Connective Tissue Disorders

Occasional Abnormalities

Large ears, cataracts, retinal detachment, glaucoma, strabismus, refractive errors, diaphragmatic hernia, hemivertebrae, colobomata of iris, cleft palate, incomplete rotation of colon, ventricular dysrhythmias, cardiomyopathy, intracranial aneurysms, sleep apnea, mild neuropsychologic impairment including learning disability and attention deficit disorder in 42% of 19 individuals (5 to 18 years of age) despite normal IQ, problems with self image, schizophrenia.

Natural History

An early diagnosis of Marfan syndrome is invaluable. Aneurysms are typically asymptomatic, whereas dissections can cause sudden death in up to 50% of individuals in whom they occur.

Aortic root dilatation is usually progressive. Its absence in children or even in adults does not exclude the diagnosis or the need for follow-up. There is good correlation between the z scores of aortic diameters (corrected for age and body surface) and the risk of type A dissection or rupture, which allows for predictive echocardiographic follow-up and well-established medical or surgical intervention guidelines. Patients with a firm diagnosis should undergo yearly echocardiograms. More frequent imaging should be performed if the aortic diameter is approaching a surgical threshold (> 4.5 cm in adults; not as well defined in children) or shows rapid change (> 0.5 cm/yr) or with concerns regarding heart or valve function. Adults with repeatedly normal aortic diameters can be seen every 2 to 3 years. Standard treatment is β-blockade, which should be initiated in children and adults even with diameters less than 40 mm, unless contraindicated, as soon as the diagnosis is made. Therapy with angiotensin receptor blockers, mainly losartan, or the combination of both, may be of benefit. Clinical trials have not demonstrated a higher efficacy in preventing dissection and mortality of losartan, and β-blockers remain first-line therapy in patients with Marfan syndrome, and losartan only if β-blockers are not tolerated or the dilation continues to progress.

Mitral valve changes may be the earliest feature, and mitral regurgitation may require surgery even before the aorta is dilated. Surgical valve-sparing root replacement now has had excellent results. Intervention on nonaortic arterial segments (iliac arteries as well as the supraaortic branches) will be needed in 20% of patients with Marfan syndrome after their first aortic intervention. The prevention and treatment of other cardiovascular risk factors, such as smoking, hyperlipidemia, obesity, and high blood pressure, is essential.

Antibiotic prophylaxis is recommended before any dental procedure when valvular mitral or aortic regurgitation is present.

Special consideration should be given to children and adolescents (< 20 years of age). In sporadic cases these children may not yet fit a diagnosis of Marfan syndrome. The term nonspecific connective tissue disorder until follow-up echocardiographic evaluation shows aortic root dilation (z ≥ 3) has been suggested. In general, patients with Marfan syndrome should avoid contact sports, exercise to exhaustion with high heart rates, and especially isometric activities involving a Valsalva maneuver. Most patients can and should participate in aerobic activities performed in moderation. The third trimester of pregnancy, labor and delivery, and the first postpartum month represent a particularly vulnerable time for dissection. An evaluation prior to pregnancy and close follow-up in pregnancy are recommended.

During childhood and adolescence, special care should be directed toward detecting scoliosis. Annual ophthalmologic evaluation to detect ectopia lentis, cataract, glaucoma, and retinal detachment is essential. Early monitoring and aggressive correction of myopia is required for children with Marfan syndrome to prevent amblyopia. For many patients well managed and treated prophylactically, life expectancy now approaches normal. Health supervision guidelines for children with Marfan syndrome have been established by the American Academy of Pediatrics, the National Marfan Foundation ( http://www.marfan.org ), and the American Heart Association/American College of Cardiology task forces.

Etiology

This disorder has an autosomal dominant inheritance pattern, with wide variability in expression. Mutations in the very large fibrillin ( FBN1 ) gene located on chromosome 15q15-21.3 are responsible. The mutation is familial is 75% of cases.

Severe Marfan syndrome diagnosed in the first 3 months of life is the result of point mutations or small deletions in the middle third of the fibrillin-1 protein, exons 25-32. Serious cardiac defects, including mitral valve prolapse, valvular regurgitation, and aortic root dilatation, occur in approximately 80% of cases, often causing heart failure. Congenital contractures are present in 64%. A very characteristic facies, dolichocephaly, a high-arched palate, micrognathia, hyperextensible joints, arachnodactyly, pes planus, chest deformity, iridodonesis, megalocornea, and lens dislocation are also frequently present at birth. Of affected children, 14% die during the first year. FBN1 mutation can cause multiple other allelic phenotypes, some partially including features of Marfan syndrome (Mitral valve, myopia, Aorta, Skin and Skeletal features [MASS] phenotype, mitral valve prolapse [MVP] syndrome, familial ectopia lentis), or unrelated phenotypes (Weil Marchesani, stiff skin syndrome, acromicric dysplasia, geleophysic dysplasia 2, and FBN1 -lipodystrophy). It can be often difficult to predict whether a novel variant in FBN1 will cause Marfan syndrome or a different phenotype, therefore prediction of a risk of aortic dilation may be challenging.

Comment

Intellectual disability (ID) occurs rarely in patients with FBN1 mutations causing Marfan syndrome. It occurs most often when a large rearrangement is present involving FBN1 and other contiguous genes. Marfanoid habitus and ID are a frequent association with very diverse genetic bases, both chromosomal rearrangements and genes such as MED12 (Lujan-Fryns syndrome) or SKI (Shprintzen Goldberg syndrome).

Occasional Abnormalities

Micrognathia; cleft palate; cranial abnormalities, including scaphocephaly, brachycephaly, dolichocephaly, and frontal bossing; subluxation of patella; iris coloboma; keratoconus; myopia; cataract, coloboma, and glaucoma, choroidal neovascularization.

Natural History

Prenatally ultrasound can reveal clinical features of arthrogryposis multiplex congenita/fetal akinesia syndrome. Physical therapy yields a gradual postnatal improvement in the joint limitations in most patient and also helps with muscle growth. Scoliosis and/or kyphosis beginning in infancy or later in childhood are progressive in 64% of the cases and are the most relevant health problem. The long-term prognosis for aortic root dilatation is unknown, but the risks appear to be much less than in Marfan syndrome.

Etiology

This disorder has an autosomal dominant inheritance pattern. Mutations in the FBN2 gene are responsible. High inter- and intrafamilial variability has been demonstrated, including incomplete penetrance. Most variants causing classic phenotypes are in-frame missense FBN2 variants that are located in a region of FBN2 including exons 24 through 35. FBN2 variants leading to a very abnormal protein are significantly underrepresented and can lead to more severe phenotypes, suggesting a possible dominant negative effect in the severe neonatal form of congenital contractural arachnodactyly. Skipping of exons 31 and 32 appear to predispose to aortic dilation that can lead to dissection.

Comment

A severe form of this disorder, lethal in early infancy, has been described. In addition to the characteristic features of Beals syndrome, severe cardiac defects occur, including interrupted aortic arch, ventricular septal defect, atrial septal defect, and aortic root dilatation, as well as gastrointestinal anomalies, including duodenal and esophageal atresia and intestinal malrotation, and pulmonary hypoplasia.

A detectable mutation in the FBN2 gene is not found in all cases of CCA. No apparent phenotypic differences exist between mutation positive and negative cases. Overlaps among phenotypes with and without major cardiovascular risks suggest that individuals with a diagnosis of CCA who have tested negative for FBN2 should be tested for hereditary connective tissue disorders with vascular involvement. The use of comprehensive genetic panels for aortopathy genes is often the safest mode of diagnosis.