Трансплантация сердца у ребенка с синдромом Нунан
Синдромы, вызванные мутациями в генах, кодирующих компоненты сигнального пути RAS/MAPK
(RASопатии), клинически и генетически гетерогенны.
Наиболее частые проявления этих синдромов - врожденные заболевания сердца и сосудов,
кардиомиопатии, скелетные аномалии, множественные лентиго, предрасположенность к новообразованиям, задержка физического и умственного развития разной степени. Известно, что
мутации более чем в 10 генах приводят к развитию RASопатий, и этот список продолжает пополняться. Развернутый клинический фенотип RASопатий очевиден, однако на ранних стадиях
заболевания постановка диагноза может вызывать определенные трудности.
Цель - в настоящей работе представлен случай успешной трансплантации сердца ребенку
с синдромом Нунан в возрасте 3 года 8 мес.
Материал и методы. Клиническое, биохимическое и инструментальное обследование включало разовые электрокардиограммы покоя и 24-часовое суточное холтеровское мониторирование, допплерографию, ультразвуковое исследование сердца, определение активности ферментов. Генетическое исследование включало классическое цитогенетическое обследование
(кариотип), секвенирование по Сенгеру кодирующих и прилегающих интронных областей генов
LMNA, PTPN11 и RAF1.
Клинический случай. Девочка впервые поступила в детское кардиологическое отделение
в возрасте 4,5 мес с симптомами сердечной недостаточности. Была диагностирована симметричная обструктивная гипертрофическая кардиомиопатия. Учитывая многочисленные особенности
фенотипа, заподозрили синдромную природу заболевания. Был диагностирован синдром Нунан, вызванный мутацией p. Gln510Glu в гене PTPN11. В связи с быстрым прогрессированием гипертрофии миокарда и сердечной недостаточности ребенку выполнена трансплантация сердца.
В течение 1 года после трансплантации состояние девочки стабильное, жалоб на состояние
Заключение. У пациентов с RASопатиями ингибирование мутантного пути RAS/MAPK может рассматриваться как возможный подход к терапии. Однако сейчас для пациентов детского возраста
с быстропрогрессирующей гипертрофией миокарда трансплантация сердца является единственным вариантом лечения с доказанной эффективностью.
Ключевые слова:гипертрофическая кардиомиопатия, синдром Нунан, RAS-каскад, трансплантация сердца, PTPN11, ДНК-диагностика
Клин. и эксперимент. хир. Журн. им. акад. Б.В. Петровского. 2017. № 3. С. 65-70.
Статья поступила в редакцию: 21.06.2017. Принята в печать: 07.07.2017.
RAS proteins bound to certain enzymes, including
RAS mitogen-activated protein kinase (MAPK),
provide regulation of signal transduction, control cellular proliferation, differentiation and survival. RASopathies are group of syndromes caused
by mutations in various genes of the RAS/MAPK
pathway. RASopathies-associated gene panel covers
five major genes, including more than 70% mutations: PTPN11, BRAF, KRAS, RAF1, and SOS1 but the
list of genetic forms was significantly expanded
. RASopathies are characterized by a combination of cardiac and skin changes, dysplastic phenotype, difficulty in learning, some patients develop
lymphoproliferative disorders. This group includes
Noonan syndrome, LEOPARD, Costello syndrome, cardio faciocutaneous syndrome, Legius syndrome and
a wide range of overlapping phenotypes . Cardiac
anomalies associated with RASopathies are characterized by the clinical phenotype of hypertrophic cardiomyopathy and manifest both as cardiac hypertrophy and congenital heart defects (pulmonary artery
stenosis and coarctation of the aorta). Skin changes are not consistent and may develop later to the
age 4-5 years old .
The prevalence of Noonan syndrome, an auto-somal dominant congenital disorder, ranges from
1:2500 to 1:1000 in newborns . About 75% of NS
patients have cardiac abnormalities among which the pulmonary artery stenosis is the most common variant. Hypertrophic cardiomyopathy is detected in 20%
of the patients.
Aim - the present case reports of the successful
heart transplantation due to rapidly progressive cardiac hypertrophy in a 3 year 8 month old girl diagnosed with Noonan syndrome.
Material and methods
Clinical and genetic study was performed based
on Helsinki declaration. Parents had given a written
consent for publication of the clinical description
and open-face pictures. Clinical and instrumental examinations comprised regular general examination,
electrocardiography, doppler echocardiography, 24-h
Holter recording. Biochemical examination included
general and biochemical testing of blood and urine,
enzyme analysis, tandem mass spectrometry (TMS).
Genetic testing involved chromosome analysis, or
karyotype, and the search for mutations in the coding
and adjacent intron regions of the LMNA, PTPN11 and
RAF1 genes by Sanger direct capillary sequencing.
