Noonan syndrome and systemic lupus erythematosus in a patient with a novel KRAS mutation
CASE REPORT
Noonan syndrome and systemic lupus erythematosus in a patient with a novel KRAS mutation
G. Leventopoulos1,3,
E. Denayer2, P. Makrythanasis1, C. Papapolychroniou3, H. Fryssira1
1Department of Clinical Genetics, University of Athens, “Aghia Sophia” Children’s Hospital, Athens, Greece;
2Department of Human Genetics, University of Leuven, Belgium;
3Department of Cardiology,
“G. Gennimatas” Hospital, Athens, Greece.
Georgios Leventopoulos, MD, PhD Ellen Denayer, MD
Periklis Makrythanasis, MD Chrysoula Papapolychroniou, MD Helen Fryssira, MD, PhD
Please address correspondence to:
Dr Georgios Leventopoulos, Fokidos 53, 11527, Athens, Greece.
E-mail: levent2669@https://www.wendangku.net/doc/4e13724718.html, Please address reprint requests to:
Dr Fryssira Helen,
Department of Clinical Genetics, University of Athens, “Aghia Sophia” Hospital, Thivon and Livadias, 11527, Athens, Greece.
E-mail: efrysira@med.uoa.gr Received on March 21, 2010; accepted in revised form on June 1, 2010.
? Copyright C LINICAL AND
E XPERIMENTAL R HEUMATOLOGY 2010. Key words: Syndrome, gene mutation, systemic lupus erythematosus, congenital cardiopathy
Competing interests: none declared.ABSTRACT
Noonan syndrome is characterised
by distinct facial stigmata, short stat-
ure and congenital cardiopathy. It
has a high genetic heterogeneity and
mutations in six different genes can
be involved. We report a patient with
Noonan syndrome and a novel KRAS
mutation who presents systemic lupus
erythematosus.
Case report
Noonan syndrome (NS) is mainly char-
acterised by short stature, distinct facial
features and congenital cardiopathy (1).
Facial features include broad forehead,
hypertelorism, down-slanted palpebral
?ssures, high palate, low set ears and
ptosis of the eyelids. PTPN11, KRAS,
SOS1, RAF1, SHOC2 and NRAS are
the responsible genes and belong to the
RAS-MAPK pathway (1-3).
The diagnosis of NS in our 3-year-old
female patient was based on clinical
criteria (4). Facial characteristics (Fig.
1A), short stature, pectus excavatum
and psychomotor retardation were in-
dicative of NS. Karyotype was normal
and DNA analysis revealed a novel
missense mutation in the KRAS gene
(c77A>T, pAsn26Ile) which has not
been described in the literature before
(Fig. 1B). Mutation analysis in both pa-
tients was negative indicating that this
is a de novo mutation and not a poly-
morphism
At the age of 18 years, the patient
presented with a papillary rash on the
lower limbs and peripheral nonerosive
arthritis. Additional clinical symptoms
were fever, headaches and fatigue.
Haematological laboratory ?ndings
were anaemia (Hct 19.9%), lympho-
penia (1125/μl) and thrombocytopenia
(6000/μl). Creatinine levels were nor-
mal and urine analysis demonstrated
microhaematuria (8–10 RBCs/HPF).
In?ammatory parameters were normal
(CRP 3.2 mg/l, C3 0.99 gr/l, C4 0.175
gr/l) except positive IgG (18.7 gr/l).
Infections were excluded. Coagulation
tests were normal and direct Coombs
was positive. The initial clinical sce-
nario led to the diagnosis of thrombotic
thrombocytopenic purpura. However,
rheumatological assessment that was
performed in an outpatient basis re-
vealed antinuclear antibody (>1:40),
high anti-DNA antibody (ELISA)
(100IU/ml) and positive IgM anti car-
diolipin (22.7 MPLU/ml, normal range
<12.5). The previous clinical and labo-
ratory ?ndings were consistent with
SLE diagnosis (5). High doses of cor-
ticosteroids (prezolone 100 mg/d) and
fresh frozen plasma were administered
and the patient was treated further with
low dose of corticosteroids being in a
remission state.
