Diagnosis of Marfan syndrome

There are 3 simple and accurate signs to detect arachnodactyly.

• The 1 finger sign, or Steinberg symptom, is when 1 finger protrudes from behind the hypothenar when the fist is clenched.
• The wrist sign, or Walker-Murdoch symptom, is the crossing of one finger over the little finger when grasping the hand in the area of the wrist joint of the other hand.
• The metacarpal index (radiological sign) is the average length of the metacarpus divided by the average width of the segment from the 2nd to the 4th metacarpal bone, normally 5.4-7.9, and with SM - more than 8.4.

The diagnosis of Morfan syndrome is based on the international Ghent criteria adopted by a group of experts. The algorithm is based on the identification of major and minor criteria characterizing the severity of connective tissue changes in organs and systems. Major criteria indicate the presence of pathologically significant changes in the corresponding organ system, minor criteria indicate the involvement of a particular system in pathology. The requirements for the diagnosis of Morfan syndrome vary depending on the hereditary anamnesis data.

For the patient being examined:

• if the family or hereditary history is not burdened, Marfan syndrome is established in the presence of major criteria in at least two different organ systems and involvement of a third system;
• In the case of a mutation known to cause Morfan syndrome in others, one major criterion in one organ system and involvement of a second system is sufficient.

Ghent criteria for the diagnosis of Marfan syndrome (De Raere A. et al., 1996)

Major criteria (signs)	Minor criteria (signs)
Bone and skeletal
Four out of eight:	Arched palate with tooth hilling
Keel-shaped chest deformity;	Moderate pectus excavatum
Funnel chest deformity requiring surgical intervention;	Joint hypermobility
Upper to lower body segment ratio <0.89 or arm span to body length ratio >1.03;	Skull deformity (dolichocephaly, hypoplasia of the zygomatic bones, enophthalmosis, downward slanting palpebral fissures, retrognathia)
Positive tests of the first finger and wrist;
Scoliosis >20' or spondylolisthesis;
Decreased ability to straighten the elbow to 170* or less;
Medial displacement of the medial malleolus resulting in flat feet;
protrusion of the acetabulum of any degree (confirmed by radiography)
Changes in the musculoskeletal system meet the major criterion if at least 4 of the above 8 major signs are detected. The musculoskeletal system is involved if at least 2 major signs or 1 major and 2 minor signs are detected.
Visual system
Subluxation of the lens	Abnormally flat cornea (based on keratometry results)
	Increased axial length of the eyeball (according to ultrasound measurements) with myopia
	Iris hypoplasia or ciliary muscle hypoplasia causing miosis
The visual system is involved if 2 minor criteria are met
Cardiovascular system
Dilation of the ascending aorta with or without regurgitation and involvement of at least the sinuses of Valsalva; or Ascending aortic dissection	Mitral valve prolapse Dilation of the pulmonary artery trunk in the absence of valvular or peripheral pulmonary stenosis or any other obvious cause in patients under 40 years of age Mitral annular calcification in patients under 40 years of age Dilation or dissection of the thoracic or abdominal aorta in patients under 50 years of age
The cardiovascular system is involved if 1 major and 1 minor criterion are met
Respiratory system
None	Spontaneous pneumothorax, or
	Apical bullae confirmed by chest radiograph
The pulmonary system is involved if 1 minor criterion is detected
Leather
None	Atrophic striae not associated with significant changes in body weight, pregnancy or frequent local mechanical stress
	Recurrent or postoperative hernias
Skin is involved if 1 minor criterion is met
Dura mater
Lumbosacral dural ectasia detected by CT or MRI	None
Family and hereditary history
The presence of close relatives who independently meet these diagnostic criteria	None
Presence of a mutation in the FBN1 gene
Presence of DNA markers of SM among relatives
Engagement with 1 major criterion

For individuals who are related to a patient diagnosed with Marfan syndrome, a major criterion in the family history is sufficient, as well as one major criterion in one organ system and involvement of another system.

In 15% of cases, cases of Morfan syndrome are sporadic, parents may have erased signs, the incidence of the disease increases when the father is over 50 years old. In families of patients, gastrointestinal diseases, vegetative and vertebrogenic disorders, eye diseases are common. If Morfan syndrome is suspected, an ophthalmological examination is mandatory. In the urine of patients, an increased content of oxyproline, glycosaminoglycans is determined, these indicators are nonspecific and occur in all disorders of connective tissue metabolism, while the excretion of oxyproline reflects the severity of the disease. The aggregation function of platelets is impaired. Mitral valve prolapse is found in most patients, with Morfan syndrome, more often than with primary mitral valve prolapse, a deflection, an increase in the size of the valves and chord disorders are detected.

Differential diagnostics are carried out with diseases that have a marfanoid phenotype. In addition to Marfan syndrome, the authors of the Ghent criteria identified hereditary conditions that are phenotypically similar to it.

• Hereditary contractural arachnodactyly (OMIM 121050).
• Familial thoracic aortic aneurysm (OMIM 607086).
• Hereditary aortic dissection (OMIM 132900).
• Hereditary ectopia lentis (OMIM 129600).
• Familial Marfanoid appearance (OMIM 154750).
• MASS phenotype (OMIM 604308).
• Hereditary mitral valve prolapse syndrome (OMIM 157700).
• Stickler syndrome (hereditary progressive arthro-ophthalmopathy, OMIM 108300).
• Spritzen-Goldberg syndrome (marfanoid syndrome with craniosynostosis, OMIM 182212).
• Homocystinuria (OMIM 236200).
• Ehlers-Danlos syndrome (kyphoscoliotic type, OMIM 225400; hypermobility type, OMIM 130020).
• Joint hypermobility syndrome (OMIM 147900).

All these hereditary connective tissue disorders have common clinical features with Morfan syndrome, which is why it is so important to strictly adhere to the diagnostic criteria. Given the complexities of molecular genetic studies, the diagnosis of Morfan syndrome and the above-mentioned syndromes that have a number of common phenotypic manifestations with it remains, first of all, a clinical task. If the patient lacks 2 major criteria in 2 systems and signs of involvement of the third, the diagnosis of Morfan syndrome cannot be made.

Among the syndromes listed above that are close to Marfan syndrome, the most common ones are Marfan-like appearance, MASS phenotype, joint hypermobility syndrome, and hereditary mitral valve prolapse syndrome, which belong to the UCTD group.

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