinical spectrum of RAS-associated autoimmune leukoproliferative disorder and emphasizes the value of securing a molecular diagnosis in children with unusual early-onset presentations with a suspected monogenic origin.
Sections du résumé
BACKGROUND
KRAS (KRAS proto-oncogene, GTPase; OMIM: 190,070) encodes one of three small guanosine triphosphatase proteins belonging to the RAS family. This group of proteins is responsible for cell proliferation, differentiation and inhibition of apoptosis. Gain-of-function variants in KRAS are commonly found in human cancers. Non-malignant somatic KRAS variants underlie a subset of RAS-associated autoimmune leukoproliferative disorders (RALD). RALD is characterized by splenomegaly, persistent monocytosis, hypergammaglobulinemia and cytopenia, but can also include autoimmune features and lymphadenopathy. In this report, we describe a non-malignant somatic variant in KRAS with prominent clinical features of massive splenomegaly, thrombocytopenia and lymphopenia.
CASE PRESENTATION
A now-11-year-old girl presented in early childhood with easy bruising and bleeding, but had an otherwise unremarkable medical history. After consulting for the first time at 5 years of age, she was discovered to have massive splenomegaly. Clinical follow-up revealed thrombocytopenia, lymphopenia and increased polyclonal immunoglobulins and C-reactive protein. The patient had an unremarkable bone marrow biopsy, flow cytometry showed no indication of expanded double negative T-cells, while malignancy and storage disorders were also excluded. When the patient was 8 years old, whole exome sequencing performed on DNA derived from whole blood revealed a heterozygous gain-of-function variant in KRAS (NM_004985.5:c.37G > T; (p.G13C)). The variant was absent from DNA derived from a buccal swab and was thus determined to be somatic.
CONCLUSIONS
This case of idiopathic splenomegaly in childhood due to a somatic variant in KRAS expands our understanding of the clinical spectrum of RAS-associated autoimmune leukoproliferative disorder and emphasizes the value of securing a molecular diagnosis in children with unusual early-onset presentations with a suspected monogenic origin.
Identifiants
pubmed: 33472608
doi: 10.1186/s12887-021-02508-3
pii: 10.1186/s12887-021-02508-3
pmc: PMC7819237
doi:
Types de publication
Case Reports
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
45Subventions
Organisme : Genome BC (CA)
ID : SIP007
Références
Blood. 2015 Apr 30;125(18):2753-8
pubmed: 25691160
Clin Immunol. 2017 Feb;175:143-146
pubmed: 28043923
Nature. 2019 Nov;575(7781):217-223
pubmed: 31666701
Immunol Rev. 2019 Jan;287(1):50-61
pubmed: 30565243
Acta Crystallogr D Biol Crystallogr. 2010 Apr;66(Pt 4):486-501
pubmed: 20383002
Cancer Res. 2012 May 15;72(10):2457-67
pubmed: 22589270
Blood. 2011 Mar 10;117(10):2883-6
pubmed: 21079152
Mol Cell Biol. 2004 Jun;24(11):4943-54
pubmed: 15143186
Front Oncol. 2019 Oct 18;9:1088
pubmed: 31681616
Proc Natl Acad Sci U S A. 2013 Mar 19;110(12):4574-9
pubmed: 23487764
Blood. 2011 Mar 10;117(10):2887-90
pubmed: 21063026
Nat Rev Drug Discov. 2019 Nov;18(12):887-891
pubmed: 31780856
J Cell Sci. 2016 Apr 1;129(7):1287-92
pubmed: 26985062