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BMJ Case Rep. 2010; 2010: bcr12.2008.1395.
Published online Mar 26, 2010. doi:  10.1136/bcr.12.2008.1395
PMCID: PMC3030133
Rare disease
The role of postmortem study in the diagnosis of the cause of death in a young man: a rare case of Ehlers–Danlos syndrome type IV
Natalia Escribano,1 Ileana Medina,1 Luis Ortega,1 Mª José Jiménez,2 Mª Concepción Millana,1 Roberto Fernández,2 Paloma Aragoncillo,1 and Juliana Fariña1
1Hospital Clínico San Carlos, Pathology, Martín Lagos s/n, Madrid, 28040, Spain
2Hospital Clínico San Carlos, Intensive Care Medicine, Martín Lagos s/n, Madrid, 28040, Spain
Correspondence to Natalia Escribano, nescriba/at/gmail.com
Diagnosis of the cause of death in young people is a challenge to both the clinician and the pathologist. Ehlers–Danlos syndrome (EDS) type IV is an inherited connective tissue disorder. It is characterised by thin translucent skin, abnormal fragility of blood vessels, and a typical facial appearance. The cause of death is usually due to large arterial rupture. We describe an unusual case of a 23-year-old man clinically diagnosed with myocarditis, who suffered from recurrent pulmonary haemorrhage and died of massive myocardial haemorrhage and ischaemia without coronary artery disease. Diagnosis of EDS type IV was made by autopsy. To our knowledge, this is the first such report in the literature. Delay in diagnosing this syndrome is common even when clinical features are typical, and the condition often goes unrecognised until necropsy. The diagnosis of EDS should be considered in young people who seek medical attention because of arterial rupture.
A fatal case of cardiogenic shock due to generalised myocardial bleeding and ischaemia without coronary artery disease in a patient with Ehlers–Danlos syndrome (EDS) type IV has not previously been reported. Among the different types of EDS, type IV is suitable for special attention due to its peculiar natural history and poor prognosis. In cases of sudden death and in patients who deteriorate quickly, the postmortem study may be the only way to determine the cause of death. This may be of great importance not only for the physicians, but also for the family of the patient, because first degree relatives may then be able to undergo possible screening to prevent other sudden deaths.
Brief relevant presenting history
A 23-year-old man was admitted to our institution with dyspnoea and fatigue of sudden onset. He was asymptomatic until the day of the admission to our hospital, at which time he did not complain of syncope, chest pain or haemoptysis, but he had progressive and severe dyspnoea and fatigue. He had no history of cocaine abuse.
Background or previous history
Six years before admission the patient had been diagnosed with myocarditis, and presented with an episode of syncope without chest pain. The electrocardiogram (ECG) showed inferior ST segment elevation, with a peak value of cardiac troponin I 2.9 ng/dl. Left ventricular ejection fraction at echocardiography was 55% without segmentary motility abnormalities, and coronary angiography was normal. The ECG changes and cardiac troponin I normalised and he was discharged.
A month later, the patient was admitted to another hospital because he had an episode of spontaneous tetraparesis and generalised parethesias from which he recuperated completely in a few hours. Brain computed tomography (CT), magnetic resonance imaging (MRI), electroencephalogram (EEG) and Doppler echography of the supra-aortic vessels were normal. He was discharged without neurological sequelae.
He also had a long history of hypotonia and recidivant spontaneous dislocation of the right knee. Surgical history included removal of a pilonidal cyst and varicotomy in the right leg.
One month before admission the patient presented with substernal chest pain, dyspnoea and haemoptysis. The ECG was normal. A diagnosis of left haemopneumothorax was achieved and he was treated with a chest tube. A high resolution CT scan of the chest, undertaken 3 days after admission, demonstrated small cavitated nodules in the right upper lobe (RUL) and micronodules in right intermediate lung (RIL) that were radiologically interpreted as tuberculous nodules. The patient was discharged 15 days later.
Physical examination
The patient was a thin, white man with a narrow face, but not “marfanoid habitus”. It was not noticed that he had translucent skin. He was conscious, cyanotic and diaphoretic. His body temperature was 37°C, pulse 138 beats/min and blood pressure 70/40 mm Hg. Peripheral O2 saturation was 70% on pulsoximetry.
Chest examination revealed tachypnoea, dyspnoea, and severe respiratory distress with use of intercostal and accessory respiratory muscles. On chest auscultation there were basal bilateral rales with left basal hypoventilation. Heart sounds were normal, without murmurs or gallops.
