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Association between pectus excavatum and congenital genetic disorders: A systematic review and practical guide for the treating physician

Open AccessPublished:April 24, 2021DOI:https://doi.org/10.1016/j.jpedsurg.2021.04.016

      Highlights

      • Twenty unique genetic disorders have been found associated with pectus excavatum.
      • Most frequent and pathognomic clinical signs of these genetic disorders are presented.
      • Pectus excavatum being part of a genetic disorder has great clinical consequences.
      • Referral of pectus excavatum patients to the clinical geneticist is often delayed.
      • Includes a scoring list to assist referral of pectus excavatum patients.

      Abstract

      Background

      Pectus excavatum (PE) could be part of a genetic disorder, which then has implications regarding comorbidity, the surgical correction of PE, and reproductive choices. However, referral of a patient presenting with PE for genetic analysis is often delayed because additional crucial clinical signs may be subtle or even missed in syndromic patients. We reviewed the literature to inventory known genetic disorders associated with PE and create a standardized protocol for clinical evaluation.

      Methods

      A systematic literature search was performed in electronic databases. Genetic disorders were considered associated with PE if studies reported at least five cases with PE. Characteristics of each genetic disorder were extracted from the literature and the OMIM database in order to create a practical guide for the clinician.

      Results

      After removal of duplicates from the initial search, 1632 citations remained. Eventually, we included 119 full text articles, representing 20 different genetic disorders. Relevant characteristics and important clinical signs of each genetic disorder were summarized providing a standardized protocol in the form of a scoring list. The most important clinical sign was a positive family history for PE and/or congenital heart defect.

      Conclusions

      Twenty unique genetic disorders have been found associated with PE. We have created a scoring list for the clinician that systematically evaluates crucial clinical signs, thereby facilitating decision making for referral to a clinical geneticist.

      Keyword

      Abbreviations

      Abbreviation
      Definition
      aCGH
      Array comparative genomic hybridization
      BAC
      Bacterial artificial chromosome
      CAP
      The College of American Pathologists
      CHG
      Comparative genomic hybridization
      CLIA
      Clinical laboratory improvements amendments
      DHPLC
      Denaturing high performance liquid chromatography
      FISH
      Fluorescence in situ hybridization
      GTG
      G-bands after trypsin and giemsa staining
      MLPA
      Multiplex ligation-dependent probe amplification
      NA
      Not applicable
      NR
      Not reported
      PCR
      Polymerase chain reaction
      PE
      Pectus excavatum
      QFQ
      Q-bands fluorescence using quinacrine
      RT-PCR
      Reverse transcription polymerase chain reaction
      RAS/MAPK
      Ras mitogen activated protein kinase
      TGF-beta
      Transforming growth factor beta
      U
      Unknown

      1. Introduction

      Pectus excavatum (PE) is the most common congenital chest wall deformity with an estimated prevalence of 1 in 300–1000 live births [
      • Shamberger R.C.
      Congenital chest wall deformities.
      ,
      • Chung C.S.
      • Myrianthopoulos N.C.
      Factors affecting risks of congenital malformations. I. Analysis of epidemiologic factors in congenital malformations.
      ]. It is characterized by anomalous growth of several ribs and the sternum, which gives the chest a sunken appearance [
      • Shamberger R.C.
      Congenital chest wall deformities.
      ,
      • Chung C.S.
      • Myrianthopoulos N.C.
      Factors affecting risks of congenital malformations. I. Analysis of epidemiologic factors in congenital malformations.
      ]. The etiology of PE is not fully understood and a direct genetic link has yet to be found [
      • Creswick H.A.
      • Stacey M.W.
      • Kelly Jr., R.E.
      Family study of the inheritance of pectus excavatum.
      ,
      • Jaroszewski D.
      • Notrica D.
      • McMahon L.
      • Steidley D.E.
      • Deschamps C.
      Current management of pectus excavatum: a review and update of therapy and treatment recommendations.
      ]. Current leading hypotheses are focused on a defective collagen metabolism, resulting in biomechanical weakness and an overgrowth of the sternocostal cartilage [
      • Brochhausen C.
      • Turial S.
      • Muller F.K.
      • et al.
      Pectus excavatum: history, hypotheses and treatment options.
      ]. Associations of PE with several genetic disorders have been suggested [
      • Creswick H.A.
      • Stacey M.W.
      • Kelly Jr., R.E.
      Family study of the inheritance of pectus excavatum.
      ,
      • Tocchioni F.
      • Ghionzoli M.
      • Messineo A.
      • Romagnoli P.
      Pectus excavatum and heritable disorders of the connective tissue.
      ,
      • Kotzot D.
      • Schwabegger A.H.
      Etiology of chest wall deformities–a genetic review for the treating physician.
      ]. The fact that PE could be part of a genetic disorder is of clinical importance and bears significance in regard to comorbidity (such as vascular fragility in Loeys-Dietz syndrome and or increased cancer risk in Noonan syndrome or Gorlin syndrome), the recurrence risk, the timing of the correction, type of surgical technique, stabilization of the sternum, long-term outcomes, and reproductive choices related to the genetic disorder [
      • Fokin A.A.
      • Steuerwald N.M.
      • Ahrens W.A.
      • Allen K.E.
      Anatomical, Histologic, and Genetic Characteristics of Congenital Chest Wall Deformities.
      ,
      • Solomon B.D.
      • Muenke M.
      When to suspect a genetic syndrome.
      ].
      Even with experienced pediatricians-pediatric surgeons primary recognition of an underlying genetic disorder in patients with PE is often difficult, because additional crucial representative signs may be subtle or even missed [
      • Delikurt T.
      • Williamson G.R.
      • Anastasiadou V.
      • Skirton H.
      A systematic review of factors that act as barriers to patient referral to genetic services.
      ]. Referral for clinical genetic evaluation and genetic analysis could therefore be delayed or not occur at all, resulting in delayed or missed diagnoses of an underlying genetic disorder [
      • Delikurt T.
      • Williamson G.R.
      • Anastasiadou V.
      • Skirton H.
      A systematic review of factors that act as barriers to patient referral to genetic services.
      ]. A standardized clinical evaluation could assist clinicians treating PE patients in their decision-making for referral.
      We performed a systematic review in order to obtain an overview of associated congenital genetic disorders with PE. Based on the findings, we then created a practical clinical guide containing a scoring list that could help the treating clinician to decide whether a patient with PE should be referred for clinical genetic evaluation.

      2. Methods

      2.1 Study design and search strategy

      We performed a systematic review of the literature and reported our strategy according to the PRISMA statement for transparent reporting of systematic reviews [
      • Moher D.
      • Liberati A.
      • Tetzlaff J.
      • Altman D.G.
      • Group P.
      Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement.
      ]. A systematic literature search was performed with assistance of a biomedical specialist (December 27th, 2019). The EMBASE, Medline (ovidSP), Web-Of-Science, Cochrane CENTRAL and Google scholar databases were searched for publications reporting PE in humans with genetic disorders (Appendix A in the supplement and Fig. 1). Keywords used in the literature search were “pectus excavatum”, “gene”, “mutation” and “syndrome”.
      Fig 1
      Fig. 1Flowchart of search strategy describing the number of articles identified, screened, eligible, and included in this review.

      2.2 Participants, interventions, comparators

      Two reviewers (RB and WM) independently screened for relevance the titles and abstracts of all citations identified from the initial search, and subsequently evaluated the full texts of relevant citations on eligibility for inclusion in this review.
      Studies meeting the following criteria were considered for inclusion: 1) available full-text article; 2) performed in humans; 3) investigating and reporting associations between PE and congenital genetic disorders; 4) written in English; and 5) cohort study, case series, and case reports. Phenotypes of rare diseases are hard to capture as publications of large case series are scarce [
      • Taboada M.
      • Rodriguez H.
      • Martinez D.
      • Pardo M.
      • Sobrido M.J.
      Automated semantic annotation of rare disease cases: a case study.
      ,
      • Hartley T.
      • Balci T.B.
      • Rojas S.K.
      • et al.
      The unsolved rare genetic disease atlas? An analysis of the unexplained phenotypic descriptions in OMIM(R).
      ]. For the purpose of this review congenital genetic disorders, including subtypes, were considered associated with PE when a minimum of 5 cases with PE were reported. Subtypes within a genetic disorder were considered similar if the clinical presentation was alike, and if affected genes causing that certain subtype within a genetic disorder, shared the same signaling pathway. The following exclusion criteria applied: 1) genetic disorders with severe comorbidity and without a spectrum 2) acquired or undefined genetic disorders; 3) cases with multiple genetic disorders; 4) duplicate cases; 5) number of cases with PE not reported. If study populations overlapped between studies, only the most extensively described study was included. Reference lists from relevant reviews were scanned for additional publications that met our inclusion criteria. All disagreements between reviewers were resolved by discussion.

