Marfan Syndrome
Arachnodactyly with Hyperextensibility, Lens Subluxation, Aortic Dilatation
Described as dolichostenomelia in the initial report by Marfan, this disorder was extensively studied and recognized as an autosomal dominant connective tissue disorder by McKusick. In 2010, an international expert panel established a revised Ghent nosology, which puts more emphasis on the cardiovascular and ocular manifestations, as well as in mutation studies, than in the 1996 Ghent criteria. The presence of both aortic root dilatation/aneurysm and ectopia lentis is sufficient for the diagnosis. There are two situations in which only one of the two cardinal features is sufficient for diagnosis: (1) if a family history or a causal FBN1 mutation has been identified, and (2) if the combined score of the associated malformations is 7 or higher. (Associated manifestations of the cardiovascular, ocular, and other organ systems contribute to a “systemic score” with a maximum of 20 points; see below). The estimated prevalence is 1 in 5000.
Abnormalities
Growth. Tendency toward tall stature with long slim limbs, little subcutaneous fat, and muscle hypotonia; mean birth length and final height 53 cm and 191 cm, respectively, in males and 52.5 cm and 175 cm, respectively, in females; peak growth velocity 2.4 years earlier than normal in boys and 2.7 years earlier in girls; mean age at menarche 11.7 years.
Skeletal. Taller than predicted for the family, decreased upper to lower segment ratio (lower than 0.85 in Caucasian adults, lower than 0.75 in African-Americans), or span-height ratio greater than 1.05 (both ratios should be compared with normal values for age in younger children); pectus carinatum; pectus excavatum; wrist and thumb sign; scoliosis greater than 20 degrees or spondylolisthesis; reduced elbow extension (< 170 degrees); pes planus with hindfoot deformity; protrusio acetabuli (protrusion/dislocation of acetabulum); joint laxity is common, but nonspecific. The combination of wrist and thumb signs is assigned 3 points in the systemic score. If either of the two signs is absent, only 1 point is assigned. Pectus carinatum, pes planus, and protrusio acetabuli, seen on radiograph, are assigned 2 points each when present. Significant pectus excavatum is assigned 1 point.
Craniofacial. Typical facial characteristics include dolichocephaly, downslanting palpebral fissures, enophthalmos, retrognathia, and malar hypoplasia. When three or more of these characteristics are present, 1 point is added to the systemic score. High palate with dental crowding is frequent.
Ocular. Lens subluxation, usually upward, but can occur in every direction, with a defect in sus–pensory ligament in 60%, flat cornea, increased axial globe length, hypoplastic iris or ciliary muscle causing decreased miosis. Myopia of more than 3 diopters, often rapidly progressive is the most common ocular finding and contributes 1 point to the systemic score. Retinal detachment.
Cardiovascular. Dilatation of the aortic root precisely measured at the level of the sinus of Valsalva (z score ≥ 2 in individuals 20 years or older and ≥ 3 in individuals less than 20, always adjusted for age and body surface) with or without aortic regurgitation is the vascular hallmark of the condition. Dissection of the ascending aorta commonly occurs in previously dilated aortas. Mitral valve prolapse (1 point in the scoring system). Dilated pulmonary artery, calcified mitral annulus, dilatation or dissection of descending thoracic or abdominal aorta. Vascular tortuosity.
Pulmonary. Spontaneous pneumothorax (2 points), apical blebs, decreased aerobic capacity owing to increased residual lung volume, causing fatigue with exertion.
Skin and Integument. Lumbosacral dural ectasia on computed tomography or magnetic resonance imaging is assigned 2 points; it can lead to bone erosion, nerve entrapment, and cerebrospinal (CSF) leaks. Skin striae not justified by marked weight changes or present in uncommon locations, particularly horizontally along the spine are assigned 1 point. Recurrent or incisional hernias occur. Joint hypermobility is frequent, particularly of the fingers.
Family/Genetic History. A family member firmly diagnosed with Marfan syndrome or the identification a causal mutation in FBN1 will lead to the diagnosis of Marfan syndrome when combined with ectopia lentis, aortic root dilatation, or a systemic score of 7 or higher.
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).
References
Marfan AB: Un cas de déformation congénitales des quatre membres plus prononcée aux extrémities charactérisée par l’allongement des os avec un certain degré d’amincissement, Bull Mem Soc Med Hop (Paris) 13:220, 1896.
Pyeritz RE, McKusick VA: The Marfan syndrome: Diagnosis and management, N Engl J Med 300:772, 1979.
Hofman KJ, et al: Increased incidence of neuropsychologic impairment in the Marfan syndrome, Am J Hum Genet 37:4A, 1985.
Gott VL, et al: Surgical treatment of aneurysms of the ascending aorta in the Marfan syndrome: Results of composite-graft repair in 50 patients, N Engl J Med 314:1070, 1986.
