Gorlin–Chaudhry–Moss Syndrome Revisited

3 downloads 17 Views 843KB Size Report
PDF Annotations (Adobe Reader version 7 or 8) – Commenting Toolbars look like this: .... Article Abstracts, Figures, Tables, Data Sets, Artwork and Selected.

CLINICAL REPORT

Gorlin–Chaudhry–Moss Syndrome Revisited: Expanding the Phenotype Rasim O. Rosti,1* Kadri Karaer,1 Birsen Karaman,2 Deniz Torun,1 Sefik Guran,3 and Muhterem Bahce1 1

DepartmentQ1of Medical Genetics, Gulhane Military Medical Academy, Ankara, Turkey 2 Istanbul Medical Faculty, Department of Medical Genetics, Istanbul University, Istanbul, Turkey 3

Department of Medical Biology, Gulhane Military Medical Academy, Ankara, Turkey

Manuscript Received: 25 October 2012; Manuscript Accepted: 9 March 2013

Gorlin–Chaudhry–Moss syndrome (OMIM 233500) is a rare congenital malformation syndrome with the cardinal manifestations of craniofacial dysostosis, hypertrichosis, underdeveloped genitalia, ocular, and dental anomalies. Since 1960, only six affected individuals have been reported. We report a 4-year and 6-month-old female patient with this phenotype and review the clinical presentation of all patients known so far. Previously unreported malformations of the extremities, larynx, and nose are also described, expanding the phenotype of this rare syndrome. Array-CGH analysis did not show pathological deletions or duplications. Ó 2013 Wiley Periodicals, Inc.

Key words: Gorlin–Chaudhry–Moss syndrome; craniofacial dysostosis; extremities; lower; extremities; upper; bifid nose; syndrome delineation

INTRODUCTION Gorlin–Chaudhry–Moss (GCM) syndrome is a rare clinical entity first reported in 1960 [Gorlin et al., 1960]. Only six patients have been reported to date. The patients share clinical findings of craniofacial dysostosis, hypertrichosis, underdeveloped genitalia, and ocular and dental anomalies [Aravena et al., 2011]. We recently evaluated a seventh patient with the typical findings and other unreported malformations.

CLINICAL REPORT The patient was born at term to unrelated healthy parents after an uneventful pregnancy. The parents had two spontaneous abortions. Her birth measurements are unknown. Multiple congenital anomalies were noted at birth. She was operated on due to coronal craniosynostosis at 18 months of age. She had laryngomalacia that became asymptomatic by the age of 3 years. At 4.5 years of age she was referred to Gulhane Military Medical Academy Medical Genetics Department due to dysmorphic features and the parents wish for a new pregnancy. Psychomotor development was within normal limits. Height was 101 cm (3rd–10th centile), weight 18 kg (50th–75th centile), and OFC 48 cm (10th–25th centile). On her

Ó 2013 Wiley Periodicals, Inc.

How to Cite this Article: Rosti RO, Karaer K, Karaman B, Torun D, Guran S, Bahce M. 2013. Gorlin– Chaudhry–Moss syndrome revisited: Expanding the phenotype. Am J Med Genet Part A 9999:1–6.

physical examination she had brachy/turricephaly, low posterior and anterior hairline, synophrys, upslanted palpebral fissures, inability to fully open or close her eyes, lateral flaring of eyebrows, long eyelashes, and bilateral upper eyelid colobomas. Underdeveloped ala nasi, prominent columella and bifid nasal tip, thin upper lip vermillion, narrow and high palate with a medial cleft of the soft palate, midface hypoplasia, and underdeveloped small ears with increased posterior angulation were also observed (Figs. 1–3). There was generalized hypertrichosis. Pectus excavatum, small thumbs, and index fingers with accompanying small nails, absent flexion crease of the thumbs, bilateral single transverse palmar creases, bilateral fifth finger clinodactyly, and bilateral cutaneous syndactyly of the second and third toes with small toenails were noted (Figs. 4–6). The labia majora were small. Ophthalmologic examination showed bilateral upper eyelid colobomas and hyperopia. Dental examination showed microdontia, irregularly shaped widely spaced teeth, oligodontia, narrow, and high arched palate with medial cleft. Audiological investigations showed bilateral mild conductive hearing loss (40 dB loss of left and right ear). Conflict of interest: none.  Correspondence to: Rasim O. Rosti, M.D., Department of Neuroscience, University of California, San Diego, 9500 Gilman Drive, M/C 0665, LBR, Rm 481 La Jolla, CA 92093-0665. E-mail: [email protected] Article first published online in Wiley Online Library (wileyonlinelibrary.com): 00 Month 2013 DOI 10.1002/ajmg.a.35954