      2.3 Data extraction, data analysis & construction of a practical guide

      All extracted data were summarized in an Excel spreadsheet (Microsoft Office, 2019). The following study characteristics were collected by two persons (RB and WM) separately: name of the congenital genetic disorder, authors, year of publication, type of study, number of cases with PE, family history, results of genetic analysis (affected gene, mutation, locus), and technique of genetic analysis.
      Characteristics and clinical signs of each heritable disorder were extracted according to the Human Phenotype Ontology (https://hpo.jax.org) from all studies and the OMIM database (https://www.omim.org/), an online catalog of human genes and genetic disorders. Identified congenital genetic disorders were categorized based on etiology and pathophysiology in order to facilitate interpretation of similarities and differences between genetic disorders. Subsequently all relevant characteristics and important clinical signs of each genetic disorder were summarized and divided into the following organ systems: craniofacial features, musculoskeletal system, cardiovascular and pulmonary system, neurologic and cognitive system, and other systems. Additionally, the prevalence rates of all relevant clinical signs of each genetic disorder were extracted from the literature. After comparison of clinical signs between genetic disorders, all overlapping clinical signs between genetic disorders as well as the most relevant and pathognomonic clinical signs for each genetic disorder were extracted. Aiming to develop a structural and practical guide for the clinician in the form of a scoring list, we categorized clinical signs into areas within the corresponding organ system. Clinical signs that were more consistently associated with multiple genetic disorders and clinical signs suggestive for the most common genetic diagnosis associated with PE (RASopathy, Turner syndrome and Marfan syndrome [
      • Kotzot D.
      • Schwabegger A.H.
      Etiology of chest wall deformities–a genetic review for the treating physician.
      ,
      • Cobben J.M.
      • Oostra R.J.
      • van Dijk F.S.
      Pectus excavatum and carinatum.
      ]) were selected and defined as major criteria. Clinical signs suggestive for other/less common genetic diagnosis associated with PE were selected and defined as minor criteria. Not easily recognizable clinical features in a surgical consultation setting were not included in the scoring list. Dysmorphic facial features were standardized following the elements of morphology [
      • Allanson J.E.
      • Cunniff C.
      • Hoyme H.E.
      • McGaughran J.
      • Muenke M.
      • Neri G.
      Elements of morphology: standard terminology for the head and face.
      ].

      2.4 Study quality assessment

      Using the tool for evaluating the methodological quality of case reports, case series and uncontrolled cohort studies proposed by Murad et al., (RB and WM) independently evaluated selected articles on study quality until consensus was reached. [
      • Murad M.H.
      • Sultan S.
      • Haffar S.
      • Bazerbachi F.
      Methodological quality and synthesis of case series and case reports.
      ]. Study quality is scored on four domains – selection, ascertainment (exposure and outcome), causality, and reporting – which assess multiple items. With regard to our research question, the “exposure” item was scored based on whether the genetic disorder was properly reported and how the genetic diagnosis was assessed. The “outcome” item was scored as the presence of PE. The causality domain was only assessed on the “follow-up” item, as all other items are relevant mainly in studies investigating adverse drug events [
      • Murad M.H.
      • Sultan S.
      • Haffar S.
      • Bazerbachi F.
      Methodological quality and synthesis of case series and case reports.
      ].

      3. Results

      The initial search yielded 2563 articles. After removal of duplicates, titles and abstracts of 1632 articles were screened on relevance and 553 articles were assessed full text. Following eligibility assessment, 119 full text articles were included in the systematic review (Fig. 1).

      3.1 Study characteristics

      Study characteristics are presented in Table 1 [
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      9q22 Deletion–first familial case.
      ,
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      Del(l8p) shown to be a cryptic translocation using a multiprobe FISH assay for subtelomeric chromosome rearrangements.
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      • Byard R.W.
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      Annuloaortic ectasia in a 16 year-old boy with Loeys-Dietz syndrome.
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      • Rahme R.J.
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      Association of intracranial aneurysm and Loeys-Dietz syndrome: case illustration, management, and literature review.
      ,
      • Suarez B.
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      • Tug E.
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      A Turkish patient of typical Loeys-Dietz syndrome with a TGFBR2 mutation.
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      • Vida V.L.
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      Traumatic aortic dissection in a boy with Loeys-Dietz syndrome.
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      • Yakovlev A.E.
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      • Karasev S.A.
      Treatment of chronic chest wall pain in a patient with Loeys-Dietz syndrome using spinal cord stimulation.
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      • Zimmermann M.T.
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      Novel pathogenic variant in TGFBR2 confirmed by molecular modeling is a rare cause of Loeys-Dietz syndrome.
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      • Ritelli M.
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      • et al.
      Further delineation of Loeys-Dietz syndrome type 4 in a family with mild vascular involvement and a TGFB2 splicing mutation.
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      • Ajmi H.
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      Valve-sparing aortic root and aortic arch replacement in a 5-year-old boy with Loeys-Dietz syndrome.
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      • Hara H.
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      Activation of TGF-β signaling in an aortic aneurysm in a patient with Loeys-Dietz syndrome caused by a novel loss-of-function variant of TGFBR1.
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      • Abanador-Kamper N.
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      Coronary aneurysm with stent dislocation leading to the diagnosis of Marfan syndrome.
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      • Barkhudaryan A.L.
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      • High K.
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      Early onset Marfan syndrome: atypical clinical presentation of two cases.
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      A novel fibrillin-1 gene missense mutation associated with neonatal Marfan syndrome: a case report and review of the mutation spectrum.
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      Novel FBN1 mutations are responsible for cardiovascular manifestations of Marfan syndrome.
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      A clinical and molecular investigation of two South African families with simpson-golabi-behmel syndrome.
      ,
      • Thomas M.
      • Enciso V.
      • Stratton R.
      • et al.
      Metastatic medulloblastoma in an adolescent with Simpson-Golabi-Behmel syndrome.
      ,

      Hughes-Benzie R.M., Pilia G., Xuan J.Y. Simpson-Golabi-Behmel syndrome: genotype/phenotype analysis of 18 affected males from 7 unrelated families. American journal of …. 1996.

      ,

      Neri G., Marini R., Cappa M., Borrelli P. Simpson-Golabi-Behmel syndrome: an X-linked encephalo-trophoschisis syndrome. American journal of …. 1988.

      ,
      • Fu Q.
      • Wang H.
      • Qi Z.
      • Zhang Y.
      Simpson–Golabi–Behmel syndrome with 46,XY disorders of sex development: a case report.
      ,

      Bialer M.G., Lawrence L., Stevenson R.E. Allan-Herndon-Dudley syndrome: clinical and linkage studies on a second family. American Journal of …. 1992.

