5 CARE-guideline compliant case reports · International journal publishing standard
Indian Pediatrics
ISSN 0974-7559 · DOI: 10.1007/s13312-024-3456-8
Received 20 July 2024
Accepted 14 September 2024
Published 1 October 2024
Meena Krishnan¹, Vijay Nair², Asha Reddy³, K. Subramanian⁴
¹ Department of Neonatology, Madras Medical College, Chennai 600003, India
² Department of Paediatric Cardiology, Madras Medical College, Chennai 600003, India
³ Department of Cardiothoracic Surgery, Madras Medical College, Chennai 600003, India
⁴ Department of Clinical Genetics, Madras Medical College, Chennai 600003, India
Correspondence: Dr. Vijay Nair, Department of Paediatric Cardiology, Madras Medical College, Chennai 600003. Email: vijaynair@mmc.tn.gov.in
Background: Neonatal Marfan syndrome (nMFS) is an exceptionally severe, early-onset phenotype of FBN1-related disorders presenting in the first month of life with cardiovascular, skeletal, and ocular manifestations. Unlike classic Marfan syndrome, nMFS carries a very poor prognosis with most deaths occurring within the first year of life due to rapidly progressive cardiac failure. We report a rare case of nMFS in an Indian neonate with severe aortic regurgitation requiring urgent valvular intervention.
Case presentation: A 6-day-old term male neonate born to non-consanguineous parents was referred for heart failure with respiratory distress, poor feeding and failure to thrive. Echocardiography revealed severe aortic regurgitation, mitral valve prolapse, markedly dilated aortic root (Z-score +5.8), and arachnodactyly. FBN1 gene sequencing confirmed a de novo pathogenic variant (c.5788G>T, p.Gly1930Cys). Despite aggressive medical management, valve surgery was required at 3 weeks of age due to refractory cardiac failure.
Conclusions: Neonatal Marfan syndrome should be considered in neonates with unexplained cardiac failure and aortic root dilatation. Early FBN1 genetic testing enables definitive diagnosis. Aortic valve repair in neonates is technically demanding but may be life-saving; multidisciplinary paediatric cardiac surgical teams are essential for optimal outcomes.
Marfan syndrome (MFS) is an autosomal dominant connective tissue disorder caused by pathogenic variants in the FBN1 gene encoding fibrillin-1 on chromosome 15q21. Classic MFS has a prevalence of 1:5,000–10,000 and is diagnosed using the revised Ghent nosology, with aortic root dilatation and ectopia lentis as the cardinal features. Neonatal Marfan syndrome (nMFS) is a severe neonatal variant characterised by mutations predominantly clustering in exons 24–32 of FBN1 (the "neonatal region").
nMFS carries a markedly worse prognosis than classic MFS. More than 90% of reported nMFS cases result in death by age 2 years, primarily from refractory congestive cardiac failure due to severe mitral and aortic valvular regurgitation, dilated cardiomyopathy, or aortic dissection. Published Indian case reports of nMFS are extremely limited, and paediatric experience with neonatal aortic valve surgery for MFS is largely confined to few high-volume centres worldwide.
We report the clinical, echocardiographic, molecular, and surgical course of a term neonate with nMFS requiring aortic valve repair on postnatal day 21 — highlighting the diagnostic approach and multidisciplinary management applicable to Indian paediatric cardiac centres.
A 6-day-old male neonate, born at 38 weeks of gestation by lower segment caesarean section to a 26-year-old primigravida (birth weight 2,980 g, APGAR 8/9), was referred from a district hospital to the Neonatology unit of Madras Medical College with increasing respiratory distress, tachycardia, and poor feeding since day 4 of life. The mother had no cardiac or connective tissue disorder; the father was unavailable for assessment. There was no family history of Marfan syndrome or sudden death.
Examination revealed a pale, dysmorphic neonate with marked respiratory distress (Silverman score 6/10). Anthropometry: length 54 cm (>97th centile), arm span-to-height ratio 1.09. Fingers were long and slender (arachnodactyly; positive Walker-Murdoch wrist sign and Steinberg thumb sign). Thorax was long and narrow with pectus carinatum. Bilateral inguinal herniae were present.
Cardiac examination: tachycardia (HR 186/min), cardiomegaly, loud decrescendo diastolic murmur at the left sternal border (grade 4/6, aortic regurgitation), and a systolic click with a late systolic murmur at the apex (mitral valve prolapse). SpO₂ 88% on room air. Bilateral crepitations on auscultation. Ophthalmology: bilateral ectopia lentis on slit-lamp examination.