Morse RP, et al: Diagnosis and management of infantile Marfan syndrome, Pediatrics 86:888, 1990.
Lee B, et al: Linkage of Marfan syndrome and a phenotypically related disorder to two different fibrillin genes, Nature 352:330, 1991.
Kainulainen K, et al: Mutations in the fibrillin gene responsible for dominant ectopia lentis and neonatal Marfan syndrome, Nat Genet 6:64, 1994.
De Paepe A, et al: Revised diagnostic criteria for the Marfan syndrome, Am J Med Genet 62:417, 1996.
Pyeritz RE: The Marfan syndrome, Annu Rev Med 51:481, 2000.
Jones EG, et al: Growth and maturation in Marfan syndrome, Am J Med Genet 109:100, 2002.
Maron BJ, et al: Recommendations for physical activity and recreational sports participation for young patients with genetic cardiovascular diseases, Circulation 109:2807, 2004.
Lacro RV, et al: Rationale and design of a randomized clinical trial of beta-blocker therapy (atenolol) versus angiotensin II receptor blocker therapy (losartan) in individuals with Marfan syndrome, Am Heart J 154:624, 2007.
Brooke BS, et al: Angiotensin II blockade and aortic-root dilation in Marfan’s syndrome, N Engl J Med 358:2787, 2008.
Loeys BL, et al: The revised Ghent nosology for the Marfan syndrome, J Med Genet 47:476, 2010.
Alberts JJ, et al: Diagnostic yield in adults screened at the Marfan outpatient clinic using the 1996 and 2010 Ghent nosologies, Am J Med Genet A 158A:982, 2012.
Pyeritz RE, et al: Evaluation of the adolescent or adult with some features of Marfan syndrome, Genet Med 14:171, 2012.
Tinkle BT, Health supervision for children with Marfan syndrome, Pediatrics 132:e1059, 2013.
Callier P, et al: Systematic molecular and cytogenetic screening of 100 patients with marfanoid syndromes and intellectual disability, Clin Genet 84:507, 2013.
Cox DA, et al: Management of the pregnant woman with Marfan syndrome complicated by ascending aorta dilation, Arch Gynecol Obstet 290:797, 2014.
Schoenhoff FS, et al: The fate of nonaortic arterial segments in Marfan patients, J Thorac Cardiovasc Surg , S0022-5223:32863, 2018.
Wallen T, et al: Elective aortic root replacement in North America: Analysis of STS adult cardiac surgery database, Ann Thorac Surg 107:1307, 2019.
Hofmann Bowman MA, et al: Update on clinical trials of losartan with and without β-blockers to block aneurysm growth in patients with Marfan syndrome: A review, JAMA Cardiol, 4:702, 2019.
FIGURE 1
Marfan syndrome.
A–C, Unrelated 9- and 13-year-old boys. Note the long slim limbs, pectus excavatum, narrow face, and reduced elbow extension.
FIGURE 2
Note the joint laxity (A), Steinberg thumb sign (B), ability to join thumb and fifth finger around the wrist (Walker-Murdoch sign) (C), pes planus (D), and striae over hips and back (E).
A–D, Courtesy Dr. Lynne M. Bird, Rady Children’s Hospital, San Diego, California.
FIGURE 3
A and B, Child with neonatal form of Marfan syndrome.
Courtesy Dr. Stephen Braddock, University of Missouri, Columbia, Missouri.
Beals Syndrome (Congenital Contractural Arachnodactyly Syndrome)
Joint Contractures, Scoliosis, Arachnodactyly, “Crumpled” Ear
Beals and Hecht described this syndrome in 1971. They found 11 probable past reports of the same entity, including the original Marfan report. In congenital contractural arachnodactyly (CCA) aortic root dilatation can be present, most often nonprogressive, and the ocular findings of Marfan syndrome are rarely seen.
Abnormalities
Growth. Tall stature (55%), marfanoid habitus.
Limbs. Long slim limbs (dolichostenomelia 40%) with arachnodactyly (81%), finger contractures (camptodactyly 84%), ulnar deviation of fingers; large joint contractures, especially of knees, elbows, and hips (83%). Muscle hypoplasia, particularly of calf and shoulder muscles.
Other Skeletal. Progressive scoliosis and/or kyphosis (64%), relatively short neck, metatarsus varus, talipes equinovarus, generalized muscle weakness (74%), hypoplasia of calf muscles, high arched palate (49%), pectus deformity (43%).
Ears. “Crumpled” appearance, with overfolding of upper helix, poorly defined conchas, and prominent crura from the root of the helix (79%).
Cardiovascular. Aortic root dilatation (12%), mitral valve prolapse (6%), and septum defects (4%). Two patients had an interrupted aortic arch or aortic coarctation, and one had transient cardiomyopathy with noncompaction.