      ,
      • Remerand G.
      • Boespflug-Tanguy O.
      • Tonduti D.
      • et al.
      Expanding the phenotypic spectrum of Allan–Herndon–Dudley syndrome in patients with SLC16A2 mutations.
      ,
      • Antia A.U.
      Familial skeletal cardiovascular syndrome (Holt-Oram) in a polygamous African family.
      ,
      • Atik T.
      • Dervisoglu H.
      • Onay H.
      • Ozkinay F.
      • Cogulu O.
      A new mutation in the TBX5 gene in holt-oram syndrome: two cases in the same family and prenatal diagnosis.
      ,
      • Chryssostomidis G.
      • Kanakis M.
      • Fotiadou V.
      • et al.
      Diversity of congenital cardiac defects and skeletal deformities associated with the Holt–Oram syndrome.
      ,
      • Oshima T.
      • Hara H.
      • Takeda N.
      • et al.
      A novel mutation of NFIX causes Sotos-like syndrome (Malan syndrome) complicated with thoracic aortic aneurysm and dissection.
      ,
      • Bufalino A.
      • Carrera M.
      • Carlos R.
      • Coletta R.D.
      Giant cell lesions in noonan syndrome: case report and review of the literature.
      ,
      • Chevallier S.
      • Cook S.
      • Goy J.J.
      Heart failure in a patient with Noonan syndrome.
      ,
      • Cohen Jr M.M.
      • Gorlin R.J
      Noonan-like/multiple giant cell lesion syndrome.
      ,
      • Hanna N.
      • Parfait B.
      • Talaat I.M.
      • Vidaud M.
      • Elsedfy H.H.
      SOS1: a new player in the Noonan-like/multiple giant cell lesion syndrome.
      ,
      • Karbach J.
      • Coerdt W.
      • Wagner W.
      • Bartsch O.
      Case report: noonan syndrome with multiple giant cell lesions and review of the literature.
      ,
      • Menon S.
      • Pierpont M.E.
      • Driscoll D.
      Giant cell aortitis and Noonan syndrome.
      ,
      • Pearl W.
      Cardiovascular anomalies in Noonan's syndrome.
      ,
      • Schon F.
      • Bowler J.
      • Baraitser M.
      Cerebral arteriovenous malformation in Noonan's syndrome.
      ,
      • Uçar B.
      • Ökten A.
      • Mocan H.
      • Erçin C.
      Noonan syndrome associated with central giant cell granuloma.
      ,
      • Sanchez Cascos A.
      The Noonan syndrome.
      ,
      • Slezak R.
      • Luczak K.
      • Kalscheuer V.
      • Neumann T.E.
      • Sasiadek M.M.
      Noonan-like/multiple giant cell lesion syndrome in two adult patients with SOS1 gene mutations.
      ,
      • Couser N.L.
      • Keelean-Fuller D.
      • Davenport M.L.
      • et al.
      Cleft palate and hypopituitarism in a patient with Noonan-like syndrome with loose anagen hair-1.
      ,
      • McDonald B.S.
      • Pigors M.
      • Kelsell D.P.
      • et al.
      Noonan syndrome with multiple lentigines and associated craniosynostosis.
      ,
      • Petrin Z.
      • Soffer B.
      • Daniels S.J.
      Sudden cardiac arrest in the field in an 18-year-old male athlete with Noonan syndrome: case presentation and 5-year follow-up.
      ,
      • Rodríguez F.
      • Ponce D.
      • Berward F.J.
      • Lopetegui B.
      • Cassorla F.
      • Aracena M.
      RAF1 variant in a patient with Noonan syndrome with multiple lentigines and craniosynostosis.
      ,
      • Gupta P.
      • Loiwal V.
      • Rai R.
      • Baruah M.C.
      • Mishra K.
      • Krishna A.
      Leopard syndrome: a tropical rarity.
      ,
      • Jóźwiak S.
      • Schwartz R.A.
      • Janniger C.K.
      • Zaremba J.
      Familial occurrence of the LEOPARD syndrome.
      ,
      • Kuburović V.
      • Vukomanović V.
      • Carcavilla A.
      • Ezquieta-Zubicaray B.
      • Kuburović N.
      Two cases of LEOPARD syndrome - RAF1 mutations firstly described in children.
      ,
      • Santoro C.
      • Pacileo G.
      • Limongelli G.
      • et al.
      LEOPARD syndrome: clinical dilemmas in differential diagnosis of RASopathies.
      ,
      • Sutton L.
      • Sutton E.
      • Sutton M.
      Leopard syndrome: progressively increasing pigmented macules in an 8-year-old boy.
      ,
      • Begić F.
      • Tahirović H.
      • Kardašević M.
      • Kalev I.
      • Muru K.
      Leopard syndrome: a report of five cases from one family in two generations.
      ,
      • Kato H.
      • Yoshida R.
      • Tsukamoto K.
      • et al.
      Familial cases of atypical clinical features genetically diagnosed as LEOPARD syndrome (multiple lentigines syndrome).
      ,
      • Jurko T.
      • Jurko A.
      • Krsiakova J.
      • Jurko A.
      • Minarik M.
      • Mestanik M.
      Importance of cardiovascular examination in patients with multiple lentigines: two cases of LEOPARD syndrome with hypertrophic cardiomyopathy.
      ,
      • Pirschner F.
      • Bastos P.M.
      • Contarato G.L.
      • Bimbato A.C.B.L.
      • Filho A.C.
      Gorlin syndrome and bilateral ovarian fibroma.
      ,
      • Snoeckx A.
      • Vanhoenacker F.M.
      • Verhaert K.
      • Chappelle K.
      • Parizel P.M.
      Gorlin–Goltz syndrome in a child: case report and clinical review.
      ,
      • Musani V.
      • Ozretić P.
      • Trnski D.
      • et al.
      Potential hot spot for de novo mutations in PTCH1 gene in Gorlin syndrome patients: a case report of twins from Croatia.
      ,
      • Hsu S.W.
      • Lin C.Y.
      • Wang C.W.
      • Chung W.H.
      • Yang C.H.
      • Chang Y.Y.
      Novel patched 1 mutations in patients with Gorlin–Goltz syndrome strategic treated by smoothened inhibitor.
      ,
      • Eliashar R.
      • Sichel J.Y.
      • Biron A.
      • Dano I.
      Multiple gastrointestinal complications in Marfan syndrome.
      ,
      • Greally M.T.
      • Carey J.C.
      • Milewicz D.M.
      • et al.
      Shprintzen–Goldberg syndrome: a clinical analysis.
      ,
      • Brady A.F.
      • Demirdas S.
      • Fournel-Gigleux S.
      • et al.
      The Ehlers–Danlos syndromes, rare types.
      ,
      • Doan M.L.
      • Guillerman R.P.
      • Dishop M.K.
      • et al.
      Clinical, radiological and pathological features of ABCA3 mutations in children.
      ,
      • Klaassens M.
      • Morrogh D.
      • Rosser E.M.
      • et al.
      Malan syndrome: sotos-like overgrowth with de novo NFIX sequence variants and deletions in six new patients and a review of the literature.
      ,
      • Van Dijck A.
      • Vulto-van Silfhout A.T.
      • Cappuyns E.
      • et al.
      Clinical presentation of a complex neurodevelopmental disorder caused by mutations in ADNP.
      ] and more detailed study chracteristics are presented in Appendix C. Sixteen uncontrolled cohort studies, 46 case series and 57 case reports have been included, representing 20 different congenital genetic disorders and 487 patients with PE and an underlying genetic disorder. Genetic disorders have been diagnosed through either genetic molecular analysis (n = 51 studies) or clinical features and family history (n = 23 studies). Forty-five studies mentioned neither genetic molecular analysis nor clinical evaluation and thus additional clinical signs. These 45 studies represent 250 patients and 11 congenital genetic disorders.
      Table 1Syndromic and study characteristics in alphabetical order.
      Included genetic disordersReported subtypes of genetic disordersAuthorType of studyTotal N cases with PE in studyInheritanceGene(s)
      9q22 deletionSiggberg et al. (2011)Case series6ADPTCH1 and / or ROR2
      18p deletion SyndromeHorsley et al. (1998)Case report1ADNR
      Pachajoa et al. (2010)Case series1ADNR
      Tekeli et al. (2015)Case report1ADNR
      Schinzel et al. (1974)Case series2ADNR
      Aarskog-Scott SyndromeBawle et al. (1984)Case report1X-linkedNR
      Bottani et al. (2007)Case report1X-linkedFGD1
      Al-Semari et al. (2013)Case series2X-linkedFGD1
      Berman et al. (1975)Case series7X-linkedNR
      ABCA3 mutationsDoan et al. (2008)Case series6ARABCA3 genes
      Allan-Herndon-Dudley syndromeBialer et al. (1992)Case series6X-linkedNR
      Remerand et al. (2019)Case series3X-linkedMCT8/ SLC16A2
      Autism spectrum disorderAlkhunaizi et al. (2018)Case report1NRADNP
      Van Dijck et al. (2019)Cohort8NRADNP
      Cutis Laxa

      Duz et al. (2017)Case report1ADELN
      Hucthagowder et al. (2006)Case report1ARFBLN4
      ARCL2Morava et al. (2008)Case series1ARATP6V0A2
      Sawyer et al. (2013)Case series1ARFBLN4
      ARCL2Tuysuz et al. (2003)Case report1ARNR
      De Barsy SyndromeKivuva et al. (2008)Case series8ARNR
      Ehlers-Danlos Syndrome type VIABrady et al. (2017)Case series12ARPLOD1 or LH1
      Holt-Oram SyndromeAtik et al. (2014)Case series1ADTBX5
      Chryssostomidis et al. (2014)Case series1ADNR
      Antia et al. (1970)Case series3ADNR
      Gorlin SyndromePirschner et al. (2012)Case report1ADNR
      Midro et al. (2004)Case report1ADPTCH
      Snoeckx et al. (2008)Case report1ADPTCH1
      Musani et al. (2018)Case report1ADNR
      Hsu et al. (2018)Case series2ADPTCH1
      Loeys-Dietz Syndrome