Neurological examination was normal; the strength of the four extremities was 5/5, with no sensory or deep tendon reflexes abnormalities.
Relevant clinical investigations and results
The ECG showed sinus tachycardia and generalised ST segment elevation in leads I, aVL, II, avF and V2–V6 (fig 1).
Figure 1
Figure 1
Electrocardiogram showing generalised ST segment elevation in leads I, aVL, II, avF and V2–V6.
The cardiothoracic ratio was normal on the chest radiograph and there was left pleural effusion without signs of pulmonary congestion. Cardiac troponin I value at admission was 0.06 ng/dl, An echocardiogram showed generalised severe hypokinesis and ruled out pericardial tamponade.
Management
The patient was in severe cardiogenic shock and underwent urgent orotracheal intubation, mechanical ventilation, pressor support and admission to the intensive care unit (ICU). A few minutes after ICU admission the patient presented pulseless electrical activity arrest (ECG monitoring showed persistent sinus tachycardia and ST segment elevation), requiring advanced cardiopulmonary resuscitation and intra-aortic balloon pump support. In spite of resuscitation efforts the patient did not recover and died 1 h after hospital admission. Because of the rapidly fatal outcome, a necropsy was performed with the presumptive diagnosis of tuberculosis and myocarditis versus myocardial infarct of toxic (cocaine) aetiology.
At autopsy, the patient was a thin, white man with a narrow face, a pinched nose and had thin translucent skin. The lungs had a combined weight of 990 g, were congested and oedematous, and showed multiple microcalcifications scattered throughout the lobes. There was a haemorrhagic cavity measuring 3 cm in the left upper lobe (fig 2). No alterations were founded in pulmonary vasculature. The heart weighed 380 g and showed massive haemorrhage in the posterior, lateral and anterior myocardial walls (fig 3). The right and left ventricles were dilated. No alterations were founded in the coronary tree.
Figure 2
Figure 2
Haemorrhagic cavity in the upper left lobe of the lungs.
Figure 3
Figure 3
Massive haemorrhage in the heart involving left and right ventricular walls.
Microscopically, the lungs showed pronounced acute diffuse alveolar haemorrhage, haemosiderosis and osseous metaplasia. No necrotising granulomatous lesions were found. Myocardial findings revealed extensive and generalised haemorrhage in the intercellular space and scattered myocardial ischaemic changes throughout all the myocardial walls. There was no evidence of inflammatory infiltrate or pericardial tamponade. Coronary and cerebral arteries had fragmented elastic tissue fibres in the walls (fig 4) but no aneurysms, dissections, stenosis or thrombi were founded. No infarcts or granulomatous lesions were found in brain. The skin showed a thinned dermis with reduction in the density of the collagen fibres and a relative increase of elastic fibres with shortening and fragmentation (fig 5).
Figure 4
Figure 4
Fragmentation of the internal elastic lamina of a coronary artery (orcein stain, ×20).
Figure 5
Figure 5
Skin showing a thinned dermis with reduction in the density of collagen fibres (haematoxylin and eosin stain, ×10).
Tests for cocaine and other toxic drugs were negative. Findings from blood, pleural effusion and lung tissue special stainings as well as cultures for bacteria, fungus and mycobacteria were negative. HIV, hepatitis B and C virus, and cardiotropic virus serology were also negative.
On the basis of these findings, vascular EDS was considered likely, so a genetic study was performed in the molecular diagnosis laboratory “Sistemas Genómicos” (Valencia, Spain). The result of the polymerase chain reaction and sequencing of genomic DNA from a skin specimen revealed a heterozygous-type mutation, c.1761+1G>A (IVS24+1G→A) in the Col 3A1 gene, confirming the diagnosis of EDS type IV.
The clinical presentation of our patient was compatible with refractory cardiogenic shock secondary to generalised myocardial ischaemia or myocarditis, leading to cardiac arrest and sudden death. Because of the rapidily fatal outcome in less than 1 h after admission, there was only one cardiac troponin I determination, which was normal. The chest radiograph showed left pleural effusion without evident signs of pulmonary congestion, and the echocardiogram showed generalised severe hypokinesis and ruled out pericardial tamponade.
There was no evidence of coronary disease (no aneurysms, dissections, stenosis or thrombi were found) that could have been the cause of the ECG changes and the fatal course. The challenge for the pathologist was to find a diagnosis that might account for the history of haemoptysis, haemopneumothorax and myocardial ischaemia or myocarditis.