AJMA-12-0880.R4(35954)

1

2

AMERICAN JOURNAL OF MEDICAL GENETICS PART A

FIG. 1. Frontal facial view of the patient. Synophrys, upslanted palpebral fissures, lateral flaring of eyebrows, long eyelashes, bilateral upper eyelid colobomas, underdeveloped ala nasi, prominent columella, bifid nasal tip, and full lips can be observed.

An X-ray of the left hand showed small distal phalanges of the first and second fingers and lateral skull X-ray showed premaxillary underdevelopment (Figs. 7 and 8). Denver developmental screening test revealed that the patient’s development was within normal limits. Abdominal ultrasonography, echocardiography and cranial magnetic resonance imaging were all normal. Chromosomal investigations showed a normal 46,XX karyotype. Array-CGH analysis (Roche, NimbleGen CGX-3, Basel, Switzerland) of the patient showed four copy number variants (CNVs). Among these, three CNVs overlapped with a polymorphism listed in the database of genomic variants (DGV) (http:// projects.tcag.ca/) for healthy individuals and were judged likely to

FIG. 3. Eyelid coloboma and configuration of the eyebrow.

be non-pathogenic. For the remaining genomic imbalance, CGH analysis was performed on the parents and it was seen that healthy father carried the 12q24.33 duplication in the heterozygous state. We concluded that this was a benign variation.

DISCUSSION Gorlin–Chaudhry–Moss (GCM) syndrome is a multiple congenital anomaly syndrome with only six patients reported to date. We have

FIG. 2. Lateral view. Low anterior hairline, lateral flaring of eyebrows, long eyelashes, full lips, small ears, with increased posterior angulation can be distinguished.

FIG. 4. Hands of the patient. Dorsal view. Small thumbs and index fingers with accompanying small nails and bilateral fifth finger clinodactyly is present.

ROSTI ET AL.

3

FIG. 5. Hands of the patient. Plantar view. Absent flexion crease of the thumbs, bilateral single transverse palmar creases, bilateral fifth finger clinodactyly are observed.

listed the cardinal, common, and rare findings of the syndrome and delineate the phenotype (Table I). Analysis of the clinical data show that stocky body build, normal intelligence, craniosynostosis, conductive hearing loss, hyperopia and facial dysmorphism, dental anomalies, extremity anomalies, hypertrichosis, umbilical hernia, and genital underdevelopment are present in a majority of the patients and comprise the cardinal findings for the syndrome. Brachycephaly, low frontal hairline, coarse hair, midface hypoplasia, short palpebral fissures, microphthalmia, high arched narrow palate, and ears with increased posterior angulation constitute the dysmorphism that was present in all of the reported patients. The patient described here also has stocky body build, normal development, common orofacial, and systemic findings as well as

FIG. 6. Feet of the patient showing bilateral 2–3 toe cutaneous syndactyly.

FIG. 7. Hand X-ray showing hypoplastic distal phalanges of the first and second fingers.

FIG. 8. Lateral skull X-ray showing premaxillary underdevelopment.

þ þ þ Normal þ þ þ þ þ þ   



þ þ þ Normal þ þ þ þ þ þ   



Aplastic nails

Cutaneous syndactyly

Small finger (seen on examination)

Ectropion of lower eyelid Increased posterior angulation of ears Somatic growth and performance Stocky body build Psychosocial motor abilities Systemic findings Coronal craniosynostosis Hypertrichosis Hyperopia Conductive hearing loss Dental anomalies Extremities Hypoplastic distal phalanges (hand and feet) Small nails

þ þ þ þ  þ þ þ þ þ   þ

þ þ þ þ  þ þ þ þ þ   þ

Orofacial findings Brachycephaly Coarse hair Low frontal hairline Midface hypoplasia Synophyris Depressed supraorbital ridges Downslanted palpebral fissures Short palpebral fissures Upper eye lid clefts Microphthalmia Prominent columella Bifid nasal tip High arched narrow palate