Patient Ksenia N. (DOB 05/05 /2012) first entered the Perinatal Cardiology Center (PCC) of the City Clinical Hospital #67 in Moscow 4.5 months
of age on 20.09.2012. It was known from her
history that the child’s mother was 25 years old
(with hereditary thrombophilia, the proband’s maternal grandmother had 10 years of infertility), the
4th pregnancy (1 pregnancy: m/a; 2 pregnancy: pre-term birth at 33-34 week, the child was born with
congenital GI anomalies, operated; 3 pregnancy:
frozen) complicated by thrombophilia, myopia,
allergic rhinitis, the threat of interruption, colpitis, anemia, ARI. The woman during pregnancy received complex treatment forthe existing diseases.
Second labor with elective induction at 39 weeks.
Birth weight - 3000 g, length - 50 cm, head circumference - 34 cm, chest circumference - 33 cm.
Cephalohematoma of the right parietal bone.
A rough systolic murmur over the heart became
noticeable 9 hours after birth. Echocardiogram
conducted at the maternity hospital revealed
echocardiographic signs of myocardial hypertro-
phy. On the 5th day of life the infant was transferred
from the maternity hospital to the State Children’s
Hospital #1 in St. Petersburg. During the examination symmetrical obstructive hypertrophic cardiomyopathy (HCM) with outflow tract obstruction
of both ventricles, grade 1-2 mitral regurgitation was revealed. Interventricular septum thick-
ness: 15 mm; LV posterior wall thickness: 3 mm;
LV/aortic pressure gradient: 35 mm Hg; combined
pulmonary artery stenosis (PAS) with the pressure gradient between the pulmonary artery and
the right ventricle of 70 mm Hg. The girl was examined for intrauterine infections (IUI), the data
suggesting IUI were not found. From birth the infant had transient factor IX deficiency (at the age
of 2 months IX factor: 37.1% (norm - 44-121%).
For obstructive HCM the child was assigned to
When examined at the PCC, a moderately dysplastic phenotype with macrocrania, exophthalmos
attracted attention (Fig. 1). There were symptoms
of atopic dermatitis. The presence of HCM in combination with the phenotypic traits required the
exclusion of both genetic syndromic pathology and
inherited metabolic disorder. Karyotype: normal female - 46,XX. The absence of macroglossia, hyperferritinemia, myopathic syndrome with the symptomatic
complex of “flaccid child” allowed to exclude Pompe
disease (glycogenosis type II). The results of one-
dimensional electrophoresis of glycosaminoglycans
made in the laboratory of the Research Centre of Medical Genetics (Moscow, RU) showed no abnormalities
which made it possible to exclude mucopolysaccharidosis in the girl. Tandem mass spectrometry (MS)
excluded organic aciduria, hereditary aminoacidopathies, and defects of mitochondrial beta-oxidation.
A slight increase in the concentration of 2-Hydroxybutyrateof homovanillic acid was of nonspecific character. Congenital pathology of the thyroid gland was
Cardiac examination at the PCC showed the presence of obstructive HCM with signs of progression
of the pathological process. Echocardiogram from
24.09.2012: RV outflow tract (RVOT) pressure gradient: 80 mm Hg; left ventricular outflow tract (LVOT)
gradient: 75 mm Hg. Left ventricular posterior wall
thickness: 20мм; interventricular septum thickness:
18мм; RV anterior wall thickness: 13 mm. Because
of symptoms of bronchial obstruction syndrome, beta-adrenergic antagonist metoprolol was replaced by atenolol, after that the wheezing in the lungs ceased to
be heard. Verospiron was added to the treatment due
to the signs of II A stage of circulatory failure.
Further dynamic observation indicated disease
progression: a sleep disorder, shortness of breath,
puffing while breathing. The girl gained weight
badly, despite of good appetite. Diuretic therapy was
strengthened by the addition of furosemide. At the
age of 8 months RV outflow tract (RVOT) pressure gradient was around 100 mm Hg. DNA-based diagnostic
testsmade it possible to exclude mutations in the
LMNA gene (laminopathies) and Hutchinson-Gilford
progeria syndrome (HGPS).