Hypertrophic cardiomyopathy was
found when Noonan clinical diagnosis
was set. Echocardiographic
?ndings
Fig. 1 A. Typical facial characteristics of Noonan syndrome.
B. Ideogram of the KRAS mutation. The position of our mutation (top) and the location of the most frequent mutated residues in cancer on KRAS (bottom) are depicted.
C. Long axis view by transthoracic ultrasonography. Asymmetric hypertrophy of the interventricular septum is illustrated and measured at 13 mm at the age of 18 years.
Clinical and Experimental Rheumatology 2010; 28: 556-557.
CASE REPORT Noonan syndrome, KRAS, lupus / G. Leventopoulos et al.
remain the same till the age of 18 (Fig. 1C) and the patient has been on β-block-er therapy.
KRAS mutations are present in around 2% of Noonan patients (6). Autoim-mune disorders are a rare manifesta-tion of NS. Co-existence of NS and SLE (?ve cases) has been reported (7, 8). According to linkage analysis the responsible region for development of SLE was located between 12q24.1 and 12q24.3 which encompasses the most common affected gene (PTPN11) in NS (9). This observation implies a potential correlation between NS and SLE. Adit-tionally, NRAS mutation was described in a patient with autoimmune lymfopro-liferative syndrome (ALPS) (10). Our patient has a novel mutation in the KRAS gene and no other cases with NS, SLE and a KRAS mutation are reported so far. The co existence of NS and SLE in a patient with a KRAS mutation denotes the complexity of the genetic contribution to SLE.Hypertrophic cardiomyopathy is more
frequent in SOS1, KRAS and RAF1
patients, whereas PTPN11 patients
most frequently have pulmonary val-
vular stenosis (4).
It is clear that more research is neces-
sary to clarify the crucial mechanisms
– if they exist – that associate Noonan
syndrome and RAS-MAPK activation
with SLE. However, it is apparent that
Noonan syndrome patients need con-
stant follow-up and demand high clini-
cal awareness in order to achieve prompt
treatment of any clinical comorbidities.
References
1. DENAYER E, D E RA VEL T, LEGIUS E: Clinical
and molecular aspects of RAS related disor-
ders. J Med Genet 2008; 45: 695-703.
2. FLOTHO C, BATZ C, HASLE H et al.: Muta-
tional analysis of SHOC2, a novel gene for
Noonan-like syndrome, in JMML. Blood
2010; 115: 913.
3. CIRSTEA IC, KUTSCHE K, DVORSKY R et al.:
A restricted spectrum of NRAS mutations
causes Noonan syndrome. Nat Genet2010;
42: 27-9.
4. V AN D ER BURGT I: Noonan syndrome.
Orphanet J Rare Dis 2007; 14: 2-4.
5. HOCHBERG MC: Updating the American Col-
lege of Rheumatology revised criteria for the
classi?cation of systemic lupus erythemato-
sus. Arthritis Rheum 1997; 40: 1725.
6. SCHUBBERT S, ZENKER M, ROWE SL et al.:
Germline KRAS mutations cause Noonan
syndrome. Nat Genet 2006; 38: 331-6.
7. LOPEZ-RANGEL E, MALLESON P, LIREN-
MAN DS, ROA B, WISZNIEWSKA J, LEWIS
S: Systemic lupus erythematosus and other
autoimmune disorders in children with Noo-
nan syndrome. Am J Med Genet 2005; 139A:
239-42.
8. LISBONA MP, MORENO M, ORELLANA C,
GRATACOS J, LARROSA M: Noonan syn-
drome associated with systemic lupus ery-
thematosus. Lupus 2009; 18: 267-9.
9. NATH SK, QUINTERO-D EL-RIO AI, KIL-
PATRICK J, FEO L, BALLESTEROS M, HAR-
LEY JB: Linkage at 12q24 with systemic lu-
pus erythematosus (SLE) is established and
con?rmed in Hispanic and European Ameri-
can families. Am J Hum Genet 2004; 74: 73-
82.
10. OLIVEIRA JB, BIDèRE N, NIEMELA JE et al.:
NRAS mutation causes a human autoim-
mune lymphoproliferative syndrome. Proc
Natl Acad Sci USA 2007; 104: 8953-8.