      Byard et al. (2017)Case report1ADSMAD3
      Type 4Fontana et al. (2014)Case report1ADSMYD2, PTPN14, CENPF, KCNK2,KCTD3, USH2A, ESRRG, SPATA17, RRP15, TGFB2 (1q41); CHRM3 (1q43);KANK1 (9p24.3); RCAN1, CLIC6, RUNX1 (21q22.12).
      Type 4Ma et al. (2012)Case report1ADTGFBR2
      Type 2Rahme et al. (2011)Case report1ADTGFBR2
      Suarez et al. (2011)Case report1ADTGFBR2
      Tug et al. (2010)Case report1ADTGFBR2
      Type 1Vida et al. (2011)Case report1ADTGFBR2
      Yakoviev et al. (2011)Case report1ADNR
      Zimmermann et al. (2017)Case report1ADTGFBR2
      Type 4Ritelli et al. (2014)Case series1ADTGFBR2
      Erkuta et al. (2010)Cohort35ADTGFBR1 or TFGBR2
      Ajmi et al. (2019)Case report1ADNR
      Hara et al. (2019)Case report1ADTGBR1
      Malan (Sotos-like) SyndromeOshima et al. (2017)Case report1ADNFIX
      Klaassens et al. (2015)Case series4ADNFIX and / or CACNA1A
      Marfan SyndromeAbanador-Kamper et al. (2014)Case report1ADFBN1
      Acherjya et al. (2018)Case report1ADNR
      Bakalli et al. (2009)Case report1ADNR
      Barkhudaryan et al. (2015)Case report1ADNR
      Datta et al. (2009)Case report1ADNR
      Ellasher et al. (1998)Case report1ADNR
      Ferrante et al. (2003)Case report1ADNR
      High et al. (2005)Case report1ADNR
      Ozyurt et al. (2015)Case series1ADNR
      Peng et al. (2016)Case report1ADFBN1
      Wang et al. (2016)Case report1ADFBN1
      Zencirci et al. (2010)Case report1ADFBN1
      Aalberts et al. (2010)Case series5ADFBN1
      Ghandi et al. (2013)Case series2ADNR
      Herzka et al. (2000)Case series2ADNR
      Reyes-Hernandez et al. (2016)Case series2ADFBN1
      Sureka et al. (2014)Case series2ADFBN1
      Baran et al. (2007)Cohort13ADNR
      De Maio et al. (2016)Cohort49ADFBN1
      Furtado et al. (2011)Cohort4ADFBN1
      Goliaday et al. (1985)Cohort7ADNR
      Hawks Arn et al. (1989)Cohort28ADNR
      Hilhorst-Hofstee et al. (2011)Cohort3ADFBN1
      Roman et al. (1989)Cohort29ADNR
      Sponseller et al. (2010)Cohort75ADNR
      Streeten et al. (1987)Cohort15ADNR
      Aggarwal et al. (2018)Case report1ADNR
      Löhnhardt et al. (2019)Case report1ADNR
      Rizvi et al. (2018)Case series1ADNR
      Wang et al. (2018)Case series1ADNR
      Zeng et al. (2018)Case report1ADFBN1
      Zakkar et al. (2019)Case series2ADNR
      Zhang et al. (2015)Cohort2ADNR
      Neurofibromatosis

      Type 1Croonen et al. (2012)Case report1ADNF1
      Type 1Raja et al. (2012)Case report1ADNR
      Segmental neurofibromatosisSezer et al. (2006)Case series1ADNR
      Type 1Rieley et al. (2011)Case series1ADNR
      Type 1Koczkowska et al. (2018)Cohort4ADNR
      Noonan SyndromeBufalino et al. (2010)Case report1ADPTPN11
      Chevallier et al. (2011)Case report1ADNR
      Cohen et al. (1991)Case series6ADNR
      Hanna et al. (2009)Case series1ADSOS1
      Karbach et al. (2012)Case series1ADPTPN11
      Menon et al. (2008)Case report1ADNR
      Pearl et al. (1977)Case series2ADNR
      Schon et al. (1992)Case report1ADNR
      Ucar et al. (1998)Case report1ADNR
      Sanchez Cascos et al. (1983)Case series9ADNR
      Slezak et al. (2010)Case series2ADSOS1
      Couser et al. (2018)Case report1ADSHOC2
      McDonald et al. (2018)Case report1ADPTPN11
      Petrin et al. (2019)Case report1ADNR
      Rodriguez et al. (2019)Case report1ADRAF1
      Noonan syndrome with multiple lentiginesGupta et al. (1998)Case report1ADNR
      Jozwiak et al. (1998)Case series1ADNR
      Type 2Kuburovic et al. (2011)Case series1ADRAF1
      Santoro et al. (2014)Case report1ADNR
      Sutton et al. (2016)Case report1ADNR
      Begic et al. (2014)Case series3ADPTPN11
      Kato et al. (2010)Case series1ADPTPN11
      Jurko et al. (2019)Case series1ADPTPN11
      Shprintzen-Goldberg SyndromeStoll et al. (2002)Case report1ARNR
      Greally et al. (1998)Case series8ARNR
      Simpson-Golabi-Behmel SyndromeYano et al. (2011)Case series2X-linkedNR
      Shawky et al. (2014)Case report1X-linkedNR
      Spencer et al. (2016)Case series1X-linkedGPC3
      Thomas et al. (2012)Case report1X-linkedGPC3
      Hughes-Benzi et al. (1996)Case series8X-linkedGPC3
      Neri et al. (1988)Case series2X-linkedNR
      Fu et al. (2019)Case report1X-linkedGPC3
      Turner SyndromeSaikia et al. (2017)Case series3NANA
      Mehta et al. (1993)Cohort3NANA
      Miguel-Neto et al. (2016)Cohort10NANA
      X-Linked myotubular myopathyAmburgey et al. (2017)Cohort8X-linkedMTM1
      Inoue et al. (2018)Case report1X-linkedMTM1
      NA = Not applicable; NR = Not reported; PE = Pectus excavatum.

      3.2 Methodological quality

      All studies had moderate methodological quality as assessed with the proposed tool for evaluating the methodological quality of case reports and case series by Murad et al. (see Appendix B) [
      • Murad M.H.
      • Sultan S.
      • Haffar S.
      • Bazerbachi F.
      Methodological quality and synthesis of case series and case reports.
      ]. More than half of the studies described the genetic disorder including the subtype, and as well described the diagnostic procedure. In more than half of the studies, cases were described with sufficient details to allow others to replicate their research or to allow practitioners to make inferences related to their own practice.