Gorlin et al. Patient #1 Patient #2

Right 2–3 (finger) Bilateral 2–3 (toe) 





þ

þ þ  þ þ

þ Normal

þ þ þ þ þ   þ þa þ þ  þ (Small medial cleft, bifid uvula)  þ



Bilateral fourth (finger) Bilateral fifth (finger), fourth and fifth (toe) 

þ

þ þ þ þ þ

þ Normal

 þ

þ þ þ þ  þ þ þ þ þ   þ

Ippel et al. Patient #3 Patient #4

TABLE I. ClinicalQ2 Manifestations









N/A

þ

þ

Right 4–5 (toe)

þ

 þ N/A  N/A

 þ

þ þ

þ þ þ þ þ  þ þ  þ þ  N/A

þ

 þ N/A  N/A

 N/A

N/A N/A

þ þ þ þ þ  þ þ  þ þ  þ (Submucosal cleft)

Aravena et al. Patient #5 Patient #6

Bilateral 1st and 2nd (finger)

Bilateral 2–3 (toe)



Bilateral first and second (finger)

þ

þ þ þ þ þ

þ Normal

 þ

þ þ þ þ þ  Upslanting þ þa þ þ þ þ (Small medial cleft)

Our patient

4 AMERICAN JOURNAL OF MEDICAL GENETICS PART A t-

ROSTI ET AL.

   þ þ   þ (PDA) þ þ     þ (Internal) N/A, not available. a Coloboma.

  þ (PDA) þ þ (External) Single transverse palmar creases Laryngomalacia Congenital heart disease Umbilical hernia Genital hypoplasia

  þ (PDA) þ þ (External)

    þ (External)

      Absent flexion creases

Ippel et al. Patient #3 Patient #4 Gorlin et al. Patient #1 Patient #2

TABLE I. (Continued )

Aravena et al. Patient #5 Patient #6

Our patient Bilateral finger thumb Bilateral þ   þ (External)

5 he extremity findings that most of the patients show (Table I). She also has an upslanted palpebral fissure compared to the downslanted palpebral fissures of the other patients, which may change the typical gestalt. The authors propose that this is a familial trait since both parents of the patient carried this palpebral orientation. Dental anomalies were emphasized in previous reports and orodental findings including large alveolar processes, malocclusion, oligodontia, microdontia, “bell-shaped” dental crowns, “spindleshaped” roots and small/missing pulp chambers were found in nearly all patients [Ippel et al., 1992]. Large alveolar processes, malocclusion, oligodontia, and microdontia were also reported in our patient. The new expanding extremity findings of the syndrome also merit discussion. Underdeveloped distal phalanges of hand and feet were reported in all patients and was the only common finding [Gorlin et al., 1960; Ippel et al., 1992]. Other features such as small nails and cutaneous syndactyly were reported in three patients. Our patient also has bilateral small nails of the thumb and second finger and bilateral cutaneous syndactyly of the second and third toes. The patient also had some features that were not reported previously. These include upslanted palpebral fissures, bifid nasal tip, small fingers (bilateral thumb and second finger), absent flexion crease of the thumbs, bilateral single transverse palmar creases, and laryngomalacia. These findings have to be substantiated by other patients to be included in the phenotypic spectrum of the disorder. The first patient of Ippel et al. [1992], the patients reported by Aravena et al. [2011] and the present patient (which we designate as group A) share some characteristic findings and a typical gestalt that are not seen in three other patients (group B). The primary distinction was the eyebrow morphology. These patients had synophyrs and a laterally widening and extending hair pattern that forms a “stair case” descending to the lateral orbital rim and canthus. The group B patients had an underdeveloped medial part, a well developed middle part, and a gradually thinning lateral part of the eyebrow. Moreover, the group of patients that include the present patient had prominent columella and relatively underdeveloped ala nasi that differed from the group B patients. The present patient also had a bifid nasal tip. It appears that the first patient of Ippel et al. [1992] may have had a bifid nasal tip (deduced from the photograph). Group A patients also did not seem to have the deeply set eyes that Group B patients had and had better developed lateral parts of the supra orbital ridges. Altogether, these features make up a different mid-face pattern that produces a distinct gestalt. The group A patients also shared small medial clefts of the palate and cutaneous syndactyly that were not encountered in Group B patients. Patient 1 of Ippel et al. [1992] had a bifid uvula that was not noted in other patients. We conclude that there are two subgroups within this syndromic complex that have both common and distinct clinical findings that affect the gestalt, which is a good diagnostic handle for dysmorphologists. As the number of patients increase and molecular etiology of the disorder is determined, it will be determined if Group A and B represent different phenotypic presentations of the same molecular entity or distinct molecular entities with significant clinical overlap. All the patients reported to date have been female with no known parental consanguinity. As the original patients reported by Gorlin et al. [1960] were siblings born to unaffected parents the condition

