Features of Marfan syndrome not listed in the Ghent nosology – the dark side of the disease

Figures & data

Figure 1. Evaluative estimation of the clinical significance of suggested features of the Marfan syndrome.

Table 1. Patients‘ symptoms reported by the German Marfan Organization

Patients complaints*
Major	Minor
Valvular features (chapter 4)
None	None
Myocardial features (chapter 5)
None	None
Electrophysiologiscal features (chapter 6)
None	Tachycardia
Aortic branching vessels (chapter 7)
None	Hypotension especially in adolescence
	Syncope especially in adolescence
Lung features (chapter 8)
None	None
Sleep physiology (chapter 9)
None	None
Abdominal features (chapter 10)
Renal cysts	Gastritis
Hepatic cysts	Splenic cysts
Gastric complaints	Canker sores
Intestinal complaints
Urogenital features (chapter 11)
Bladder problems	Incontinence
Urinary tract infection	Maldescensus testis
Pregnancy with premature labor	Ovarian Cysts
	Kidney stones
Musculo-skeletal features (chapter 12)
Otitis media	Deviated nasal septum including surgical correction in adolescence
Sinusitis	Recurrent infections including angina tonsillitis, otitis media, sinusitis
	Hemangioma of thoracic vertebral body
	Ingrown nails of the big toe
	Manifest osteoporosis
	Pelvic tilt
Dermatological features (chapter 13)
Psoriasis (located only on the head)	Plantar soft tissue tumors, sometimes with necrotizing
	Dry, scaly skin
Dental features (chapter 14)
Dental roots that are elongated, or wondrous, or elongated bending upward or downward	Dental enamel problems
	Gum bleeding
Headache as neurological feature (chapter 15)
Headache
Migraine
Psychological features (chapter 16)
Autism	Developmental delay
Asperger syndrome
Attention Deficit Syndrome (ADS)
Joint pain
Hemostatic features (chapter 17)
None	Recurrent thrombosis
	Coagulation disease
Eye features (chapter 18)
Early onset cataract	Prolonged conjunctival wound healing

*We considered symptoms major with frequent mentioning, and minor with clearly less frequent mentioning.

Table 2. Initial Medline search for features or symptoms of Marfan syndrome

Cluster	Organ	Organ involvement	Number of publications*
1	Heart valves
		Mitral valve prolapse	4
		Tricuspid valve prolapse	13
		Bicuspid aortic valve	3
		Pulmonary valve disease	1
2	Myocardium
		Cardiomyopathy	17
3	Cardiac arrhythmia
		Ventricular arrhythmia	21
		Wolff-Parkinson-White syndrome	8
		Long-QT	1
		Heart block	5
6	Vascular
		Coronary artery	2
		Cerebral artery aneurysm	17
		Visceral arteries	3
		Tortuosity or aneurysm of medium sized arteries	11
7	Atherosclerosis
		Cardiovascular risk factors	5
		Atherosclerotic disease/Coronary artery disease	1
4	Sleep-disordered breathing
		Obstructive sleep apnea (OSA), central sleep apnea (CSA)	19
5	Lung
		Emphysema	11
		Bronchiectasis	8
		Lung Custs	2
8	Abdomen
		Hepatic cysts	8
		Diaphragmatic hernia	21
		Obturator hernia	3
		Paraesophageal hernia	2
		Other hernia	21
		Diverticula	7
		Biliary tract	1
		Colon manifestations	2
		Sigmoid volvulus	3
		Other abdominal	9
9	Urogenital
		Kidney cysts	4
		Kidney diseases	27
		Testicular hydrocele	3
10	Musculoskeletal
		Osteoporosis	11
		Craniofacial manifestations	1
		Myopathy	2
11	Skin
		Striae and other signs	2
12	Dental
		Oral manifestations	4
13	Neurology
		Spontaneous cerebrospinal fluid leaks	15
		Vasomotor dysfunction	1
14	Psychology
		Fatigue	3
		Cognitive dysfunction	1
		Chronic pain	1
		Psychiatric	3
15	Thrombopathy
		Platelet dysfunction	3

*The specific references are available as supplementary data.

Table 3. Association of feature with syndrome

		Association of feature with syndrome			Number of publications*
Chapter	Suggested features of MFS	MFS	LDS	vEDS	LDS	vEDS
4	Valvular features
	Bicuspid aortic valve	-	+	-	6	1
	Mitral valve prolapse	+++	++	+	15	8
	Pulmonary valve prolapse/regurgitation	++			2	1
	Tricuspid valve prolapse	+++	+	-	1
5	Myocardial features
	Heart failure	+	+	-	7	2
	Cardiomyopathy	+++	+	-	2	2
6	Electrophysiological features
	Supraventricular arrhythmia	+	+	-		4
	Ventricular arrhythmia	++	+	-	2	1
	Abnormal repolarization	+	+	-	1
7	Aortic branching vessels
	Coronary Artery Disease
	Spontaneous coronary artery dissection	++	++	+++	4	11
	Anomalous coronary arteries	+	+	-	4	1
	Atherosclerotic coronary artery disease	-	-	-
	Other aortic branching vessels
	Tortuosity, aneurysm, and dissection	+++	+++	+++	2	1
	Cerebral/carotid arteries	++	+++	++	11	1
	Visceral arteries	++	+++	+++	2	10
	Spontaneous cervical artery dissection	++	++	+++	3	18
8	Lung features
	Restrictive lung disease	++	+	-		1
	Parenchymal lung disease	++	-	-	3	1
	Airway disorders	++	+	-		1
9	Sleep physiology features
	Obstructive sleep apnea	+++	++	-	1	6
	Central sleep-apnea	++		-
10	Abdominal features
	Liver and kidney cysts	+++		-		1
	Biliary tract features	-	-	-		1
	Diaphragmatic hernia	++	++	+	3
	Adiposity	+++		-
11	Urogenital features
	Preterm labor	-	+	+++	1	3
	Urinary incontinence	+		-	1	7
12	Musculo-skeletal features
	Myopathy	++	++	++		2
	Reduced bone mineral density	++	+	+	1	1
	Craniofacial manifestations	+++	+++	+++	3
13	Dermatological features
	Atrophic scars	++	++	+++	1
14	Dental features
	Caries	+	+		1	5
	Craniomandibular dysfunction	+++	+++	+++		3
15	Headache
	Migraine	+	+	+	1	2
	Spontaneous cerebrospinal fluid leakage	+++	++	-	1	4
16	Psychological features
	Cognitive dysfunction	-	+	-	3	2
	Schizophrenia	-	-	-
	Depression	+	+	+
	Fatigue	++	++	++		2
	Pain	+++	+++	+++		1
17	Hemostatic features
	Activated fibrinolysis, thrombin, platelets	+	+	+		4
	Acquired von Willebrand disease type 2a					1
	Platelet dysfunction				1	3

MFS identifies Marfan syndrome; LDS, Loeys-Dietz syndrome; and vEDS, vascular type of Ehlers-Danlos syndrome.

We grade the strength of association of a respective feature with a respective syndrome as -, with no association with the respective syndrome; +, likely association, ++, strong association; +++, as very strong association.

*The specific references are available as supplementary data.