      3.3 Findings

      Twenty congenital genetic disorders could be divided into five categories: chromosomal disorders (n = 3), connective tissue diseases (n = 5), neurological disorders (n = 3), syndromic disorders (n = 8), and other disorders (n = 1). These genetic disorders and their most relevant clinical signs are presented in Table 2, ranked from highest prevalence of PE to lowest as reported by the literature [
      • Siggberg L.
      • Peippo M.
      • Sipponen M.
      • et al.
      9q22 Deletion–first familial case.
      ,
      • Erkula G.
      • Sponseller P.D.
      • Paulsen L.C.
      • Oswald G.L.
      • Loeys B.L.
      • Dietz H.C.
      Musculoskeletal findings of Loeys-Dietz syndrome.
      ,
      • Amburgey K.
      • Tsuchiya E.
      • de Chastonay S.
      • et al.
      A natural history study of X-linked myotubular myopathy.
      ,
      • Greally M.T.
      • Carey J.C.
      • Milewicz D.M.
      • et al.
      Shprintzen–Goldberg syndrome: a clinical analysis.
      ,
      • Brady A.F.
      • Demirdas S.
      • Fournel-Gigleux S.
      • et al.
      The Ehlers–Danlos syndromes, rare types.
      ,
      • Doan M.L.
      • Guillerman R.P.
      • Dishop M.K.
      • et al.
      Clinical, radiological and pathological features of ABCA3 mutations in children.
      ,
      • Klaassens M.
      • Morrogh D.
      • Rosser E.M.
      • et al.
      Malan syndrome: sotos-like overgrowth with de novo NFIX sequence variants and deletions in six new patients and a review of the literature.
      ,
      • Van Dijck A.
      • Vulto-van Silfhout A.T.
      • Cappuyns E.
      • et al.
      Clinical presentation of a complex neurodevelopmental disorder caused by mutations in ADNP.
      ,
      • Dabrowski E.
      • Jensen R.
      • Johnson E.K.
      • Habiby R.L.
      • Brickman W.J.
      • Finlayson C.
      Turner syndrome systematic review: spontaneous thelarche and menarche stratified by karyotype.
      ,
      • Gravholt C.H.
      • Andersen N.H.
      • Conway G.S.
      • et al.
      Clinical practice guidelines for the care of girls and women with Turner syndrome: proceedings from the 2016 Cincinnati International Turner Syndrome Meeting.
      ,
      • Cayrol J.
      • Nightingale M.
      • Challis J.
      • Campbell M.
      • Sullivan M.
      • Heloury Y.
      Wilms tumor associated with the 9q22.3 microdeletion syndrome: 2 new case reports and a review of the literature.
      ,
      • Wester U.
      • Bondeson M.L.
      • Edeby C.
      • Anneren G.
      Clinical and molecular characterization of individuals with 18p deletion: a genotype-phenotype correlation.
      ,
      • Goyal M.
      • Jain M.
      • Singhal S.
      • Nandimath K.
      18p deletion syndrome: case report with clinical consideration and management.
      ,
      • van de Laar I.M.
      • Oldenburg R.A.
      • Pals G.
      • et al.
      Mutations in SMAD3 cause a syndromic form of aortic aneurysms and dissections with early-onset osteoarthritis.
      ,
      • Pepe G.
      • Giusti B.
      • Sticchi E.
      • Abbate R.
      • Gensini G.F.
      • Nistri S.
      Marfan syndrome: current perspectives.
      ,
      • Judge D.P.
      • Dietz H.C.
      Marfan's syndrome.
      ,
      • Pyeritz R.E.
      • Wappel M.A.
      Mitral valve dysfunction in the Marfan syndrome. Clinical and echocardiographic study of prevalence and natural history.
      ,
      • Bollero P.
      • Arcuri L.
      • Miranda M.
      • Ottria L.
      • Franco R.
      • Barlattani Jr., A.
      Marfan Syndrome: oral implication and management.
      ,
      • Ting B.L.
      • Mathur D.
      • Loeys B.L.
      • Dietz 3rd, H.C.
      • Sponseller P.D.
      The diagnostic value of the facial features of Marfan syndrome.
      ,
      • Lindsey J.M.
      • Michelson J.D.
      • MacWilliams B.A.
      • Sponseller P.D.
      • Miller N.H.
      The foot in Marfan syndrome: clinical findings and weight-distribution patterns.
      ,
      • Demetracopoulos C.A.
      • Sponseller P.D.
      Spinal deformities in Marfan syndrome.
      ,
      • Esfandiari H.
      • Ansari S.
      • Mohammad-Rabei H.
      • Mets M.B.
      Management strategies of ocular abnormalities in patients with marfan syndrome: current perspective.
      ,
      • De Maio F.
      • Fichera A.
      • De Luna V.
      • Mancini F.
      • Caterini R.
      Orthopaedic aspects of Marfan syndrome: the experience of a referral center for diagnosis of rare diseases.
      ,
      • Stheneur C.
      • Tubach F.
      • Jouneaux M.
      • et al.
      Study of phenotype evolution during childhood in Marfan syndrome to improve clinical recognition.
      ,
      • Mahesh Kappanayil S.N.
      • Kannan Rajesh
      • Renard Marjolijn
      • Coucke Paul
      • Malfait Fransiska
      • Menon Swapna
      • et al.
      Anne De Paepe Characterization of a distinct lethal arteriopathy syndrome in twenty-two infants associated with an identical, novel mutation in FBLN4 gene, confirms fibulin-4 as a critical determinant of human vascular elastogenesis.
      ,
      • Beyens A.
      • Boel A.
      • Symoens S.
      • Callewaert B.
      Cutis laxa: a comprehensive overview of clinical characteristics and pathophysiology.
      ,
      • Callewaert B.
      • Renard M.
      • Hucthagowder V.
      • et al.
      New insights into the pathogenesis of autosomal-dominant cutis laxa with report of five ELN mutations.
      ,
      • Nunley K.S.
      • Gao F.
      • Albers A.C.
      • Bayliss S.J.
      • Gutmann D.H.
      Predictive value of cafe au lait macules at initial consultation in the diagnosis of neurofibromatosis type 1.
      ,
      • Cimino P.J.
      • Gutmann D.H.
      Neurofibromatosis type 1.
      ,
      • Yao Z.
      • Guo D.
      • Li H.
      • et al.
      Surgical treatment of dystrophic scoliosis in neurofibromatosis type 1: outcomes and complications.
      ,
      • Fois A.
      • Calistri L.
      • Balestri P.
      • et al.
      Relationship between cafe-au-lait spots as the only symptom and peripheral neurofibromatosis (NF1): a follow-up study.
      ,
      • Gorlin R.J.
      Nevoid basal cell carcinoma (Gorlin) syndrome.
      ,
      • Kimonis V.E.
      • Goldstein A.M.
      • Pastakia B.
      • et al.
      Clinical manifestations in 105 persons with nevoid basal cell carcinoma syndrome.
      ,
      • Priolo M.
      • Schanze D.
      • Tatton-Brown K.
      • et al.
      Further delineation of Malan syndrome.
      ,
      • Gelb B.D.
      • Tartaglia M
      Noonan syndrome with multiple lentigines.
      ,
      • Digilio M.C.
      • Conti E.
      • Sarkozy A.
      • et al.
      Grouping of multiple-lentigines/LEOPARD and Noonan syndromes on the PTPN11 gene.
      ,
      • Sarret C.
      • Oliver Petit I.
      • Tonduti D.
      Allan-Herndon-Dudley syndrome.
      ,
      • Remerand G.
      • Boespflug-Tanguy O.
      • Tonduti D.
      • et al.
      Expanding the phenotypic spectrum of Allan-Herndon-Dudley syndrome in patients with SLC16A2 mutations.
      ,
      Cassidy JCCABDVSB.
      Aarskog syndrome. Cassidy and Allanson's management of genetic syndromes.
      ,
      • Tenorio J.
      • Arias P.
      • Martinez-Glez V.
      • et al.
      Simpson-Golabi-Behmel syndrome types I and II.
      ,
      • Cottereau E.
      • Mortemousque I.
      • Moizard M.P.
      • et al.
      Phenotypic spectrum of Simpson-Golabi-Behmel syndrome in a series of 42 cases with a mutation in GPC3 and review of the literature.
      ,
      • McDermott D.A.
      • Fong J.C.
      • Basson C.T
      Holt-Oram Syndrome.
      ,
      • Barisic I.
      • Boban L.
      • Greenlees R.
      • et al.
      Holt Oram syndrome: a registry-based study in Europe.
      ,
      • Allanson J.E.
      • Roberts A.E
      Noonan Syndrome.
      ,
      • Jorge A.A.
      • Malaquias A.C.
      • Arnhold I.J.
      • Mendonca B.B.
      Noonan syndrome and related disorders: a review of clinical features and mutations in genes of the RAS/MAPK pathway.
      ,
      • Lee N.B.
      • Kelly L.
      • Sharland M.
      Ocular manifestations of Noonan syndrome.
      ,
      • Tartaglia M.
      • Zampino G.
      • Gelb B.D.
      Noonan syndrome: clinical aspects and molecular pathogenesis.
      ,
      • Smpokou P.
      • Tworog-Dube E.
      • Kucherlapati R.S.
      • Roberts A.E.
      Medical complications, clinical findings, and educational outcomes in adults with Noonan syndrome.
      ,
      • Tekendo-Ngongang C.
      • Agenbag G.
      • Bope C.D.
      • Esterhuizen A.I.
      • Wonkam A.
      Noonan syndrome in South Africa: clinical and molecular profiles.
      ]. A more detailed summary is presented in Appendix D.
      Table 2congenital genetic disorders and their most relevant clinical signs divided by organ system.
      Genetic disordersPectus excavatum (prevalence in%)Clinical signs (prevalence in%)
      ABCA3 mutationsPE (67%)Musculoskeletal system
      • -
        Clubbing fingers (67%)
      Cardiovascular and pulmonary system
      • -
        Pulmonary symptoms (cough, tachypnoea, dyspnea and exercise intolerance) (100%)
      Other systems:
      • -
        Failure to thrive (56%)
      Loeys-Dietz Syndrome (1–5) (TGF- β pathway)PE (54%)Craniofacial features:
      • -
        Bifid uvula (25–90%), cleft palate (25–90%), hypertelorism (0–90%), craniosynostosis (0–48%)
      Musculoskeletal system:
      • -
        Joint hypermobility (68–100%), cervical congenital malformations (29%), talipes equinovarus (17%), limb joint contractures (5%)
      Cardiovascular and pulmonary system:
      • -
        Aortic-arterial aneurysms and arterial tortuosity (52–90%)
      Other system:
      • -
        Translucent skin (25%), high bruising susceptibility (25%)
      Aarskog-Scott SyndromePE (50–75%)Craniofacial features:
      • -
        Hypertelorism (>75%), short nose (>75%), widow's peak (50–75%)
      Musculoskeletal system:
      • -
        Short stature (>75%), brachydactyly (>75%), joint hypermobility (50–75%)
      Other systems:
      • -
        Shawl scrotum (>75), inguinal hernia (50–75%)
      Shprintzen-Goldberg SyndromePE (47%)Craniofacial features:
      • -
        High-arched palate (100%), micrognathia (94%), hypertelorism (88%), down-slanting palpebral fissures (82%), low-set posteriorly rotated ears (76%), craniosynostosis (41%)