6 is considered to be inherited in an autosomal recessive manner. However, the lack of consanguinity in a disorder that is so rarely encountered combined with the fact that all affected patients are female could suggest a de novo X-linked dominant disorder with male lethality. In this case, the mothers of the patients of Gorlin et al. [1960] and Aravena et al. [2011] may have gonadal mosaicism for the causative mutation. As more patients are reported, the mode of inheritance for this disorder will be clarified. Patient 2 of Ippel et al. [1992] was reported as being involuntarily childless. She had irregular menstrual cycles, a short vagina, and a small uterus. The follow up information of the original patients did not include their reproductive histories. We also have no information about patient 1 of Ippel et al. [1992] who may likely be in her third decade at this writing. This information on fertility could be important in establishing recurrence risks. Additionally, an accompanying infertility aspect of the syndrome complex could account for the rare incidence. Since the a-CGH analysis of the patient described here was negative, we propose that the mutation responsible for the syndrome is either a point mutation or a small copy number variation that was not detected by a-CGH. A family with one affected individual may be given an estimated gonadal mosaicism recurrence rate considering the syndrome as a X-linked dominant disorder with male lethality. There are other syndromes that have overlapping features with Gorlin–Chaudhry–Moss syndrome and should be considered in the differential diagnosis. One is Petty syndrome (OMIM 612289), a congenital progeroid syndrome with pre- and post-natal growth restriction, decreased subcutaneous fat with loose skin, coronal synostosis, unruly hair pattern, thick eyebrows, and normal or near normal development [Petty et al., 1990]. Although the present patient shared some findings with Petty syndrome such as coronal synostosis, extremity anomalies, and some orofacial findings, she did not have decreased subcutaneous fat with loose skin or unruly hair pattern and had extra findings (such as prominent hypertrichosis, conductive hearing loss) that patients with Petty syndrome do not exhibit but are common in Gorlin–Chaudhry–Moss syndrome. Another syndrome that is mentioned alongside Gorlin–

AMERICAN JOURNAL OF MEDICAL GENETICS PART A Chaudhry–Moss syndrome is Saethre–Chotzen syndrome. In a recent report, a female patient was considered to have features reminiscent of Gorlin–Chaudhry–Moss syndrome [Preis et al., 1995]. That patient clearly lacked the hypertrichosis, hearing loss, the striking eyebrow pattern and the picture is more similar to Saethre–Chotzen phenotype. This patient also has coronal and metopic synostosis, which has not been reported in Gorlin– Chaudhry–Moss syndrome but is reported in patients with Saethre–Chotzen. In conclusion, we report the seventh case of Gorlin–Chaudhry– Moss syndrome and review the clinical presentations of the previously published patients in order to ascertain the cardinal, common, and uncommon findings of the disorder. We report a set of hitherto unencountered findings of laryngomalacia, extremity, and nasal findings that may expand the phenotype of the syndrome. Certain extremity anomalies that were present in the patient reported here suggest that these features can be added to the clinical synopsis of the disorder now that they are found in more than one patient. We have also discussed possible subgrouping, inheritance model, and the fertility aspect of the syndrome.

REFERENCES Aravena T, Passalacqua C, Pizarro O, Aracena M. 2011. Two sisters resembling Gorlin–Chaudhry–Moss syndrome. Am J Med Genet Part A 155A:2552–2555. Gorlin RJ, Chaudhry AP, Moss ML. 1960. Craniofacial dysostosis, patent ductus arteriosus, hypertrichosis, hypoplasia of labia majora, dental and eye anomalies-A new syndrome? J Pediatr 56:778–785. Ippel PF, Gorlin RJ, Lenz W, van Doorne JM, Bijlsma JB. 1992. Craniofacial dysostosis, hypertrichosis, genital hypoplasia, ocular, dental, and digital defects: Confirmation of the Gorlin–Chaudhry–Moss syndrome. AmQ3 J Med Genet 44:518–522. Petty M, Laxova R, Wiedemann H. 1990. Previously unrecognized congenital progeroid disorder. AmQ4 J Med Genet 35:383–387. Preis S, Kaewel EV, Majewski F. 1995. Gorlin–Chaudhry–Moss or Saethre– Chotzen syndrome? Clin Genet 47:267–269.

