European Journal of Medical Genetics 57 (2014) 414e417

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Pectus excavatum and carinatum Jan M. Cobben a, b, *, Roelof-Jan Oostra c, Fleur S. van Dijk d a

Department of Pediatrics, AMC University Hospital, Amsterdam, The Netherlands Department of Clinical Genetics, AMC University Hospital, Amsterdam, The Netherlands c Department of Anatomy, Embryology and Physiology, AMC University Hospital, Amsterdam, The Netherlands d Department of Clinical Genetics, VU University Medical Center, Amsterdam, The Netherlands b

a r t i c l e i n f o

a b s t r a c t

Article history: Received 16 January 2014 Accepted 30 April 2014 Available online 10 May 2014

Pectus excavatum and carinatum are the most common morphological chest wall abnormalities. For both pectus excavatum and carinatum the pathogenesis is largely unknown although various hypotheses exist. Usually, exclusion of an underlying syndromal or connective tissue disorder is the reason for referral for genetic evaluation. A detailed anamnesis and family history are needed as well as a complete dysmorphological physical examination. If no features of an underlying disorder are detected, then the pectus excavatum/carinatum can be considered as an isolated abnormality and no further genetic studies seem indicated. Although cases of non-syndromal pectus excavatum/carinatum with a positive family history fitting Mendelian inheritance have been described, it is possible that these pedigrees represent multifactorial inheritance, as no genetic cause for familial isolated pectus excavatum/carinatum has been described yet. The recurrence risk for a non-familial iolated pectus excavatum/carinatum is unknown, but thought to be low. If other symptoms are found then appropriate further diagnostic studies are indicated as pectus excavatum/carinatum can be part of many syndromes. However, the most important and most frequently observed monogenic syndromes with pectus excavatum/carinatum are Marfan Syndrome and Noonan Syndrome. Ó 2014 Elsevier Masson SAS. All rights reserved.

Keywords: Pectus carinatum Pectus excavatum

1. Introduction Pectus excavatum and carinatum are the most common morphological chest wall abnormalities. Although most authors list Pectus excavatum and carinatum as congenital malformations [Fokin et al., 2009], in fact they are often not congenital. Pectus excavatum can be present at birth but is usually recognized only during early childhood. During adolescent growth many patients experience a marked increase in the severity of the depression [Jaroszewski et al., 2010]. The same is true for pectus carinatum, which is usully recognized in early youth and becomes more apparent in puberty [Desmarais and Keller, 2013]. So in many cases the pectus abnormality is by definition not a malformation, which is defined as being congenital [Hennekam et al., 2013]. In pectus excavatum there is a depression of the anterior chest wall as result of dorsal deviation of the sternum and the third to seventh rib or costal cartilage [Bochhausen et al., 2012].

* Corresponding author. Department of Pediatrics & Clinical Genetics, AMC University Hospital, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands. Tel.: þ31 20 5667508; fax: þ31 20 6917735. E-mail address: [email protected] (J.M. Cobben). http://dx.doi.org/10.1016/j.ejmg.2014.04.017 1769-7212/Ó 2014 Elsevier Masson SAS. All rights reserved.

Pectus Carinatum is defined by anterior protrusion of the sternum and adjacent cartilages [Desmarais and Keller, 2013].

2. Pathophysiological hypotheses and epidemiology 2.1. Pathogenesis The pathogenesis of pectus excavatum is still unknown [Bochhauser et al., 2012]. Many hypotheses have been forwarded over the years. Some of these pathogenetic hypotheses are obsolete, like intrauterine mechanical factors. Others seem only valid in a certain minority of cases, like imbalance of respiratory muscles in a disease like Spinal Muscular Atrophy type I. Today’s leading hypotheses focus on a defective metabolism or a developmental disorder with maturation disturbances of the sternocostal cartilage, and indeed histological changes in the sternocostal cartilage of pectus excavatum patients have been demonstrated. In contrast to what has long been assumed, the sternal primordia do not originate from the paraxial mesoderm (as do the ribs) but from the lateral plate mesoderm (reviewed by Van der Merwe et al. [2013]). Perhaps this difference in embryonic origin underlies the sternocostal growth disturbances