At the age of 10 months (March 2013) the child
was quite active. The moderately dysplastic phenotype was preserved: a brachycephalic skull, macrocrania with a pronounced venous pattern, smaller facial
features, larger eyes with Von Graefe’s sign, and low
set ears. The girl was undernourished (body weight at
admission - 6320 g, length - 69 cm, head circumference - 42 cm, chest circumference - 39 cm). Body weight deficiency in relation to height was 25% (second degree malnutrition). Muscular tone and skin
turgor were reduced. Moderate dyspnea with respi-
ration rate of 36-40 breathsper minute. Blood pressure - 90/60 mm Hg. Heart rate - 104-120 beats per
minute. The borders of relative cardiac dullness were
significantly expanded to the left: upper 2ICS; left
along the left anterior axillary line; right along the
right parasternal line. Heart sounds were sonorous,
rhythmic, a tendency to bradycardia, rough systolic
murmurs with chordalclicks over the whole heart with
an epicenter in 2LICS conducting to the back were
heard. All peripheral pulses were well palpable. The
liver - +2.0 cm. The spleen - +2.0 cm. No teeth.
The child sat down, got up, walked with support,
played with toys on her own, babbled.
The results of the cardiac examination did not
reveal any cardiac rhythm disturbances in the infant, but there were signs of symmetric obstructive
hypertrophic cardiomyopathy with LVEF - 91%; mitral valve regurgitation: grade 2; the left ventricular
outflow gradient - 70 mm Hg; the right ventricular
outflow gradient - 90 mm Hg. The stenoses were
mainly infundibular in nature. The thickness of the
myocardium did not undergo significant changes.
A functioning ductus arteriosus with a left-to-right
shunting of 3.5 mm, as well as sinusoids within the
interventricular septum were detected. There was
no effusion in the pericardial cavity (Fig. 2). Due to
heart failure symptoms treatment with beta-blockers
and diuretics was continued. During examination the child was diagnosed with microscopic hematuria
without signs of urinary tract pathology according to
Fig. 2. Echo-CG
of patient K.
at 4.5 months old.
А - B-mode; В - M-mode
Ksenia N. has had some characteristic extra-cardiac features becoming more prominent with an age.
Postnatal growth retardation was observed. Transitory
micro-hematuria wasfoundalong witha normal renal
ultrasound examination. Ksenia N.’s cognitive development was not impaired.
Genetic screening for the suspected inherited
syndrome was continued in both clinics (Cincinnati,
USA, and Moscow, RU). Mutationр. Gln510Glu in the
PTPN11 gene was revealed (Fig. 3). Diagnosis of the
Noonan syndrome was established based on clinical
appearance and genetic data.
Thus, as a result of the comprehensive examination, the child was diagnosed with the following
clinical diagnosis: Noonan syndrome. Symmetric obstructive hypertrophic cardiomyopathy. Mitral incompetence 2+, tricuspid valve regurgitation 1+. Patent
arterial duct (PDA). Circulatory failure of IIa degree.
ROSS functional class II. Protein-energy undernutri-
tion (PEU) of the II degree.
Given the serious form of the disorder characterized by severe myocardial hypertrophy of both ventricles and interventricular septum with severe bilateral
obstruction and increase in left and right ventricular outflow gradients, symptoms of heart failure, no
response to conservative therapy, and high risk of
sudden death syndrome, on July 22, 2013 Ksenia N.
entered the Heart Institute at Cincinnati Children’s
Hospital Medical Center (Ohio, USA) where the ques-
tion of performing auxiliary surgery for the existing
diseases was considered.
A comprehensive examination showed the impossibility of surgical correction of the existing disorders and the inexpediency of such intervention.
Echocardiogram recorded the following parameters:
LVED - 2.57 cm; LVES - 0.71 cm; RVED - 1.54 cm;
the peak left ventricular outflow gradient - 121 mm
Hg; the systolic gradient - 58 mm Hg; the peak right
ventricular gradient - 107 mm Hg. Almost complete
obliteration of the right ventricle cavity during systole. Interventricular septum thickness in diastole
(IVSd) - 19 mm; interventricular septum thickness in
systole (IVSs) - 23 mm; LV posterior wall thickness
in diastole - 14.6 mm; LV posterior wall thickness
in systole(LVPWs) - 22.7 mm. The ratio of inter-ventricular septum to left posterior ventricular wall
thickness - 1.31. Grade 2 mitral regurgitation, grade
1 aortic insufficiency, grade 1 pulmonary valve insufficiency, moderate left atrial enlargement, hyperdynamic myocardial function. LVEF - 73%.
LV mass - 161.62 g, LV mass index - 311.2 g/m2. The
ductus arteriosus with left-to-right shunt of blood
flow. Absence of pericardial effusion. Accordingly,
the child had HCM with severe right and left ventricular outflow tract obstruction, moderate mitral valve
regurgitation with left atrial dilation, and patent ductusarteriosus.
It was decided that heart transplantation was
the only way to provide real assistance to this patient.