      Musculoskeletal system:
      • -
        Muscular hypotonia (82%), arachnodactyly (71%), camptodactyly (59%), joint hypermobility (53%), scoliosis (41%), disproportionate tall stature (U), increased length of extremities (U)
      Neurologic and cognitive system:
      • -
        Intellectual disability (82%)
      Other systems:
      • -
        Inguinal or umbilical hernia (41–59%)
      Marfan Syndrome (Fibrilin/TGF- β pathway)PE (41%)Craniofacial features:
      • -
        Enophthalmos (71%), retrognathia (63%), dolichocephaly (60%), down-slanting palpebral fissures (58%), malar hypoplasia (36–78%)
      Musculoskeletal system:
      • -
        Joint hypermobility (63%), increased length of extremities (62–92%), disproportionate tall stature (60–88%), scoliosis (53%), thoracolumbar kyphosis (40%), pes planus (25 - 34%), limited elbow extension (15%)
      Cardiovascular and pulmonary system:
      • -
        Aortic aneurysm (77%), mitral valve prolapse (68%), history of pneumothorax (4–15%)
      Neurologic and cognitive system:
      • -
        Dural ectasia (63–92%)
      Other systems:
      • -
        Myopia (34–44%), striae distensae (30%)
      Malan SyndromePE (40%)Craniofacial features:
      • -
        High forehead (96%), long narrow face (85%)
      Musculoskeletal system:
      • -
        Advanced bone age (76%), slender habitus (59%), scoliosis (32%)
      Neurologic and cognitive system:
      • -
        Intellectual disability (100%), macrocephaly (33%)
      Other systems:
      • -
        Postnatal overgrowth (33%)
      Simpson-Golabi-Behmel SyndromePE (25%)Craniofacial features:
      • -
        Coarse facies (90%), hypertelorism (53%), cleft palate and/or bifid uvula(13–26%)
      Cardiovascular and pulmonary system:
      • -
        Congenital heart defects (36–46%)
      Other systems:
      • -
        Kidney anomalies (64–82%), developmental delay (47%), pre- and postnatal overgrowth (43%), diaphragmatic hernia (10%)
      X-Linked myotubular myopathy (phosphatase, endocytose and membrane trafficking)PE (24%)Craniofacial features:
      • -
        Long face (92%)
      Musculoskeletal system:
      • -
        Muscular hypotonia (100%), long slender fingers (17%)
      Cardiovascular and pulmonary system:
      • -
        Respiratory problems (due to hypotonia) (96%)
      Other systems:
      • -
        Feeding problems (due to hypotonia) (92%)
      Noonan SyndromePE (23%)Craniofacial features:
      • -
        Short or webbed neck (95%), hypertelorism (67%), low-set posteriorly rotated ears (44–90%), down-slanting palpebral fissures (38%), a high-arched palate (34–45%), Broad forehead (U)
      Musculoskeletal system:
      • -
        Short stature (40–80%), scoliosis (10–54%)
      Cardiovascular and pulmonary system:
      • -
        Pulmonic stenosis (20–50%), hypertrophic cardiomyopathy (10–30%)
      Neurologic and cognitive system:
      • -
        Intellectual disability (25%)
      Other systems:
      • -
        Cryptorchidism (60–80%), bleeding diathesis (10–89%)
      Neurofibromatosis type 1PE (22%)Musculoskeletal system:
      • -
        Kyphoscoliosis (10–60%)
      Neurologic and cognitive system:
      • -
        Neurofibromas (27- 56%)
      Other systems:
      • -
        Cafe-au-lait spots (100%), Lisch nodules in the eye (95–100%)
      9q22 deletion SyndromePE (20%)Craniofacial features:
      • -
        Epicanthi (57%), short neck (23%), low-set ears (23%), thick ears (17%), thin upper lip vermilion (17%), broad eyebrows (17%), cleft palate (13%), narrow mouth (13%), broad eyebrows (17%), cleft palate (13%), narrow mouth (13%), broad eyebrows (17%)
      Musculoskeletal system:
      • -
        Scoliosis (20%), kyphosis (10%)
      Neurologic and cognitive system:
      • -
        Intellectual disability (80%), seizures (17%)
      Turner SyndromePE (20%)Craniofacial features:
      • -
        Low hairline (40%), short-webbed neck (25–40%), low-set ears (15%)
      Musculoskeletal system:
      • -
        short stature (95–100%)
      Cardiovascular and pulmonary system:
      • -
        Hypertension (50%), anomalies of cardiovascular system (3–42%)
      Neurologic and cognitive system:
      • -
        Hearing impairments (30%)
      Other systems:
      • -
        Only females (100%), amenorrhea (34–91%),%), lymphedema of hands and feet (25%), spoon-shaped nails (10%), anomalies of renal/collecting system (3–15%)
      Kyphoscoliotic Ehlers-Danlos SyndromePE (16%)Craniofacial features:
      • -
        High palate, epicanthi (U), down‐slanting palpebral fissures (U), synophrys (U) and low‐set ears (U)
      Musculoskeletal system:
      • -
        Joint hypermobility (93%), kyphoscoliosis (74%), disproportionate tall stature (26%), increased length of extremities (26%), joint dislocations (24%), pes planus (15%), muscular hypotonia (U)
      Other systems:
      • -
        Hyperextensible skin (65%), myopia (22%)
      Autism Spectrum Disorder (Based on ADNP gene mutation)PE (15%)Craniofacial features:
      • -
        Thin upper lip vermilion (70%), prominent forehead with a high anterior hairline (50–66%), wide and depressed nasal bridge (50%), short nose with full, upturned nasal tip (47–49%), everted lower lip vermilion (46%), long philtrum (39%), small or dysplastic low-set and posteriorly rotated ears (12–49%), pointed chin (U)
      Musculoskeletal system:
      • -
        Muscular hypotonia (78%), short stature (29%),
      Cardiovascular and pulmonary system:
      • -
        Congenital heart defects (38%)
      Neurologic and cognitive system:
      • -
        Mild to severe intellectual disability, autism (100%), severe speech and motor delay (96–99%), epilepsy (16%)
      Other systems:
      • -
        Gastrointestinal problems (83%), visual problems (74%), hormonal deficiencies (24%)
      Gorlin SyndromePE (13–20%)Craniofacial features:
      • -
        Coarse face (54%), facial milia (50–60%), frontal bossing (27%)
      Musculoskeletal system:
      • -
        Bifid ribs (26%), wedge-shaped vertebrae (15%)
      Cardiovascular and pulmonary system:
      • -
        Cardiac fibromas (3%)
      Neurologic and cognitive system:
      • -
        Macrocephaly (50%)
      Other systems:
      • -
        Multiple jaw keratocysts (74%), basal cell carcinomas (74%), ovarian fibromas (17%)
      Allan-Herndon-Dudley SyndromePE (9–58%)Musculoskeletal system:
      • -
        Muscular hypotonia (75–100%)
      Neurologic and cognitive system:
      • -
        Spastic paraplegia (71–94%), athetoid movements (50%), dysarthria (25%), severely impaired intellectual development (17–83%)
      18p deletion SyndromePE (U)Craniofacial features:
      • -
        Dental anomalies (29%), wide mouth, (14–57%), round face (U), dysplastic ears (U)
      Musculoskeletal system:
      • -
        Muscular hypotonia (86%)
      Neurologic and cognitive system:
      • -
        Intellectual disability (100%)
      Other systems:
      • -
        Growth retardation (85%)
      Cutis Laxa (ELN, FBLN4, De Barsy Syndrome (cutis laxa) and ARCL2)PE (U)Craniofacial features (prevalence in%):
      • -
        Long philtrum (90%), large ears (66%), high forehead (29%), beaked nose (17%)
      Musculoskeletal system (prevalence in%):
      • -
        Joint hypermobility (29%)
      Cardiovascular and pulmonary system (prevalence in%):
      • -
        Aortic root dilatation (55–66%), bicuspid aortic valves (33%), and emphysema (17%)
      Other systems (prevalence in%):
      • -
        Loose redundant skin (neck, axillar regions, trunk, and groin) (52%), progeria-like appearance (U), diaphragmatic hernia (U)
      Holt-Oram SyndromePE (U)Musculoskeletal system (prevalence in%):
      • -
        Thumb anomaly (Absent thumb or triphalangeal, non-opposable, finger-like digit. The thumb metacarpal has both a proximal and a distal epiphyseal ossification center) (3–30%), bilateral asymmetric limb defects (Radial hypoplasia, absence of radius, ulnar hypoplasia. narrow, sloping shoulders) (1–40%)
      Cardiovascular and pulmonary system (prevalence in%):
      • -
        Atrial septal defect (75%)
      Noonan Syndrome with multiple lentiginesPE (U)Craniofacial features (prevalence in%):
      • -
        Hypertelorism (82%)
      Cardiovascular and pulmonary system (prevalence in%):
      • -
        Hypertrophic cardiomyopathy (70%), pulmonic stenosis (25%)
      Neurologic and cognitive system (prevalence in%):
      • -
        Sensorineural deafness (20%)
      Other systems (prevalence in%):
      • -
        Multiple lentigines (100%), growth retardation (50%), cryptorchidism
      PE = Pectus excavatum; U = unknown.
      The most frequent overlapping clinical signs between genetic disorders within the craniofacial, musculoskeletal, cardiovascular and pulmonary, neurocognitive and other systems are presented in Table 3.
      Table 3frequency of overlapping clinical signs.
      CategoriesAreasClinical signsN overlapping clinical signs between genetic disorders
      CraniofacialHeadProminent forehead4
      Craniosynostosis2
      Undersized jaw3
      FaceCoarse face2
      Epicanthi2
      Down-slanting palpebral fissures4
      EyesHypertelorism6
      Myopia2
      NoseBeaked nose OR short nose3
      MouthCleft plate3
      Bifid uvula2
      High arched palate3
      Thin upper lip vermilion2
      NeckShort (webbed) neck3
      EarsLow-set6
      SkeletalStatureShort stature4
      Marfanoid appearance3
      SpineScoliosis7
      Kyphosis2
      ExtremitiesJoint hypermobility AND/OR Joint dislocations6
      Pes planus2
      MusclesMuscular hypotonia6
      Cardiovascular and pulmonaryCardiacAll congenital cardiac anomalies9
      VascularAortic-arterial aneurysms2
      Neurologic and cognitiveIntellectual disability4
      Intellectual disability3
      Seizures2
      Hearing impairments2
      OtherSkinLoose skin OR hyperextensible skin2
      Lesions (fibromas, cafe-au-lait spots, multiple lentigines, basal cell carcinomas)3
      HerniasDiaphragmatic hernia2
      Inguinal AND/OR umbilical hernia2
      UrogenitalCryptorchidism3
      Anomalies of renal/collecting system2
      These clinical signs were summarized, divided by organ system and the corresponding area, in a scoring list (Fig. 2).
      Fig 2
      Fig. 2A structural and practical referral scoring list for the clinician treating patients with a pectus excavatum.

