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Hellenic J Cardiol 2013; 54: 143-146
Case Report
Idiopathic Pulmonary Arterial Hypertension in a
Young Patient with the Cohen Syndrome
Philip Cokkinos, Aggeliki Gkouziouta, George Karavolias, Panagiotis Kariofillis,
Vassilis Voudris
Second Cardiology Department, Onassis Cardiac Surgery Centre, Athens, Greece
Key words:
Cohen syndrome,
Pulmonary
Hypertension.
Manuscript received:
July 29, 2011;
Accepted:
December 22, 2011.
Address:
Philip Cokkinos
Second Department of
Cardiology
Onassis Cardiac Surgery
Centre
356 Syngrou Avenue
176 74 Athens, Greece
e-mail: philipcokkinos@
yahoo.com
We admitted a 16-year-old boy with the Cohen syndrome to our institution for increasing dyspnoea. Investigations revealed idiopathic pulmonary hypertension. He was commenced on bosentan and oral anticoagulation and was followed up for nearly 7 years, during which he was readmitted for dynamic measurements of
pulmonary artery pressure. Despite initial improvement, the right heart pressures increased again and sildenafil was added. His final hospitalisation was due to increasing breathlessness and episodes of syncope.
The addition of prostacyclin conferred no reduction in pulmonary artery pressure. The patient suffered a cardiac arrest and remained intubated for 2 weeks, during which Klebsiella pneumonia and superinfection with
the H1N1 swine flu virus occurred. The patient died due to multi-organ failure, nearly 7 years after his initial
diagnosis. The Cohen syndrome, its phenotype and clinical findings, and the incidence and treatment of pulmonary hypertension are discussed.
W
e describe the rare case of a
young patient with the Cohen
syndrome (an autosomal recessive disorder, MIM 216550)1 and idiopathic pulmonary hypertension which was
diagnosed in our institution. He was followed up for nearly 7 years before dying
from worsening heart failure, complicated
by pneumonia and superinfection with the
H1N1 swine flu virus. To our knowledge,
this is the first such case to be described.
Case presentation
A 16-year-old boy with the Cohen syndrome was referred to our institution because of increasing dyspnoea. In the 12
months before admission he had frequent
breathlessness on exertion, could not walk
more then 100 m outdoors, and exhibited
agitation. Some episodes were relieved by
squatting, but there was no cyanosis. The
boy had suffered from epilepsy since the
age of 2 but there were no recent fits or
syncopal episodes.
The patient had been born of healthy
parents with a normal, full-term delivery.
His family lived on an Aegean island, and
the boy was diagnosed with the Cohen
syndrome at the age of 23 months. He was
being followed up in a specialist paediatric
unit, where the 8q21.2/8q21.3 translocation1,2 had been originally identified.
An older sister, who may have had the
same phenotype, had died in childhood
after the administration of a general anaesthetic, but no autopsy had been performed.
On clinical examination, the features
of the Cohen syndrome were apparent
and further confirmed: 1 microcephaly,
small cranial base, micrognathia with a
short philtrum, prominent incisors, high
palate, long fingers, truncal obesity, scissors gait, hypotonia, lateral nystagmus,
mild optic atrophy and temporal hetero(Hellenic Journal of Cardiology) HJC • 143
P. Cokkinos et al
chromia iridis (Figures 1 & 2). The patient had mental retardation with a recorded IQ <50 and a vocabulary of less than 100 words at age 16.
Figure 1. The young patient on admission at age 16. Photograph
used with parental permission.
Figure 2. Facial features include microcephaly, prominent upper
incisors and high nasal bridge. Photograph used with parental
permission.
144 • HJC (Hellenic Journal of Cardiology)
Cardiovascular examination revealed an elevated jugular venous pressure, a prominent parasternal
right ventricular heave, an ejection systolic murmur
of 3/6 intensity over the pulmonary area, normal arterial blood pressure of 100/65 mmHg, and clear lung
fields. The 12-lead electrocardiogram demonstrated
characteristic right ventricular hypertrophy and strain
with right axis deviation (Figure 3).
Transthoracic and transoesophageal echocardiography showed a normal left ventricle, a dilated right
ventricle with preserved systolic function, moderate
tricuspid regurgitation with an estimated right ventricular systolic pressure of 90 mmHg, and no intracardiac shunt.
Left and right cardiac catheterization revealed
normal coronary arteries, a systolic pulmonary artery
pressure (SPAP) of 96 mmHg, and a pulmonary vascular resistance (PVR) of 6.9 Wood units.3 No shunt
or congenital abnormality was detected.
We further investigated the patient with spiral
chest CT and a ventilation/perfusion lung scan, both
of which were negative for pulmonary embolism.
Lung function tests were within normal limits and no
restrictive lung pattern was observed. A sleep study
revealed no episodes of apnoea. All tests for thrombophilic conditions were negative and the coagulation
and immunology screen was normal. No neutropenia
was observed. During his hospitalisation, one of the
central venous catheterisations resulted in a right-sided pneumothorax, and the parents refused to proceed
to a proposed lung biopsy.
The young patient was treated with frusemide, a
β-blocker, and sodium valproate for his epilepsy. Oral
anticoagulation with a coumarinic agent was started.