J.M. Cobben et al. / European Journal of Medical Genetics 57 (2014) 414e417

that characterize pectus excavatum. A thorough overview of the different pathogenetic hypotheses is given by Bochhausen et al. [2012]. For pectus carinatum the exact pathogenesis is unknown as well, though the main hypothesis is the same as for pectus excavatum, namely that the underlying defect is in the sternocostal cartilage [Desmarais and Keller, 2013]. 2.2. Epidemiology Pectus excavatum and carinatum are common morphologic abnormalities of the thoracic skeleton. The incidence of pectus excavatum has been estimated between 0.1 and 0.8 per 100 persons [Brochhausen et al., 2012], though a large autopsy series reports a lower incidence of 62/50,946 (0.12%) [Kelly et al., 2005]. A birth prevalence for pectus excavatum of 1/400 is commonly cited [Chung and Myrianthopoulos, 1975]. Pectus carinatum appears to be 2e4 times less frequent than pectus excavatum [Desmarais and Keller, 2013]. There is a male to female preponderance of pectus carinatum of about 4:1 [Desmarais and keller, 2013] and of pectus excavatum between 2:1 and 9:1 [Brochhausen et al., 2012]. 3. Genetic evaluation 3.1. Isolated pectus excavatum and carinatum Although many studies on pectus excavatum have reported physical symptoms or complaints, it is mainly thought to be caused by mechanical forces and symptoms affecting daily life are rare [Bochhausen et al., 2012]. Still, to assess the anatomical situation of the heart and possible compression, as well as lung function, in cases of pectus excavatum routine echocardiography and static and exercise pulmonary function testing are recommended [Colombani 2009]. For pectus carinatum, only static and exercise pulmonary function assessment are recommended [Colombani 2009]. In Table 1 recommendations for initial genetic evaluation for pectus excavatum and carinatum are listed, with the addition that echocardiography in pectus excavatum is to analyse possible mechanical compression also and it might be left out in cases of apparently isolated pectus carinatum. For genetic evaluation (Table 1), a detailed anamnesis and family history are needed as well as a complete dysmorphological physical examination. If no features of an underlying disorder are detected, then the pectus excavatum/carinatum can be considered to be an isolated abnormality and no further genetic studies seem indicated. It has been reported that pectus excavatum is associated with aortic root dilatation in patients without suspicion of Marfan syndrome or related connective tissue disorders [Rhee et al., 2008]. However, it is not certain that these patients were thoroughly investigated for symptoms of these conditions. If other symptoms are found in patients with pectus excavatum/carinatum, for instance mental retardation, dysmorphism, other congenital abnormalities or clear signs during examination or from the family history of a connective tissue disorder such as Marfan Syndrome, then appropriate further studies are indicated. Difficult to evaluate are those cases of pectus excavatum/carinatum with just a few minor clinical signs of a possible underlying connective tissue disorder. Judgement will differ from case to case, but it seems prudent to stay on the safe side and have a wide indication for DNA analysis of the FBN1 gene, especially in children where symptoms of Marfan Syndrome may not be clear at a young age.

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Table 1 Diagnostic recommendations for initial genetic evaluation of pectus excavatum and carinatum. Anamnesis - myopia, dislocated lens - aortic dilatation or rupture, mitral valve prolapse, palpitations or arrhythmias, - easy bruising, poor healing, hernias - fractures, decreased bone mineral density - pulmonary valve stenosis, hypertrophic cardiomyopathy - respiratory/lung disorders - developmental delay - bicuspid aortic valve, coarctation of aorta - renal anomalies - menstruation cycle Family history - family members with pectus excavatum/carinatum - family members with symptoms/diagnosis of a connective tissue disorder such as Marfan syndrome or with symptoms/diagnosis Noonan syndrome (see also “Anamnesis”) Physical examination - length, weight, head circumference - facial dysmorphism, including light eyes/hair - high narrow palate - low posterior hairline, short or webbed neck - assessment of pectus, carinatum, excavatum, assymmetry etc. - long extremities and fingers - scoliosis - pes planus - joint laxity (Beighton score) - small penis, cryptorchidism - striae, soft skin, fair complexion/freckles Echocardiography In case of suspicion on: 1 connective tissue disorder with aortic dilatation/rupture as a hallmark such as Marfan syndrome 2 monogenetic disorder such as Noonan syndrome 3 chromosomal disorder such as Turner syndrome Chromosomal studies In case of suspicion on Turner syndrome or other chromosomal disorder DNA studies If an underlying syndromal or connective tissue disorder is suspected because of additional findings

3.2. Syndromal pectus excavatum and carinatum Pectus excavatum/carinatum can be part of many syndromes. A standard textbook for dysmorphologists lists 32 syndromes with pectus excavatum/carinatum as a frequent feature and 27 syndromes as an occasional feature [Jones and del Campo, 2013]. A dysmorphologic database retrieves 328 matches for syndromes in which pectus excavatum/carinatum has been reported. However, the vast majority of these syndromes and entities are rare or even very rare. An extensive overview of the more important, but mostly still rare, syndromes with pectus excavatum/carinatum is given in a review by Kotzot and Schwabegger [2009]. However, the most important and most frequently observed monogenic syndromes with pectus excavatum/carinatum are Marfan Syndrome and Noonan Syndrome. When it comes to chromosomal disorders, Turner syndrome tops the frequency list. 3.2.1. Marfan Syndrome Marfan Syndrome is a systemic disorder with a prevalence of 1/ 5000-1/10.000. The main features are aortic root dilatation or complications, eye lens dislocation, significant scoliosis and other skeletal abnormalities, among them pectus excavatum and carinatum [Loeys, 2010]. The vast majority of clinically well-defined