      4. Discussion

      In daily practice clinicians treating patients with PE are mostly only aware of a potential underlying connective tissue disease [
      • Tocchioni F.
      • Ghionzoli M.
      • Messineo A.
      • Romagnoli P.
      Pectus excavatum and heritable disorders of the connective tissue.
      ]. Genetic analysis is therefore typically performed on genes associated with connective tissue diseases, such as Marfan syndrome [
      • Tocchioni F.
      • Ghionzoli M.
      • Messineo A.
      • Romagnoli P.
      Pectus excavatum and heritable disorders of the connective tissue.
      ]. From our systematic review we may conclude that PE can be associated not only with connective tissue disorders, but also with several chromosomal disorders, neurologic disorders, syndromic disorders, and pathogenic variants in the ACAD3 gene. When interpreting these associations, one should be aware that some of these genetic disorders are very rare (estimated prevalence ≥1:1 000 000)[
      • Kivuva E.C.
      • Parker M.J.
      • Cohen M.C.
      • Wagner B.E.
      • Sobey G.
      De Barsy syndrome: a review of the phenotype.
      ,
      • Tenorio J.
      • Arias P.
      • Martinez-Glez V.
      • et al.
      Simpson-Golabi-Behmel syndrome types I and II.
      ,
      • E Muller L.H.
      9q22.3 Microdeletion..
      ,
      • Sarkozy A.
      • Digilio M.C.
      • Dallapiccola B.
      Leopard syndrome.
      ,
      • C Sarret I.P.
      • Tonduti D.
      Allan-Herndon-Dudley syndrome.
      ,
      • Morava E.
      • Guillard M.
      • Lefeber D.J.
      • Wevers R.A.
      Autosomal recessive cutis laxa syndrome revisited.
      ,
      • Oshima T.
      • Hara H.
      • Takeda N.
      • et al.
      A novel mutation of NFIX causes Sotos-like syndrome (Malan syndrome) complicated with thoracic aortic aneurysm and dissection.
      ,
      • O'Dougherty G.R.
      • Fulkerson D.H.
      • Kern M.
      • Haldar K.
      • Calhoun B.
      Complications of insufficient dura and blood loss during surgical intervention in Shprintzen–Goldberg syndrome: a case report.
      ], while others are more common such as Turner syndrome (estimated prevalence 1:2 500 females)[

      M Mazzocco A.Q., M. Murphy, M. McCloskey. Genetic Syndromes as Model Pathways to Mathematical Learning Difficulties: Fragile X, Turner, and 22q Deletion Syndromes. 2016.

      ], and RASopathies such as Marfan syndrome (estimated prevalence 1:5 000–10 000)[
      • Cobben J.M.
      • Oostra R.J.
      • van Dijk F.S.
      Pectus excavatum and carinatum.
      ], Noonan syndrome (estimated prevalence 1:1 000–2 500)[
      van der Burgt I. Noonan syndrome.
      ], and neurofibromatosis type 1 (estimated prevalence 1:3 000)[
      • Friedman J.M.
      Epidemiology of neurofibromatosis type 1.
      ]. Furthermore, some of these genetic disorders only occur in women, such as Turner syndrome [

      M Mazzocco A.Q., M. Murphy, M. McCloskey. Genetic Syndromes as Model Pathways to Mathematical Learning Difficulties: Fragile X, Turner, and 22q Deletion Syndromes. 2016.