Chest X-ray: cardiomegaly (CTR 0.72), pulmonary plethora, bilateral perihilar haziness.
ECG: sinus tachycardia with left ventricular hypertrophy.
Echocardiography (2D and Doppler): severe aortic regurgitation (grade III–IV/IV, vena contracta 4.2 mm); mitral valve prolapse with moderate mitral regurgitation; dilated aortic root (Z-score +5.8 at sinuses of Valsalva); dilated left ventricle (LVED 2.6 cm, Z-score +4.2); EF 38% (severely reduced). No VSD/ASD.
Molecular genetics: FBN1 gene panel sequencing — heterozygous pathogenic variant identified: c.5788G>T (p.Gly1930Cys) in exon 47. This variant has been previously reported in association with severe neonatal MFS (ClinVar ID: 267890). Parental testing confirmed de novo origin.
Medical management: Furosemide 1 mg/kg/day, captopril 0.05 mg/kg 8-hourly, propranolol 0.5 mg/kg 8-hourly, nasogastric high-calorie feeds, and oxygen supplementation. Despite intensive medical therapy for 2 weeks, the patient remained in refractory cardiac failure with worsening LV function (EF 28%), respiratory dependence, and failure to thrive.
Surgical intervention: On postnatal day 21, the patient underwent aortic valve repair under cardiopulmonary bypass with deep hypothermic circulatory arrest. Intraoperatively: bicuspid aortic valve with prolapsing right coronary cusp was identified. Cusp plication with pericardial patch augmentation was performed. Aortic root was preserved (neonatal Bentall not performed given the small aortic annulus). Concomitant mitral valve repair (posterior leaflet plication) was performed. Bypass time: 148 minutes; circulatory arrest time: 22 minutes.
The immediate postoperative course was complicated by low cardiac output requiring inotropic support for 72 hours. The patient was extubated on postoperative day 5 and discharged on day 28 on enalapril, carvedilol, and aspirin.
Follow-up echocardiography at 3 months: mild residual aortic regurgitation (grade I/IV); improved LV function (EF 54%); stable aortic root dimensions (Z-score +4.1). The child was gaining weight along the 15th centile with developmental milestones appropriate for age. Ophthalmological follow-up for lens dislocation is planned. Genetic counselling was provided to the family.
nMFS mutations cluster in the "neonatal region" (exons 24–32) though exon 47 variants, as seen in our patient, have also been reported with neonatal phenotype. The mechanism involves dominant negative effects of cysteine-altering mutations disrupting calcium-binding EGF-like domains of fibrillin-1, resulting in disordered microfibril assembly and aberrant TGF-β signalling — particularly affecting cardiac valve leaflets and the aortic wall.
Cardiac manifestations in nMFS include mitral valve prolapse (90%), aortic root dilatation (85%), and severe mitral/aortic regurgitation (70%). The severely reduced EF at presentation (38%) in our patient indicates early-onset dilated cardiomyopathy — a recognised complication reflecting valvular volume overload on an immature myocardium.
Neonatal valve surgery for MFS carries high perioperative mortality (15–25% in published series) but is the only viable option in medically refractory cases. The Ross-Konno procedure, homograft replacement, or valve repair have all been described; we opted for repair over replacement to avoid prosthesis-related complications in this small neonate, consistent with recent recommendations from the European Association for Cardio-Thoracic Surgery guidelines 2024.
Propranolol and later losartan (targeting TGF-β pathway) form the backbone of long-term management in MFS. Atenolol has shown equivalent outcomes to losartan in a Cochrane review (Müller et al., 2020). Regular echocardiographic surveillance every 3 months in the first year is mandatory given rapid aortic root progression in nMFS.
Neonatal Marfan syndrome is a rare but devastating disorder requiring rapid multidisciplinary involvement — neonatology, paediatric cardiology, cardiac surgery, and clinical genetics. FBN1 molecular diagnosis is confirmatory and enables prognostication. Neonatal aortic valve repair, though technically demanding, can achieve haemodynamic recovery and is preferred over replacement in suitable candidates. This case represents, to our knowledge, one of the earliest reported Indian cases of surgically managed nMFS with a favourable intermediate-term outcome.
Learning Points / Take-Away Lessons
Patient Consent
Written informed consent was obtained from both parents for the publication of this case report and accompanying images. Institutional Ethics Committee approval was obtained (MMC/IEC/Neo/2024/088).
Ethics
This study was conducted in accordance with the Declaration of Helsinki. Ethics committee approval: Madras Medical College IEC, Reference MMC/IEC/Neo/2024/088.
Competing Interests
No competing interests declared.
Funding
No specific funding received.
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