The girl was put on the UNOS heart transplant
waiting list in 2013 (status 1B). Preoperative preparation involved genetic testing, nutritional correction, compulsory preventive vaccination, treatment
of dental caries, and continuation of drug therapy
for severe right and left ventricular outflow tract obstruction. The waiting period for the organ transplant
was 2.5 years. During the whole waiting period the
child’s condition was regarded as very serious. On the
29th January, 2016 Ksenia N. (3 y. 8 m. old) underwent orthotopic heart transplantation at the Heart
Institute of Cincinnati Children’s Hospital Medical
Center (Ohio, USA). The surgery and the nearest post-operative period proceeded without complications.
During histological examination Parvovirus B19 was
found both in the native and donor hearts. Appropriate treatment with intravenous immunoglobulin
was carried out. During 2016 and up to now the child
has received complex immunosuppressive therapy
according to the scheme [the calcineurin inhibitor tacrolimus, antiproliferative agent CellCept® (mycophenolatemofetil), corticosteroid prednisolone]
under the control of regularly conducted catheterizations and endomyocardial biopsies. There were no
signs of rejection and changes in the coronary arteries of the donor heart in the postoperative period
(outcome 1A). To prevent dental caries antimicrobial
therapy was prescribed to the infant. After surgery the
girl’s condition has significantly improved: motor activity has increased (she is learning to ride a scooter,
skates, and a bicycle), her appetite has normalized,
microcirculatory flow has been improved (warm limbs,
pink lips). The child has gained weight which may be
partly caused by corticosteroids. She has a growth
delay: a typical sign of Noonan syndrome. Examination reveals mild pericardial and pleural effusions.
It cannot be ruled out that these changes are also
due to the side effects associated with glucocorticoid
It was one year after cardiac transplantation
on 29.01.2017 (Fig. 4). The child up to the present
time has lived and been observed at the Heart Institute of Cincinnati Children’s Hospital Medical Center
(Ohio, USA). In May 2017 the girl turns 5 years old.
Fig. 4. 1 year after heart
Mutation p. Gln510Glu in the PTPN11 gene was
first described in patients with Noonan syndrome and
rapidly progressive HCM in 2005 . Later this mutation was also found in patients with rapidly progressive severe biventricular obstructive HCM, ventricular
arrhythmias, mitral valve defects, facial dysmorphic
features, “cafe-au-lait” spots, and multiple lentigines
corresponding to the LEOPARD syndrome [4, 5].
Noonan and LEOPARD syndromes caused by mutations in the PTPN11 gene are allelic disorders, and
share most of phenotypic features including high
prevalence of the cardiac hypertrophy .
The myocardial hypertrophy in Ksenia N.’s case
was also severe, symmetrical, and obstructive. The
results of the cardiac examination conducted both
at the Perinatal Cardiology Center in Moscow and
the Heart Institute of Cincinnati Children’s Hospital
Medical Center, and previous clinical descriptions
have completely coincided pointing out the stability
of cardiac phenotype and severe prognosis for the
carriers of thep. Gln510Glu mutation.
Remarkably that thisp. Gln510Glu mutation in
the PTPN11 gene was found in patients with different
clinical phenotype, with Noonan syndrome with
and without multiple lentigines, and clear LEOPARD
Genotype-phenotype correlations in Noonan
syndrome and other RASopathies are now being
actively studied. The prevalence rate of HCM in LS
has been reported to be much higher than that in NS
(70-80% versus 10-25%) . It was shown mutation
in the PTPN11 gene leading to the NS usually
enhance Erk pathway . On the other hand, LEOPARD
syndrome mutations almost exclusively impair
catalytic activity of the PTPN11 . Two independent research groups had studied functional effects
of the p. Gln510Glu mutation, and it seems that
mutant protein share those properties [7, 10].
This clinical observation is more consistent with
Noonan syndrome phenotype at the moment. But
we cannot exclude that additional clinical feature
as skin involvement might appear in our patient
The future perspective of the therapy could be
a gene-specific treatment approach. The promising
results of the target inhibition of RAS/MAPK pathway
was shown in transgenic mice harboring dominant-
negative p. Y279C mutation in the PTPN11 gene
treated by rapamicyne . Rapamicyne inhibits
Akt/mTOR pathway which is usually up-regulated
in LEOPARD syndrome model cells, and it was shown
to completely reverse cardiac hypertrophy inLSmut+/-
mice . The single case of the successful palliative
treatment of the Noonan syndrome infant with rapidly
progressive cardiac hypertrophy with everolimus
(a rapamicyne analogue) was published recently .
It suggests that mutation-specific RAS/MAPK
pathway inhibition might be considered for patients
with RASopathies at least as a bridge therapy before
heart transplantation. Further study is needed to
analyze better short-term and long-term results
of the treatment with ramapicyne and analogues. But
for now the heart transplantation is the only proven
option for pediatric patients with rapidly progressing
The authors thank the parents of the patient for
their cooperation and permission to publish data and
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