We concluded that this was a case of idiopathic pulmonary hypertension and initiated treatment with
bosentan (Tracleer), a dual endothelin-receptor antagonist, at a starting dose of 62.5 mg bd, progressing
to 125 mg bd as his liver function tests remained stable.3,4 Attempts to treat him with nebulised prostacyclin failed due to very poor compliance, although he
had initially responded to a dynamic trial.
There was some clinical improvement (to New
York Heart Association, NYHA class II), and subsequent echocardiograms and readmissions for right
heart catheterisation at 6-monthly intervals showed
a reduction of the SPAP to 60 mmHg. Four years after initial diagnosis, the patient’s dyspnoea returned
to NYHA III and the SPAP to 90 mmHg, so we added sildenafil (Viagra) 25 mg bd, with prompt clinical and haemodynamic improvement.3,4 However, 2
Idiopathic pulmonary hypertension and Cohen syndrome
Figure 3. The patient’s 12-lead ECG on admission, showing right ventricular hypertrophy and strain with right axis deviation.
years later (6.5 years after initial diagnosis), at the
age of 23, he was urgently readmitted due to severe
shortness of breath (NYHA IV) and recurrent syncopal episodes which were not attributable to epilepsy.
Immediate echocardiography showed a markedly dilated right ventricle, and the patient suffered a cardiac arrest with pulseless electrical activity before a
palliative atrial septostomy could be attempted. He
was successfully resuscitated, but developed resistant
high-grade fever within 24 hours. Urgent right heart
catheterisation revealed a SPAP of 98 mmHg and a
PVR of 6.5 Wood units. He remained intubated for
2 weeks, during which intravenous prostacyclin, inotropes and nitric oxide were also administered. His
condition was further complicated by multi-resistant Klebsiella pneumonia and superinfection with
the swine flu H1N1 virus strain on pharyngeal smear
polymerase chain reaction.5 Multiple antibiotics and
oseltamivir (Tamiflu)6 were administered, but uncontrolled sepsis developed and the young man died of
multi-organ failure on the 16th day of his last admission, nearly 7 years after the initial diagnosis of idiopathic pulmonary hypertension.
Discussion
We describe a rare case of idiopathic pulmonary arterial hypertension (PH) in a young patient with the
Cohen syndrome. To our knowledge, this is the first
such fully presented case, with a survival of nearly 7
years from initial diagnosis.
First described by Dr Michael Cohen in 1973,7
this syndrome constitutes an autosomal recessive disorder (MIM 216550) which is over-represented in
Finland. 8 The typical clinical picture includes psychomotor retardation, microcephaly with characteristic facial features, early hypotonia, and retinochoroidal dystrophy.8,9 Granulocytopenia has also been
described.10
More than one genetic abnormality has been described and in some series no chromosomal abnormalities have been found, but the best described is
linked to a mutation of the COH1 gene11 on chromosome 8q, which is common in Finland; this was also
the case in our patient.2,11 Genetic and clinical heterogeneity can exist among described series.
The cardiovascular system is sometimes involved
(Hellenic Journal of Cardiology) HJC • 145
P. Cokkinos et al
in these patients, with reports of mitral valve prolapse
and decreasing left ventricular function with advancing age.12,13
The syndrome manifests differently at different
ages and diagnosis remains difficult in infancy. The
prognosis is variable and patients can remain in good
health into middle age.12
Although pulmonary hypertension has been mentioned in association with this syndrome, no specific
case reports have been published in the international literature, and certainly none with such a detailed
workup and follow up. The mechanism for pulmonary
hypertension is unclear, and although multiple coagulation defects, a restrictive lung pattern, and asplenia
have been implicated in some patients,14 it appeared
to be idiopathic in our case.
These patients are of anaesthetic concern during
surgical procedures because of facial asymmetry and
mandibular hypoplasia, which can make tracheal intubation difficult.15
The recommended treatment for PH is the use of
prostaglandin analogues by continuous intravenous
infusion or in nebulised form. Bosentan (Tracleer) is
a relatively recently introduced dual endothelin-receptor antagonist which downgrades smooth muscle
cell proliferation and constriction of the pulmonary
vasculature. Placebo-controlled trials have shown it
to improve symptoms and 6-minute walk capacity,
while reducing mean pulmonary pressure and vascular resistance and increasing cardiac output. It has
been proven to increase 3-year survival in patients
with PH, either in isolated use or combined with other agents such as epoprostenol.3,4,16 The drug binds to
albumin, is metabolised in the liver and excreted in
bile, so hepatic enzymes must be closely monitored.
Sildenafil (Viagra), a selective phosphodiesterase-5 inhibitor, has demonstrated favourable effects
in PH, with improvement in exercise capacity, haemodynamic parameters, and functional class.3,4 Many patients receive combination therapy.
Specialist centres are necessary for the proper
evaluation and follow-up of patients with pulmonary
hypertension. 17 Survival rarely exceeds 5 years. In
our case, the first such described of idiopathic pulmonary hypertension in the Cohen syndrome, survival
was nearly 7 years from diagnosis before the disease’s
inexorable progression, the development of resistant pneumonia and superinfection with H1N1 swine
flu caused our young patient’s dramatic decline and
eventual demise.
We believe that the novel diagnosis of the Cohen
146 • HJC (Hellenic Journal of Cardiology)
syndrome in a young patient should inspire proper
cardiac work-up to exclude pulmonary hypertension,
which carries an adverse prognosis.
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