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.
References
Beals RK, Hecht F: Delineation of another heritable disorder of connective tissue, J Bone Joint Surg Am 53:987, 1971.
Hecht F, Beals RK: “New” syndrome of congenital contractural arachnodactyly originally described by Marfan in 1896, Pediatrics 49:574, 1972.
Anderson RA, et al: Cardiovascular findings in congenital contractural arachnodactyly: Report of an affected kindred, Am J Med Genet 18:265, 1984.
Ramos Arroyo MA, et al: Congenital contractural arachnodactyly. Report of four additional families and review of literature, Clin Genet 25:570, 1985.
Lee B, et al: Linkage of Marfan syndrome and a phenotypically related disorder to two different fibrillin genes, Nature 352:330, 1991.
Viljoen D: Congenital contractural arachnodactyly (Beals syndrome), J Med Genet 31:640, 1994.
Putnam EA, et al: Fibrillin-2 ( FBN2 ) mutations result in the Marfan-like disorder, congenital contractural arachnodactyly, Nat Genet 11:456, 1995.
Wang M, et al: Familial occurrence of typical and severe lethal contractural arachnodactyly caused by mis–splicing of exon 34 of fibrillin-2, Am J Hum Genet 59:1027, 1996.
Gupta PA, et al: Ten novel FBN-2 mutations in congenital contractural arachnodactyly: Delineation of the molecular pathogenesis and clinical phenotype, Hum Mutat 19:39, 2002.
Gupta PA, et al: FBN2 mutation associated with manifestations of Marfan syndrome and congenital contractural arachnodactyly, J Med Genet 41:334, 2004.
Takaesu-Miyagi S, et al: Ocular findings of Beals syndrome, Jpn J Ophthalmol 48:470, 2004.
Matsumoto T, et al: Transient cardiomyopathy in a patient with congenital contractural arachnodactyly (Beals syndrome), J Nihon Med Sch 73:285, 2006.
Callewaert BL, et al: Comprehensive clinical and molecular assessment of 32 probands with congenital contractural arachnodactyly: Report of 14 novel mutations and review of the literature, Hum Mutat 30:334, 2009.
Inbar-Feigenberg M, et al: Beals syndrome (congenital contractural arachnodactyly): Prenatal ultrasound findings and molecular analysis, Ultrasound Obstet Gynecol 44:486, 2014.
Takeda N, et al: Congenital contractural arachnodactyly complicated with aortic dilatation and dissection: Case report and review of literature, Am J Med Genet A 167A:2382, 2015.
Woolnough R, et al: Are patients with Loeys-Dietz syndrome misdiagnosed with Beals syndrome? Pediatrics 139. pii: e20161281, 2017.
FIGURE 1
A 1-month-old boy with Beals contractural arachnodactyly syndrome showing narrow palate, retrognathia, typical “crumpled ear,” and long fingers with characteristic camptodactyly and with ulnar deviation of thumb and second fingers causing overlap.
FIGURE 2
Beals syndrome.
A and B, Young infant showing folded helices of ears and relative arachnodactyly with camptodactyly. Severe scoliosis developed by 2 years of age.
Shprintzen-Goldberg Syndrome (Marfanoid-Craniosynostosis Syndrome)
Marfanoid Habitus, Dolichocephaly, Micrognathia, Ocular Proptosis
In 1982, Shprintzen and Goldberg described two unrelated males with craniosynostosis and marfanoid habitus. Robinson and colleagues (2005) provide a good review of 37 cases and suggest a set of craniofacial, skeletal, and radiographic diagnostic features for these patients, who commonly have intellectual disability and only rarely have cardiovascular abnormalities. Carmignac and colleagues and Doyle and colleagues (2012), confirmed the phenotypic features, but found more frequent and severe mitral valve dysfunction and aortic root dilation in patients with confirmed molecular diagnosis.
Abnormalities
Growth. Birth length tends to be increased; with increasing age weight frequently drops below the third percentile and is associated with decreased subcutaneous fat.
Performance. Hypotonia, delayed developmental milestones, mild to moderate intellectual disability.
Craniofacial. Craniosynostosis of the sagittal, coronal, or lambdoid sutures (50%); dolichocephaly; scaphocephaly; large anterior fontanel; high prominent forehead; ocular proptosis; strabismus; hypertelorism; downslanting palpebral fissures; ptosis; maxillary hypoplasia; broad secondary alveolar ridge; micrognathia; low-set, posteriorly rotated ears.
Skeletal. Arachnodactyly, camptodactyly, genu valgum, genu recurvatum, pectus excavatum, pectus carinatum, hyperextensible joints, joint contractures, metatarsus adductus, talipes equinovarus, pes planus, scoliosis.