      ], and others only in men, such as Allan–Herndon–Dudley syndrome [
      • C Sarret I.P.
      • Tonduti D.
      Allan-Herndon-Dudley syndrome.
      ], and Simpson–Golabi–Behmel syndrome [
      • O'Dougherty G.R.
      • Fulkerson D.H.
      • Kern M.
      • Haldar K.
      • Calhoun B.
      Complications of insufficient dura and blood loss during surgical intervention in Shprintzen–Goldberg syndrome: a case report.
      ]. Lastly, affected genes of associated genetic disorders with PE are involved with multiple signaling pathways. The most observed affected signaling pathways include the TGF-beta pathway [
      • Priolo M.
      • Schanze D.
      • Tatton-Brown K.
      • et al.
      Further delineation of Malan syndrome.
      ,
      • Urban Z.
      • Davis E.C.
      Cutis laxa: intersection of elastic fiber biogenesis, TGFbeta signaling, the secretory pathway and metabolism.
      ,
      • Qi Y.
      • Xu R.
      Roles of PLODs in collagen synthesis and cancer progression.
      ,
      • Pezzini A.
      • Del Zotto E.
      • Giossi A.
      • Volonghi I.
      • Costa P.
      • Padovani A.
      Transforming growth factor beta signaling perturbation in the Loeys–Dietz syndrome.
      ,
      • Matt P.
      • Schoenhoff F.
      • Habashi J.
      • et al.
      Circulating transforming growth factor-beta in Marfan syndrome.
      ,
      • Doyle A.J.
      • Doyle J.J.
      • Bessling S.L.
      • et al.
      Mutations in the TGF-beta repressor SKI cause Shprintzen-Goldberg syndrome with aortic aneurysm.
      ] and the RAS/MAPK pathway [
      • Tidyman W.E.
      • Rauen K.A.
      The RASopathies: developmental syndromes of Ras/MAPK pathway dysregulation.
      ,
      • Jouhilahti E.M.
      • Peltonen S.
      • Heape A.M.
      • Peltonen J.
      The pathoetiology of neurofibromatosis 1.
      ]. Knowledge of these genetic disorders and the associated signaling pathways, not only broadens the differential diagnosis of the suspected underlying genetic disorder in patients with PE, but could also have implications on the genetic panel used for genetic analysis.
      Twenty unique genetic disorders were found to be associated with PE. Our results are in line with part of the reviews of Kotzot et al., and Cobben et al., which present comprehensive overviews regarding associations between genetic disorders and multiple chest wall deformities, including pectus excavatum, pectus carinatum, and cleft chest [
      • Kotzot D.
      • Schwabegger A.H.
      Etiology of chest wall deformities–a genetic review for the treating physician.
      ,
      • Cobben J.M.
      • Oostra R.J.
      • van Dijk F.S.
      Pectus excavatum and carinatum.
      ]. As the chest wall deformities had not been analyzed separately, we have extended on their research in order to identify genetic disorders specifically associated with PE.
      Several studies propose that PE might be part of a genetic disorder, such as a chromosomal disorder, RASopathy or Marfan syndrome [
      • Kotzot D.
      • Schwabegger A.H.
      Etiology of chest wall deformities–a genetic review for the treating physician.
      ,
      • Cobben J.M.
      • Oostra R.J.
      • van Dijk F.S.
      Pectus excavatum and carinatum.
      ]. Nevertheless, the incidence of such syndromes/disorders among patients seen for their PE is still unclear. The authors of these studies state that PE is most often isolated and that genetic causes are rare. This statement is illustrated by Behr et al., who reported that 5.3% of their cohort of 187 PE patients was affected by Marfan syndrome, and by Akcali et al., who reported that 2.7% of their 24 PE patients was affected by neurofibromatosis type 1 [
      • Behr C.A.
      • Denning N.L.
      • Kallis M.P.
      • et al.
      The incidence of Marfan syndrome and cardiac anomalies in patients presenting with pectus deformities.
      ,
      • Akcali Y.
      • Ceyran H.
      • Hasdiraz L.
      Chest wall deformities.
      ]. It is however of great clinical importance to recognize those patients with an underlying genetic disorder as a cause of PE, primarily, because the comorbidity and prognosis of the genetic disorder could have great consequences for the patient and his or her psychosocial wellbeing, but also for the family members [
      • Biesecker B.B.
      Goals of genetic counseling.
      ,
      • Rubio-Perez C.
      • Guney E.
      • Aguilar D.
      • et al.
      Genetic and functional characterization of disease associations explains comorbidity.
      ]. Understanding the options to deal with regarding the risk of recurrence of the genetic disorder in relatives and the corresponding reproductive choices make genetic counseling imperative in these patients [
      • Biesecker B.B.
      Goals of genetic counseling.
      ,
      • Rubio-Perez C.
      • Guney E.
      • Aguilar D.
      • et al.
      Genetic and functional characterization of disease associations explains comorbidity.
      ]. Furthermore, the presence of a genetic disorder could influence the choice of anesthesia, the timing of the correction of PE, surgical technique, stabilization of the sternum, and long-term outcome [
      • Fokin A.A.
      • Steuerwald N.M.
      • Ahrens W.A.
      • Allen K.E.
      Anatomical, Histologic, and Genetic Characteristics of Congenital Chest Wall Deformities.
      ]. For example, in patients with Marfan syndrome, the suppleness of the chest wall is increased, resulting in a greater risk of recurrence following any surgical intervention [
      • Fraser S.
      • Child A.
      • Hunt I.
      Pectus updates and special considerations in Marfan syndrome.
      ]. In case of a minimal invasive approach, a longer duration of the Nuss bar should therefore be considered [
      • Fraser S.
      • Child A.
      • Hunt I.
      Pectus updates and special considerations in Marfan syndrome.
      ,
      • Arn P.H.
      • Scherer L.R.
      • Haller Jr., J.A.
      • Pyeritz R.E
      Outcome of pectus excavatum in patients with Marfan syndrome and in the general population.
      ]. Open procedures are feasible as well, but the need for cardiac surgery should be evaluated and concomitant procedures should be performed where appropriate [
      • Fraser S.
      • Child A.
      • Hunt I.
      Pectus updates and special considerations in Marfan syndrome.
      ]. A second important example is Noonan syndrome, as it is associated with an increased risk of bleeding, bruising and a variety of bleeding abnormalities, such as factor XI deficiency and platelet abnormalities [
      • Nugent D.J.
      • Romano A.A.
      • Sabharwal S.
      • Cooper D.L.
      Evaluation of bleeding disorders in patients with Noonan syndrome: a systematic review.
      ]. Therefore, patients with Noonan syndrome should be clinically evaluated prior to any surgical procedure. Even if blood tests are normal, these patients must be carefully monitored as the risk for bleeding events is still present [
      • Nugent D.J.
      • Romano A.A.
      • Sabharwal S.
      • Cooper D.L.
      Evaluation of bleeding disorders in patients with Noonan syndrome: a systematic review.
      ].
      We created a standardized protocol for clinical evaluation, in the form of a scoring list (Fig. 2), aimed to assess whether a patient with PE should be referred for genetic analysis. Standardizing this clinical evaluation was deemed essential, since associated genetic disorders can differ greatly in severity. For example, patients with Marfan syndrome may have disorders that can range from mild dysmorphic features or an isolated pectoral deformity, to those associated with severe, life-threatening complications such as pneumothorax or aortic aneurysm [
      • Takeda N.
      • Inuzuka R.
      • Maemura S.
      • et al.
      Impact of pathogenic FBN1 variant types on the progression of aortic disease in patients with Marfan syndrome.
      ]. Additional crucial representative clinical signs may therefore be subtle or even missed in patients with genetic disorders. Moreover, many representative clinical signs are not likely to be linked to genetic disorders, because of the rarity of genetic disorders associated with PE. These obstacles make the decision to refer a patient presenting with PE for genetic analysis often difficult mandating a standardized approach [
      • Solomon B.D.
      • Muenke M.
      When to suspect a genetic syndrome.
      ,
      • Delikurt T.
      • Williamson G.R.
      • Anastasiadou V.
      • Skirton H.
      A systematic review of factors that act as barriers to patient referral to genetic services.
      ].
      Added to the scoring list were a positive family history for PE, a congenital cardiac anomaly and/or genetic disorder, as these characteristics increase the probability of the presence of a genetic disorder [
      • Solomon B.D.
      • Muenke M.
      When to suspect a genetic syndrome.
      ]. Our scoring list includes only family history and relevant clinical signs; additional diagnostic tests are not required, thus making it feasible to use in an outpatient clinic setting. We recommend routine use of our scoring list by clinicians treating PE patients. Its widespread use could potentially result in fewer delayed and missed diagnoses of underlying genetic disorders in patients with PE [
      • Solomon B.D.
      • Muenke M.
      When to suspect a genetic syndrome.
      ]. Implementation research is recommended to assess whether the scoring list is effectively implemented and has the desired result.

      4.1 Limitations

      This systematic review faces several limitations. An underestimation of the number of unique genetic disorders associated with PE is likely, as not all patients affected by PE and a genetic disorder are reported in the literature or in genetic databases. Consequently, the data on prevalence of PE within each genetic disorder is incomplete. Furthermore, a few genetic disorders have multiple subtypes. As some studies did not report the affected gene or genes – thus subtype of the reported genetic disorder – for some genetic disorders it is unclear which subtypes are associated with PE. As many genetic disorders are quite rare, this review is limited to mainly case reports and case series with a moderate methodological quality. When interpreting the results of this review, one should be aware of these limitations.

      5. Conclusion

      Twenty unique genetic disorders were found to be associated with PE. Clinicians treating PE could easily miss representative crucial clinical signs of an underlying disorder. We, therefore, recommend routine use of our scoring list to prevent delayed and missed diagnoses of underlying genetic disorders in patients with PE, as this will facilitate decision making on referral for genetic analysis.

      Author contributions

      J. Schnater conceived the study idea. R. Billar and W. Manoubi coordinated the systematic review. R. Billar and W. Manoubi screened abstracts and full texts. R. Billar and W. Manoubi wrote the first draft of the manuscript and judged risk of bias in the studies. R. Billar, W. Manoubi, S. Demirdas, S. Kant, and J. Schnater interpreted the data. R. Billar, W. Manoubi, S. Demirdas, S. Kant, R. Wijnen and J. Schnater critically revised the manuscript. R. Billar made all figures and the final drafts of all tables. R. Billar, W. Manoubi, S. Demirdas, S. Kant, R. Wijnen and J. Schnater had full access to all of the data in the study and can take responsibility for the integrity of the data and the accuracy of the data analysis. S. Demirdas and J. Schnater contributed equally. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.

      Declaration of Competing Interest

      All authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

      Acknowledgments

      We kindly thank Wichor Bramer, biomedical information specialist, Erasmus University Medical Center, Rotterdam, the Netherlands; for his expertise with the literature search. Ko Hagoort, MA, Erasmus University Medical Center, Rotterdam, the Netherlands, is thanked for providing editorial advice.

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