Indian Pediatrics Case Reports

: 2021  |  Volume : 1  |  Issue : 3  |  Page : 199--201

Neonatal marfan syndrome due to missense mutation in exon 26 of fbn1 gene

Hitesh Patel, Seema Balasubramaniam 
 Consultant Neonatologist, Neoplus ICU and Children Hospital, Surat, Gujarat, India

Correspondence Address:
Seema Balasubramaniam
Neoplus ICU and Children Hospital, LP Savani Road, Surat - 395 009, Gujarat


Background: Neonatal Marfan syndrome (MFS) lies at the most severe end of the MFS clinical spectrum, sharing some characteristics of MFS, but with a more severe clinical phenotype, slightly variable genotype, and a poor prognosis. We report a case of neonatal MFS diagnosed antenatally and in whom diagnosis was established postnatally by clinical exome sequencing. Clinical Description: A routine antenatal ultrasonography identified a dilated aortic root, oligohydramnios, fetal femur, and long bones length >99th percentile for the period of gestation findings in a fetus at 35 weeks of gestation. The baby was born by a cesarean section due to nonprogress of the labor. At birth, he had multiple anomalies including bilaterally cloudy cornea, bluish sclera, long slender fingers, hyperflexion of the wrist, ankle joints, and pulsatile precordium. Management: The patient developed severe respiratory distress immediately after birth and was intubated and initiated on positive pressure ventilation. The baby was supportive of fluid and inotropic management. The diagnosis was established based on characteristic echocardiographic findings and identification of a likely pathogenic variant disrupting the p.Cys1068 amino acid residue in FBN1, located at exon 26, which is the “neonatal” region known to be associated with neonatal MFS. The baby succumbed. Conclusion: Although neonatal MFS has a poor prognosis, multidisciplinary intervention is required to determine the best course of action.

How to cite this article:
Patel H, Balasubramaniam S. Neonatal marfan syndrome due to missense mutation in exon 26 of fbn1 gene.Indian Pediatr Case Rep 2021;1:199-201

How to cite this URL:
Patel H, Balasubramaniam S. Neonatal marfan syndrome due to missense mutation in exon 26 of fbn1 gene. Indian Pediatr Case Rep [serial online] 2021 [cited 2021 Oct 25 ];1:199-201
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Full Text

In 1896, Antoine Marfan described Marfan syndrome (MFS) as an autosomal dominant connective tissue disorder that exhibits characteristic musculoskeletal, ocular, and cardiac manifestations.[1] There is variability in the clinical manifestations and the life expectancy of untreated, affected individuals is reduced (~32 ± 16 years). Neonatal MFS, a related clinical condition, lies at the extreme end of the MFS clinical spectrum. In terms of severity, though it does share some characteristics of MFS, it displays unique manifestations, in terms of clinical phenotype, genotype, and prognosis. The most salient features apparent from birth include musculoskeletal (arachnodactyly, flexion deformities, hyperextensible joints, anterior chest deformity, and dolichocephaly), characteristic facies (high-arched palate, micrognathia, and crumpled ears), ocular anomalies (iridodonesis, megalocornea, and dislocated lenses), and loose skin giving a “senile” appearance.[2],[3] Cardiac involvement is more severe and presents much earlier in neonatal MFS. Mitral and/or tricuspid valve insufficiency is the common causes of neonatal or infantile congestive cardiac failure in contrast to aortic and aortic root involvement in classical MFS.[1],[2] Respiratory complications include infantile pulmonary emphysema in neonatal MFS.[3]

Prenatal diagnosis is often incidental and suspected based on ultrasonic findings. Since neonatal MFS is caused by a number of diverse de novo genetic mutations, prenatal genetic testing becomes challenging.[4] The prognosis is poor and most children do not survive without cardiovascular surgical correction of the major cardiovascular congenital anomalies. Nonetheless, multidisciplinary collaboration between the obstetrician, fetal medicine specialist, radiologist, neonatologist, cardiologist, cardiovascular surgeon, and geneticist is critical for attaining the best possible outcomes.

We report a case of neonatal MFS that was suspected on an ultrasonogram performed in the third trimester, in whom the diagnosis was confirmed postnatally by genetic testing.

 Clinical Description

A booked primigravida with a hitherto uneventful antenatal period underwent a routine third-trimester ultrasonogram in the 35th week of gestation for monitoring fetal growth parameters. Radiological findings of the length of the fetal femur and long bones >99th percentile for the gestational age and a dilated aortic root, with oligohydramnios were suggestive of MFS. The Doppler study of the umbilical artery, middle cerebral artery, ductus venosus, and uterine arteries was normal. The parents were counseled, and the mother was closely monitored by the obstetrician for the remaining pregnancy. The mother was hospitalized, and the neonatal intensive care unit (NICU) informed when she went into labor at 39 weeks of gestation. A lower segment cesarean section was performed due to nonprogress of labor. A term appropriate for age baby boy was born with a birth weight of 2675 g and Apgar scores of 6 and 9 in the 1st and 5th min, respectively. The baby had a weak cry, multiple congenital anomalies (described later), and displayed generalized hypotonia. The baby developed severe respiratory distress immediately after birth. He was transferred to the NICU suspecting congestive heart failure or congenital pulmonary emphysema, both known complications of neonatal MFS. There was no significant family history of any previous unexplained neonatal, infantile, or sudden adult death or any family member with an unusual appearance or cardiac disease.

