A 14-year-old White adolescent boy presented to our pediatric primary care office for an initial well-child examination and sports physical examination. He stated that the high school coach was recruiting him to play basketball because he was tall and had long arms and large hands, which allowed him to "easily recover rebounds." On the preparticipation physical examination form (American Academy of Family Physicians et al., 2010), he denied syncopal episodes, chest pain or pressure with exercise, palpitations, or shortness of breath, and he did not have a past medical history of heart problems or seizures. He did, however, have a positive family history of two relatives dying suddenly from "heart problems" in their 40s. His family did not know any details of their family's heart problems and was unaware of any genetic diseases in the family.
The adolescent resided with his biological family and was an only child. He was born full term by vaginal birth without any complications. He reached his developmental milestones at appropriate ages. His mother stated that he has always been "long and lean" and was proud of being "double jointed." He excelled at volleyball and basketball because of his tall height and long arms. He was an A/B student in high school without any intellectual disabilities and had many friends.
The adolescent was cooperative, bright, tall, and lean with thick glasses. At 6 feet 0 inches his height was above the 95th percentile for a 14-year-old boy, his weight was 132 pounds (75th percentile), and his body mass index was 17.9 kg/m (29th percentile). His vital signs were normal. Upon examination, he had a high-arched upper palate without any dental abnormalities and wore thick glasses for myopia. His heart and lung sounds were normal without a murmur (no obvious mitral valve prolapse or aortic insufficiency), but he was pigeon chested (pectus carinatum; Figure 1, Figure 2). His musculoskeletal examination showed extremely long, slender fingers and toes (arachnodactyly; Figure 3, Figure 4), with widened space between the hallux and second toe and a positive wrist and thumb sign (Figure 5, Figure 6). He was extremely flexible, with an increased range of motion in the joints of his fingers, arms, and legs (hyperflexiblity and hyperlaxity; Figure 7, Figure 8, Figure 9). His arms were long and hung below his mid-thighs (arm span > height). His back had an outward curvature (kyphosis) and a lateral curvature (scoliosis) with striae in the lumbar area from rapid vertical growth.
We suspected the patient had Marfan syndrome (MFS) and referred him to a cardiologist to evaluate for an aortic root abnormality and to an ophthalmologist to evaluate for dislocated lens. The cardiologist performed three transthoracic echocardiographic images and did not find an enlargement of the aortic root. The Z-score, an accurate method of quantifying aortic dilatation, was calculated based on the diameter of the aortic root and was 1.75 cm (normal adult thoracic aortic diameter for adult male = 3.61–3.91 cm) after correcting for age and body size (Hiratzka et al., 2010, Mariucci et al., 2016). The cardiac evaluation showed no evidence of aortic enlargement, dissection, or aneurysm. The ophthalmologist diagnosed a dislocated lens (ectopia lentis) and moderate myopia.
Even though the patient had a family history of two relatives who died of "heart problems," he did not have a confirmed family history of MFS. Based on the Ghent diagnostic criteria, a diagnosis of MFS could not be confirmed with a defect in the ocular system (ectopia lentis) and a systemic feature score of 9 out of 20 with a negative family history of MFS (Table). Therefore, the patient was referred for genetic testing to identify a FBN1 mutation for MFS and to rule out other similar genetic disorders of connective tissue, including Ehlers-Danlos syndrome, Loeys-Dietz syndrome, and MASS phenotype, which have some similar physical features but have important differences such as the location of the genetic mutation and long-term outcomes.
The clinical geneticist confirmed that the patient met the Ghent diagnostic criteria for MFS. The genetic testing on 65 exons of the FBN1 gene showed a nonsense mutation (R429X) causing a protein truncation in exon 10 (Rommel, Karck, Haverich, Schmidtke, & Arslan-Kirchner, 2002). The patient was confirmed to have MFS with ocular involvement (ectopia lentis), systemic involvement (score of 9/20, Table), and a mutation in the FBN1 gene known to cause aortic root dissection.
MFS (Mendelian Inheritance in Man 154700) is an autosomal dominant genetic, systemic disorder of the connective tissue that can lead to premature death and disability when left untreated. Classic MFS is caused by a mutation in the FBN1 gene (Pyeritz, 2013, Sakai et al., 2016). As of 2014, there were 1,847 different mutations cataloged in the Marfan database. The FBN1 universal mutation database (UMD-FBN1) standardized mutational information (available at https://www.umd.be/FBN1/) correlates the genotype and phenotype relationships and identifies the effects of the specific fibrillin-1 mutation (Collod-Béroud et al., 2003).
In 1991, mutations in the gene encoding fibrillin-1 were shown to cause MFS (Dietz et al., 1991). A structural protein, fibrillin-1 is also a regulator of the transforming growth factor-β (TGF-β) signaling pathway. Dysregulation of the TGF-β pathway results in excessive signaling, which produces the physical alterations of MFS. This is the basis for the development of some of the new treatment modalities discussed in the "Future Therapies" section.
Even though the aortic root measurements were normal at 14 years of age, the patient was given atenolol, a beta-blocker, and was monitored annually with an echocardiogram for progression of aortic root dilatation by the cardiologist. The beta-blockers decrease the enlargement of the aortic root, and annual transthoracic echocardiographic images are used to monitor aortic dilation. Preventative surgery is considered when the diameter of the aorta reaches 5.0 cm (Loeys et al., 2010, Mariucci et al., 2016). This preventative surgery and medical management may double the boy's life span by preventing aortic rupture (Van Karnebeek, Naeff, Mulder, Hennekam, & Offringa, 2001). In the meantime, the adolescent patient learned to avoid contact sports, including basketball, and exercising to exhaustion.
At 34 years of age, the diameter of the aorta reached 5.0 cm, and he had preventative cardiac surgery to avoid a ruptured aortic aneurysm. He and his wife decided to use donor sperm to conceive their three children, avoiding the risk of passing the autosomal dominant MFS gene to their children; otherwise, the patient would have a 50% chance of having an affected offspring with every pregnancy. The patient was diagnosed early with MFS and expected to have a full life span to 70 years or more after he had the corrective cardiac surgery.
J Pediatr Health Care. 2017;31(5):609-617. © 2017 Mosby, Inc.