What is the recommended initial work‑up and management for a 9‑month‑old infant with suspected Marfan syndrome?

Initial Work-Up and Management for a 9-Month-Old Infant with Suspected Marfan Syndrome

Immediately obtain a transthoracic echocardiogram to measure aortic root dimensions at the annulus, sinuses of Valsalva, sinotubular junction, and ascending aorta, as aortic root dilation is present in most infants with Marfan syndrome and serves as an objective diagnostic indicator, while mitral valve prolapse and progressive mitral regurgitation represent the leading causes of cardiovascular morbidity in this age group. 1

Cardiovascular Assessment (First Priority)

Echocardiography is the cornerstone of diagnosis and must be performed urgently:

• Measure aortic root diameter at four specific locations: aortic annulus, sinuses of Valsalva, sinotubular junction, and distal ascending aorta 2, 3
• Calculate Z-scores indexed to body surface area; a Z-score ≥+2 standard deviations defines aortic root dilation 3
• Assess for mitral valve prolapse, which occurs in nearly all affected infants and may progress rapidly 1
• Evaluate for mitral regurgitation severity, as this is the primary cause of cardiovascular morbidity requiring valve replacement in early childhood 1
• Document left ventricular function and assess for tricuspid valve abnormalities 2, 3

Critical finding: In a landmark study of 15 infants diagnosed before age 4 years, aortic root dilation was present in all patients by follow-up, and the rate of increase generally exceeded predictions based on body surface area alone 1. Nine of 13 patients developed progressive mitral valve dysfunction requiring valve replacement in 4 cases, with one perioperative death 1.

Ophthalmologic Evaluation

Arrange urgent dilated slit-lamp examination by an ophthalmologist experienced with Marfan syndrome:

• Definitively exclude or confirm ectopia lentis, which combined with aortic root dilation establishes the diagnosis even without other features 3
• Ectopia lentis is one of the two cardinal features in the revised Ghent nosology 3

Skeletal System Documentation

Perform systematic skeletal assessment looking for at least four of eight major criteria:

• Pectus carinatum or pectus excavatum requiring surgery 3
• Wrist and thumb signs (Walker-Murdoch wrist sign, Steinberg thumb sign) 3
• Reduced upper-to-lower segment ratio or arm span-to-height ratio >1.05 3
• Scoliosis >20° or spondylolisthesis 3
• Reduced elbow extension (<170°) 3
• Pes planus with medial displacement of the medial malleolus 3
• Protrusio acetabuli 3
• Characteristic facial features (dolichocephaly, malar hypoplasia, enophthalmos, retrognathia, down-slanting palpebral fissures) 3

Family History and Genetic Evaluation

Obtain detailed three-generation family history:

• Document any family history of aortic dissection, aneurysm, or sudden cardiac death 3
• Record relatives with ectopia lentis or skeletal features consistent with Marfan syndrome 3
• Personally examine siblings and parents, as many diagnostic features are clinically silent 3
• Consider FBN1 genetic testing when clinical features are present but insufficient to meet Ghent criteria, or when the infant is young and age-dependent features have not yet manifested 3

Important caveat: FBN1 mutations are detected in only 90-95% of unequivocal cases, so molecular testing cannot replace clinical diagnosis 3. In neonatal Marfan syndrome, de novo mutations altering disulfide bonds or calcium-binding sites in cbEGF domains encoded by exons 25-33 are associated with increased risk for severe phenotype 4.

Diagnostic Criteria Application (Revised Ghent Nosology)

For infants without family history, diagnosis requires one of the following:

• Aortic root dilation (Z-score ≥2) AND ectopia lentis 3
• Aortic root dilation AND FBN1 mutation 3
• Aortic root dilation AND systemic score ≥7 points 3
• Ectopia lentis AND FBN1 mutation known to cause aortic disease 3

Surveillance Protocol Once Diagnosed

Establish intensive monitoring schedule:

• Repeat echocardiography at 6 months after initial diagnosis to determine rate of aortic growth 2
• If aortic diameters are stable, perform annual surveillance echocardiography 2
• If aortic root exceeds 4.5 cm (unlikely at 9 months but possible in severe neonatal forms), increase frequency to every 6 months 2
• Perform MRI or CT of entire thoracic aorta after initial echocardiogram to assess segments beyond the root 2

Medical Management Considerations

Beta-blocker therapy:

• Current standard of care for prevention of aortic complications remains beta-blockade in most centers 2
• Beta-blockers slow aortic dilation and may reduce TGF-β activation 5
• Maintain strict blood pressure control with systolic <110 mmHg 2

Emerging therapies:

• Angiotensin II receptor blockers (losartan) are potentially useful due to TGF-β antagonism, though clinical trials are ongoing 2

Critical Differential Diagnoses to Exclude

Systematically rule out overlapping conditions:

• Loeys-Dietz syndrome (arterial tortuosity, bifid uvula, craniosynostosis, dissection at smaller aortic diameters) 2, 3
• Ehlers-Danlos syndrome, hypermobile type 3
• Familial thoracic aortic aneurysm 3
• MASS phenotype (Mitral valve prolapse, Aortic enlargement, Skin and Skeletal findings without ectopia lentis) 3

Common Pitfalls to Avoid

Do not delay echocardiography based on normal physical examination – thoracic aortic disease is typically asymptomatic until catastrophic dissection occurs 2, 6. In infants presenting before age 4 years, only 2 of 15 patients had normal initial echocardiograms, yet all eventually developed aortic root dilation 1.

Do not assume safety with small aortic diameter alone – approximately 15% of dissections occur at diameters <5.0 cm 6, and in neonatal Marfan syndrome, cardiovascular dysfunction progresses rapidly 4.

Do not underestimate mitral valve disease in infancy – mitral regurgitation requiring valve replacement is the leading cause of cardiovascular morbidity in early childhood Marfan syndrome, not aortic disease 1.

Multidisciplinary Team Assembly

Coordinate care with specialists:

• Pediatric cardiologist experienced with Marfan syndrome 2
• Ophthalmologist familiar with ectopia lentis diagnosis 3
• Medical geneticist for diagnostic confirmation and family counseling 2, 7
• Orthopedic surgeon for skeletal manifestations 7

The diagnosis of Marfan syndrome in a 9-month-old infant is eminently clinical and requires early integral management by a multidisciplinary group to obtain the best quality of life and survival 7. Early diagnosis is critical for adequate treatment and specific follow-up, significantly impacting prognosis 8.