Cardiac. Aortic root dilatation, mitral valve prolapse, mitral regurgitation/incompetence, aortic regurgitation.
Radiologic. Thin ribs; 13 pairs of ribs; square, box-like vertebral bodies; C1-C2 abnormality; bowing of femora; hypoplastic hooked clavicles; osteopenia.
Other. Hydrocephalus (40%), large anterior fontanel, myopia, umbilical hernia, cryptorchidism.
Occasional Abnormalities
Microcephaly; fine, sparse hair; hyperelastic skin; ptosis; hearing loss; upturned nose; Chiari I malformation; bifid uvula; cleft palate; choanal atresia/stenosis; vocal cord paralysis; dental malocclusion; prominent/malformed ears; tetralogy of Fallot; subvalvar aortic stenosis; arterial tortuosity; other arterial aneurysms; inguinal hernia; joint dislocation; bowing of ribs, ulna, radii, tibiae, or fibulae; thin ribs, fusion of vertebrae; dural ectasia; abdominal wall defects; hypospadias; cryptorchidism; growth hormone deficiency.
Natural History
Severe hypotonia with feeding difficulties (often requiring nasogastric tube feeding), stridorous breathing during sleep, cyanosis, and respiratory compromise are frequent in infancy. Obstructive apnea is common and infrequently requires tracheostomy. Fixation of cervical spine instability may be necessary.
With advancing age linear growth rate begins to decrease. Delay in attainment of developmental milestones is usual. Mild to severe degrees of intellectual disability have occurred in most patients. Aortic aneurysm and dissection can be life-threatening and should be closely monitored.
Etiology
Autosomal dominant transmission seems clear and clinical evidence of germline mosaicism has been reported in two patients, but most cases are sporadic. Mutations in FBN1 causing Marfan syndrome and in the genes causing Loeys Dietz syndrome were initially reported, given the high phenotypic overlap. However, SKI , involved in the TGF-ß SMAD signaling pathway, is considered to be the only gene causing Shprintzen Goldberg syndrome. Distinguishing features include hypotonia and intellectual disability as well as specific radiographic findings, such as C1/C2 abnormality, 13 pairs of ribs, square-shaped vertebral bodies, Chiari I malformation. Aortic root dilatation is less frequent than in Marfan and Loeys Dietz syndromes, but it can be severe.
The Sloan-Kettering Institute (SKI) family of proteins, which also includes the SKI-like protein SKIL, negatively regulate SMAD-dependent TGF-ß signaling. Most mutations cluster in a few residues in the R-SMAD binding domain in the first half of exon 1 of SKI. All are heterozygous missense changes, no deletions or duplications have been reported. Mutations in SKI lead to an excess of canonic TGF-ß signaling, also caused by FBN1 mutations (Marfan syndrome) and TGFBR1 and TGFBR2 mutations (Loeys-Dietz syndrome).
References
Sugarman G, Vogel MW: Case report 76: Craniofacial and musculoskeletal abnormalities—a questionable connective tissue disease, Synd Ident 7:16, 1981.
Shprintzen RJ, Goldberg RB: A recurrent pattern syndrome of craniosynostosis associated with arachnodactyly and abdominal hernias, J Craniofac Genet Dev Biol 2:65, 1982.
Adès LC, et al: Distinct skeletal abnormalities in four girls with Shprintzen-Goldberg syndrome, Am J Med Genet 57:565, 1995.
Sood S, et al: Mutation in fibrillin-1 and marfanoid-craniosynostosis (Shprintzen-Goldberg) syndrome, Nat Genet 12:209, 1996.
Greally MT, et al: Shprintzen-Goldberg syndrome: A clinical analysis, Am J Med Genet 76:202, 1998.
Robinson PN, et al: Shprintzen-Goldberg syndrome: Fourteen new patients and a clinical analysis, Am J Med Genet A 135:251, 2005.
Kosaki K, et al: Molecular pathology of Shprintzen-Goldberg syndrome, Am J Med Genet A 140:104, 2006.
van Steensel MA, et al: Shprintzen-Goldberg syndrome associated with a novel missense mutation in TGFBR2 , Exp Dermatol 17:362, 2008.
Doyle AJ, et al: Mutations in the TGF-ß repressor SKI cause Shprintzen-Goldberg syndrome with aortic aneurysm, Nat Genet 44:1249, 2012.
Shanske AL: Germline mosaicism in Shprintzen-Goldberg syndrome, Am J Med Genet A 158A:1574, 2012.
Carmignac V, et al: In-frame mutations in exon 1 of SKI cause dominant Shprintzen-Goldberg syndrome, Am J Hum Genet 91:950, 2012.
Schepers D, et al: The SMAD-binding domain of SKI: A hotspot for de novo mutations causing Shprintzen–Goldberg syndrome, Eur J Hum Genet 23:224, 2015.
