PERINATAL/NEONATAL CASE PRESENTATION A novel mutation of the fibrillin-1 gene in a newborn with severe Marfan syndrome L Kochilas 1,2 , F Gundogan 2,3 , M Atalay 2,4 , JM Bliss 2,5 , M Vatta 6 , LS Pena 6 and D Abuelo 2,7 1 Department of Pediatrics, Division of Pediatric Cardiology, Hasbro Children’s Hospital, Providence, RI, USA; 2 Warren Alpert Medical School of Brown University, Providence, RI, USA; 3 Department of Pathology, Women & Infants Hospital, Providence, RI, USA; 4 Department of Diagnostic Imaging, Rhode Island Hospital, Providence, RI, USA; 5 Department of Pediatrics, Division of Neonatology, Women & Infants Hospital, Providence, RI, USA; 6 Department of Pediatrics (Cardiology), John Welsh Cardiovascular Diagnostic Laboratory, Baylor College of Medicine, Texas Children’s Hospital, Houston, TX, USA and 7 Department of Genetics, Hasbro Children’s Hospital, Providence, RI, USA Marfan syndrome in the neonatal age represents a severe early and commonly lethal manifestation of Marfan syndrome, which is caused by mutations in the gene encoding fibrillin-1 (FBN1). Here, we report a newborn with severe Marfan syndrome and a novel mutation involving cysteine substitution within one of the epidermal growth factor-like domains of FBN1. Journal of Perinatology (2008) 28, 303–305; doi:10.1038/sj.jp.7211915 Keywords: fibrillin-1 (FBN1); Marfan syndrome; neonate Case report The proband is a 2.9 kg female infant born at 37 weeks gestation by cesarean section for decreased fetal movement and breech presentation. She was noted to be dysmorphic with frontal bossing, dolichocephaly, down-slanting palpebral fissures, deep sunken eyes and simplified ears (Figure 1a). Other features included redundant skin with reduced skeletal muscle and subcutaneous tissue giving her a senile appearance, scoliosis, joint contractures, long and deformed feet and pronounced arachnodactyly with hyperextensible fingers and toes. In addition, she had a weak cry, high-arched palate, generalized hypotonia, shallow respirations and a single horizontal palmar crease. Her cardiac examination revealed a hyperactive precordium, systolic clicks, a diastolic regurgitant murmur at the left parasternal border and a high-pitched systolic murmur at the apex. Ophthalmologic examination revealed lens dislocation and iridodonesis bilaterally. A chest radiograph revealed cardiomegaly, thin ribs and eventration of the right hemidiaphragm (Figure 1b). Bone radiographs showed slender and bowed long bones and lumbar scoliosis, while abdominal ultrasound revealed right sided hydronephrosis. Transthoracic echocardiography demonstrated dilation of all cardiac chambers and prolapsing atrioventricular valves with redundant tissue bilaterally (Figures 1d and e). There was moderate mitral and mild tricuspid valve regurgitation, while the semilunar valves were dysplastic and moderately regurgitant at birth. The aortic root was severely dilated and measuring 23 mm at the sinuses of Valsalva (z-score>5) (Figures 1c–e). In addition, there was severe dilation of the pulmonary root up to 40 mm (z-score>5) (Figure 1f). The ventricles were dilated and demonstrated dyssynergic contraction with hyperdynamic systolic function of the left ventricle. On the basis of the above findings, the diagnosis of neonatal Marfan syndrome (nMFS) was made and a blood sample was sent to the John Welsh Cardiovascular Diagnostic Laboratory (Houston, TX, USA) for mutation analysis of fibrillin-1 (FBN1). Comprehensive open reading frame/splice investigation of the 65 exons contained in the FBN1 gene was performed. The sequence analysis identified a heterozygous 3256T>C nucleotide change in exon 26 (Figure 2a). This nucleotide change was not observed in 200 ethnic-matched control subjects and predicts an amino-acid substitution of cysteine to arginine at the highly conserved position 1086 (C1086R) (Figure 2b). Analysis of parents genomic DNA revealed normal sequence, consistent with a de novo mutation in this region. The sequence analysis of the proband’s DNA also identified three benign homozygous polymorphisms (1415G>A, IVS56 þ 17C>G, IVS60113C>A), which have not been associated with disease. No other alteration in the FBN1 coding region was identified in the patient or her parents. The patient developed heart failure and respiratory distress that necessitated positive pressure ventilation despite ongoing therapy with diuretics and captopril. At 6 weeks, she was switched to losartan, an angiotensin II type I receptor blocker that has potential role in the treatment of Marfan’s syndrome. 1 The losartan dose was titrated for blood pressure response (final dose 1.6 mg kg 1 per day) without adverse effects. However, mitral valve regurgitation progressed rapidly and a cardiac magnetic Received 30 July 2007; revised 20 November 2007; accepted 29 November 2007 Correspondence: Dr L Kochilas, Department of Pediatrics, Division of Pediatric Cardiology, Rhode Island Hospital, Coro W (third floor), 1 Hoppin Street, Providence, RI 02903, USA. E-mail: Lazaros_Kochilas@brown.edu Journal of Perinatology (2008) 28, 303–305 r 2008 Nature Publishing Group All rights reserved. 0743-8346/08 $30 www.nature.com/jp