 Management and Outcome

The baby was in cold stress (temperature 36.4F) and cyanosed on being received in the NICU. He had severe respiratory distress with respiratory rates of 64/min, chest retractions, a Silverman Anderson score of 8, and oxygen saturation of 70% in room air that increased to only 82% with 100% oxygen support. The capillary refill time was >3 s, peripheral pulses were of low volume, and noninvasive blood pressure was 48/32 mmHg with a mean BP of 38 mm Hg. Anthropometry was not taken as the baby was intubated immediately and positive pressure ventilation initiated with synchronized intermittent mandatory ventilation mode. The random blood sugar was 64 mg/dl, and arterial blood gas analysis revealed metabolic acidosis, hypoxia, and hypercarbia (pH 7.14, PCO2 63.9, PO247, and HCO3 20.6). Fluid management of the peripheral circulatory failure proceeded as per the standard protocol. A detailed examination was challenging in the given circumstances. The dysmorphic features that were apparent on general physical examination are listed in [Table 1] and appreciable in [Figure 1]. Significant systemic examination findings included a visibly pulsatile precordium with a holosystolic murmur heard at the left lower sternal border, and the absence of abdominal organomegaly. We were unable to perform an in-depth ocular evaluation. Referring to Faivre et al,[5] and considering the recent Ghent's criteria.{Table 1}{Figure 1}

A chest X-ray revealed bilateral hazy lungs but no evidence of emphysema. Salient bedside 2D echocardiogram findings included severe tricuspid regurgitation, moderate mitral regurgitation (MR) due to tricuspid, and mitral valve prolapse, a moderate-sized (2.5 mm) patent ductus arteriosus (PDA) with the left to right shunting, dilation of the right atrium and right ventricle, and severe pulmonary artery hypertension. The other vascular structures (coronaries, aortic valve, arch of aorta, pulmonary valve, and pulmonary artery) were normal. Hematological and biochemical investigations were normal.

The clinical diagnosis of neonatal MFS was suspected based on the antenatal radiological phenotype, clinical phenotype, and echocardiographic findings, and a sample for clinical exome sequencing (CES) was sent for analysis. Unfortunately, the baby succumbed at 24 h of life despite escalating ventilatory and inotropic support. It had already been decided that surgical intervention would not be undertaken. CES revealed a likely pathogenic variant disrupting the p.Cys1068 amino acid residue in FBN1, located at exon 26. The patient was heterozygous for this missense mutation which causes the nucleotide thymine (located at position 3202 in exon 26 of FBN1 gene on chromosome 15), to convert to the nucleotide guanine. The final diagnosis was neonatal MFS due to the presence of the missense mutation in exon 26 of the FBN1 gene, and the parents were offered genetic counseling.


The most (86.4%) neonatal MFS mutations are found within the exon region 24–33,[6] in contrast to that of classic and incomplete MFS, which is only 17.4% in the same region. Neonatal MFS may rarely arise due to the mutations outside this region. A literature search revealed three case reports; twice in exon 4 and once in exon 21.[1] This newborn had a heterozygous missense mutation in exon 26 that caused the ultimate amino acid sequence to change from cysteine to glycine at codon 1068. Cysteine residues are believed to be involved in the formation of intermolecular disulfide bridges within the FBN1 protein structure. Missense substitutions affecting cysteine residues within these domains are significantly overrepresented among patients with MFS and mutations in exons 25–26 are associated with shorter survival.[6]

The clinical diagnosis of MFS can be made based on the defined parameters, the “Ghent criteria.” According to this, any patient fulfilling certain combinations of aortic dilation, ectopia lentis, systemic features, family history, and FBN1 mutation can be diagnosed as MFS based on a scoring pattern.

These have been developed to facilitate recognition and improve patient management.[7] Stheneur et al. showed that valvular insufficiencies, diaphragmatic hernia, and mutations in exons 25 and 26 are associated with worse prognosis in infants with MFS.[8] Our patient had mitral valve prolapse, with severe tricuspid, and moderate MR and a moderate-sized PDA. PDA is rarely seen in neonatal MFS and is associated with risks of aneurysm formation, rupture, and acceleration of aortic dilation.[6]

Bender et al, reports that the earliest possible sonographic findings leading to a suspicion of neonatal MFS are femur length >95% at 22 weeks.[4] It may also be suspected in instances of unexplained development of dilated cardiomyopathy in the third trimester[9] Earlier diagnosis is possible in cases of familial MFS with a preidentified disease-causing allele by Chorionic Villous Sampling at 10–12 weeks of gestation, and amniocentesis at 15–18 weeks of gestation, though the disease spectrum and severity cannot be ascertained,[4] and it is not possible to establish whether the phenotype will be neonatal or classical MFS.[10] Early recognition of neonatal MFS is vital to allow for attempted multidisciplinary planning and prognosis modification, though the prognosis is usually quite grim, especially in developing countries where availability and access to tertiary level institutes with state of the art cardiothoracic-vascular surgical facilities are limited.[1] Medical therapy of congestive heart failure arising from the cardiac lesions is often unsuccessful, without surgical intervention. Heart surgery is complex and carries a high risk of mortality and morbidity. Parents must be counseled beforehand and involved in making an educated decision regarding the course of action after birth.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.


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Conflicts of interest

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