The differential diagnosis can include infections, cardiovascular disorders, cocaine abuse, connective tissue disorders, and collagen vascular diseases. Pneumothorax, haemoptysis and cardiovascular complications can occur in patients with Marfan syndrome and EDS. Tuberculosis and cocaine are other possible causes of haemoptysis, pneumothorax and myocardial ischaemia. The microscopic examination at autopsy showed a connective tissue alteration that involved the skin, blood vessels and lung parenchyma, leading to the suspicion of a connective tissue disease. These findings could be consistent with Marfan syndrome, but there was no mention of arachnodactyly, scoliosis or joint hypermobility, and no arterial aneurysms were found. Although it was not noticed on a previous physical examination, at autopsy the skin was noted to be very thin and translucent, which is a hallmark of the vascular type of EDS. A skin sample was submitted for genetic testing, confirming our suspected diagnosis.
EDS type IV is an inherited connective tissue disorder that is caused by a structural defect in the proα1 (III) chain of type III collagen, encoded by the COL3A1 gene. Extensive bruising, spontaneous arterial rupture and a typical facial appearance are predominant features of this type. The cause of death is usually due to large arterial rupture. The precise incidence and prevalence of vascular EDS are not known, and in part because of its rarity, the diagnosis is often made only after a catastrophic complication or at a postmortem examination.1
In reported EDS type IV patients, pneumothorax is the most common pulmonary clinical manifestation and haemoptysis occurs in approximately 25% of patients.2 As in our case, other EDS type IV patients who experienced repeated pulmonary haemorrhage showed pulmonary anomalies that consist of haemosiderosis and osseous metaplasia.3 Diffuse osseous metaplasia is an uncommon condition that it is usually not diagnosed clinically and may be apparent radiographically only when extensive. Even experienced radiologists may confuse it with other entities such as chronic granulomatous disease.4
Acute myocardial infarction in EDS type IV patients is a rarely reported complication (only 10 cases in the literature), and most of them were due to coronary dissection or rupture.5,6 To our knowledge, a fatal case of cardiogenic shock due to generalised myocardial bleeding and ischaemia without coronary artery disease in a patient with EDS type IV has not previously been reported. In one case autopsy revealed myocardial injury in the distribution of the left coronary artery and aneurysms of the sinuses of Valsalva, but no occlusive coronary disease.7 One patient developed an inferior acute myocardial infarction 2 h after a thoracotomy for haemopneumothorax and died 1 week later because of spontaneous rupture of the splenic artery and haemorrhagic shock. His autopsy revealed scattered fibrotic foci surrounding peripheral coronary veins extending into the intercellular space in inferior and lateral myocardial walls, and ruled out coronary artery disease.8 In two cases, the diagnosis of myocardial infarction was based on localised changes in the ECG and serum enzymes, but coronary disease could not be ruled out because coronary angiography was not performed and both patients were discharged.9
Multivessel coronary vasospasm leading to cardiac arrest could not be ruled out in this case. Usually it is associated with ventricular arrhythmias and in some cases related to arterial hyperreactivity because of local inflammation in the coronary arterial wall10; however, our patient did not have ventricular arrhythmias and there was no evidence of coronary or myocardial inflammatory infiltrate at autopsy.
The exact nature of vascular lesions has been a matter of debate and confusion in the literature.11 It has been suggested that the liability of the capillary vessels to rupture is due to a defect in the surrounding supporting connective tissue. In our case, it is most likely that the fragility of the small heart vessels together with a defect in the interstitial collagen may have caused the generalised myocardial haemorrhage and ischaemic changes, compounded by hypoxaemia secondary to severe pulmonary involvement.
In the present case, the patient had no siblings. His family had no symptoms and denied performing a genetic study, so we could not confirm if this patient represents a sporadic or an hereditary case.
Learning points
  • A fatal case of cardiogenic shock due to generalised myocardial bleeding and ischaemia without coronary artery disease in a patient with Ehlers–Danlos syndrome (EDS) type IV has not previously been reported.
  • This case emphasises the importance of considering developmental vascular abnormalities in young adults who present with unusual spontaneous lung haemorrhage, and underlines the implication of autopsy findings for relatives.
  • Early recognition of the disease by clinical manifestations and past medical history is of extreme importance to prevent complications of investigative and surgical procedures.
Footnotes
Competing interests: None.
Patient consent: Patient/guardian consent was obtained for publication.
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