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cases of Marfan Syndrome are caused by heterozygous mutations of the FBN1 gene encoding Fibrillin-1. The pectus abnormality in Marfan Syndrome can be quite typical and in older published criteria for the diagnosis of Marfan Syndrome, an asymmetric pectus excavatum or carinatum was considered to be the most specific skeletal feature of Marfan Syndrome [Beighton et al. 1988]. It is the asymmetry that is typical, and different forms of excavatum or carinatum deformities can be seen. In Fig. 1, three examples of a typical anterior chest deformity in patients with Marfan Syndrome are depicted (Fig. 1). 3.2.2. Noonan Syndrome Noonan syndrome occurs in 1/1000e1/2500 persons and is characterized by short stature, facial dysmorphism, a congenital heart defect (often pulmonary valve stenosis) and developmental delay of variable degree [Allanson and Roberts, 2011]. Its cause are mutations in the PTPN11 gene and other Ras/MAPK pathway related genes. An anterior chest wall abnormality is a common symptom in patients with Noonan Syndrome, the shape can be quite characteristic with a superior pectus carinatum and inferior pectus excavatum [Allanson and Roberts, 2011]. The severity of the pectus excavatum/carinatum apparently does not lead often to surgical intervention, as in large series of surgical cases of pectus excavatum, Noonan patients are hardly mentioned, in contrast to Marfan patients who appear in small percentages in most surgical cohorts. Fig. 2 shows a typical example of the chest wall abnormality in Noonan Syndrome (Fig. 2). 3.2.3. Turner syndrome Turner syndrome or 45X syndrome has a prevalence of 1/2500 female births. Major characteristics are short stature, ovarian dysgenesis, congenital lymphoedema, low posterior hairline and/or short and/or webbed posterior neck. Renal and cardiac defects (mostly bicuspid aortic valve and coarctation of aorta) are also common. In most patients there is no developmental delay. The major chest abnormality in Turner syndrome is named shield chest and it is present in 53% of patients with Turner syndrome [Hennekam, 2010]. Often mild pectus excavatum is present [Jones and del Campo, 2013] (Fig. 3) not requiring surgical intervention. 3.3. Genetic counselling Recurrence risk is not often an important question for patients and families seen by a clinical geneticist for pectus excavatum/ carinatum. Usually, exclusion of an underlying syndromal or connective tissue disorder is the reason for referral. In cases of syndromal pectus excavatum/carinatum, the recurrence risk for relatives is of course determined by the inheritance pattern of the underlying disorder. Pectus excavatum is reported in Online Mendelian Inheritane in Man (OMIM) as an apparently rare autosomal dominant trait [MIM 169300], for pectus carinatum no entry is listed. In contrast, many surgical series for pectus excavatum report a positive family history in a significant proportion of cases, up to 42% [Fonkalsrud et al., 2000]. A complicating factor is that in most patient cohorts it is not clear whether syndromal forms or connective tissue disorders are ruled out in these familial cases. Pedigrees have been reported in one systematic family study, fitting autosomal dominant, recessive and X-linked recessive inheritance, with the majority of reported families fitting multifactorial inheritance Fig. 1. A: A 14-year old girl with Marfan Syndrome caused by a complete FBN1 deletion. She has mild aortic root dilatation without other major features. There is a pectus excavatum which is clearly asymmetrical. B: A 13-year old girl with Marfan Syndrome caused by a pathogenic FBN1 mutation (c.6113G>A; p.Cys2038Tyr). She has mild aortic root dilatation and mild eye lens luxation. There is a pectus carinatum which is clearly

asymmetrical, protruding to the left. C: A 11-year old boy with Marfan Syndrome caused by a pathogenic FBN1 mutation (c.7486T>C; p.Cys2496Arg). He has mild root aortic dilatation. There is a combination of a central pectus excavatum with an asymmetrical pectus carinatum, protruding to the left.

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Fig. 3. A young girl with Turner syndrome. Webbing of the neck is present. The chest is broad, the nipples are widely spaced. A mild, symmetrical pectus excavatum is visible.

and carinatum the pathogenesis is largely unknown although various hypotheses exist. Genetic evaluation is warranted for exclusion of an underlying syndromal or connective tissue disorder, the most important and frequent being Marfan syndrome and Noonan syndrome. No genetic cause for familiair isolated pectus excavatum/carinatum has been reported yet. References

Fig. 2. A, B: An 11-year old boy with Noonan Syndrome caused by a pathogenic PTPN11 mutation (c.855T>G; p.Phe285Leu). There is a clear pectus excavatum of the inferior part of the sternum with a relatively sharp border halfway the sternum, with a slight carinatum deformity of the superior part. The abnormality is quite symmetrical.

[Creswick et al., 2006]. Since no major genetic cause for nonsyndromal pectus excavatum/carinatum has been described yet, it is possible that all or most familial cases represent multifactorial inheritance. From clinical experience, the recurrence risk for isolated pectus excavatum/carinatum will be low in most cases [Kotzot and Schwabegger, 2009], but since no systematic study on the recurrence risk is reported in the literature, the recurrence risk is in fact unknown. 4. Conclusion Pectus excavatum and carinatum are the common morphological anterior chest wall abnormalities. For both pectus excavatum

Allanson JE, Roberts AE. Noonan syndrome. Gene reviews, http://www.ncbi.nlm. nih.gov/gtr/condition/C0041409; 2011. Beighton P, de Paepe A, Danks D, Finidori G, Gedde-Dahl T, Goodman R, et al. International nosology of heritable disorders of connective tissue, Berlin, 1986. Am J Med Genet 1988;29:581e94. Brochhausen C, Turial S, Müller FK, Schmitt VH, Coerdt W, Wihlm JM, et al. Pectus excavatum: history, hypotheses and treatment options. Interact Cardiovasc Thorac Surg 2012;14:801e6. Chung CS, Myrianthopoulos NC. Factors affecting risks of congenital malformations. I. Analysis of epidemiologic factors in congenital malformations. Report from the collaborative perinatal project. Birth Defects Orig Artic Ser 1975;11:1e22. Colombani PM. Preoperative assessment of chest wall deformities. Semin Thorac Cardiovasc Surg 2009 Spring;21:58e63. Creswick HA, Stacey MW, Kelly Jr RE, Gustin T, Nuss D, Harvey H, et al. Family study of the inheritance of pectus excavatum. J Pediatr Surg 2006;41:1699e703. Desmarais TJ, Keller MS. Pectus carinatum. Curr Opin Pediatr 2013;25:375e81. Fokin AA, Steuerwald NM, Ahrens WA, Allen KE. Anatomical, histologic, and genetic characteristics of congenital chest wall deformities. Semin Thorac Cardiovasc Surg 2009 Spring;21:44e57. Fonkalsrud EW, Dunn JCY, Atkinson JB. Repair of pectus excavatum deformities: 30 years of experience with 375 patients. Ann Surg 2000;231:443e8. Hennekam RC, Krantz ID, Allanson JE. Gorlin’s Syndrome of the head and neck. fifth ed. New York: Oxford University Press, Inc; 2010. Hennekam RC, Biesecker LG, Allanson JE, Hall JG, Opitz JM, Temple IK, et al. Elements of morphology consortium. Elements of morphology: general terms for congenital anomalies. Am J Med Genet A 2013;161A:2726e33. Jaroszewski D, Notrica D, McMahon L, Steidley DE, Deschamps C. Current management of pectus excavatum: a review and update of therapy and treatment recommendations. J Am Board Fam Med 2010;23:230e9. Jones KL, del Campo Crandall M. Smith’s recognizable patterns of human malformation. seventh ed. Philadelphia (PA): WB Saunders; 2013. Kelly Jr RE, Lawson ML, Paidas CN, Hruban RH. Pectus excavatum in a 112-year autopsy series: anatomic findings and the effect on survival. J Pediatr Surg 2005;40:1275e8. Kotzot D, Schwabegger AH. Etiology of chest wall deformitiesea genetic review for the treating physician. J Pediatr Surg 2009;44:2004e11. Rhee D, Solowiejczyk D, Altmann K, Prakash A, Gersony WM, Stolar C, et al. Incidence of aortic root dilatation in pectus excavatum and its association with Marfan syndrome. Arch Pediatr Adolesc Med 2008;16:882e5. Van der Merwe AE, Weston DA, Oostra RJ, Maat GJ. A review of the embryological development and associated developmental abnormalities of the sternum in the light of a rare palaeopathological case of sternal clefting. Homo 2013;64: 129e41.

Pectus excavatum and carinatum.

Pectus excavatum and carinatum are the most common morphological chest wall abnormalities. For both pectus excavatum and carinatum the pathogenesis is...
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