AUTHOR QUERY FORM JOURNAL: AMERICAN JOURNAL OF MEDICAL GENETICS PART A Article: ajmga35954 Dear Author, During the copyediting of your paper, the following queries arose. Please respond to these by annotating your proofs with the necessary changes/additions using the E-annotation guidelines attached after the last page of this article. We recommend that you provide additional clarification of answers to queries by entering your answers on the query sheet, in addition to the text mark-up. Query No.

Query

Q1

Please check the affiliation(s) and corresponding link symbol(s) with the author name(s).

Q2

Please check this table.

Q3

Please specify whether it belongs to Part A, B, or C.

Q4

Please specify whether it belongs to Part A, B, or C.

Remark

INSTRUCTIONS FOR CHECKING PAGE PROOFS A PDF page proof of your article is provided with these instructions. Its purpose is for you to: ƒ ƒ ƒ

Proofread your article. Answer any queries (which, if present, are in a query list at the end of the article). Check the content and positioning of tables and figures.

It is important that you check this proof very carefully and answer all the queries. Please note that only essential corrections can be made at this stage. Also note that changes you make to your article that do not comply with the style of the Journal and those that are grammatically incorrect will not be incorporated. Proofreading instructions Read over your article carefully, and check that: ƒ ƒ ƒ ƒ ƒ

There are no errors in the article (including data, equations and references). Author and address details are accurate. Content and positioning of tables and figures is correct (note that some photographs in the file may appear blurry, as figures in the PDF are low resolution). Special characters such as figure legend symbols and Greek letters have not corrupted. Any previously submitted amendments have been incorporated correctly.

Queries ƒ Any queries are listed on the last page of the proof, with a corresponding number in the margin next to the relevant text. ƒ Please ensure all queries are answered in full. Return of approval to publish ƒ Add corrections or answers to any queries using e-Annotation. The instructions for for using e-Annotation tools are on the following pages. ƒ Retain a copy of your corrections for your records. ƒ Email the Production Editor your approval to publish your article (either with or without amendment) and any corrections required. The Production Editor’s contact details are given in the covering email. ƒ Prompt notification of your approval to publish your article is very much appreciated. ƒ Please contact the Production Editor if you have any queries.

USING E-ANNOTATION TOOLS FOR ELECTRONIC PROOF CORRECTION Required Software Adobe Acrobat Professional or Acrobat Reader (version 7.0 or above) is required to e-annotate PDFs. Acrobat 8 Reader is a free download: http://www.adobe.com/products/acrobat/readstep2.html. For help with system requirements, go to: http://www.adobe.com/support/. Once you have Acrobat Reader on your PC and open the proof, you will see the Commenting Toolbar (if it does not appear automatically go to Tools>Commenting>Commenting Toolbar). If these options are not available in your Adobe Reader menus then it is possible that your Adobe version is lower than 7 or the PDF has not been prepared properly.

PDF Annotations (Adobe Reader version 7 or 8) – Commenting Toolbars look like this:

(PC, Adobe version 7)

(PC, Adobe version 8, rightͲclick on title bar (Comment & Markup) to show additional icons)

(Mac)

PDF Annotations (Adobe Reader version 9) If you experience problems annotating files in Adobe Acrobat Reader 9 then you may need to change a preference setting in order to edit.

The default for the Commenting toolbar is set to ‘off’ in version 9. To change this setting select ‘Edit | Preferences’, then ‘Documents’ (at left under ‘Categories’), then select the option ‘Never’ for ‘PDF/A View Mode’. (the Commenting toolbar is the same as in version 8).

PLEASE DO NOT ATTEMPT TO EDIT THE ARTICLE TEXT ITSELF TO INDICATE INSERT, REPLACE, OR REMOVE TEXT x

Insert text

Click the ‘Text Edits’ button on the Commenting toolbar. Click to set the cursor location in the text and simply start typing. The text will appear in a commenting box. You may also cut-and-paste text from another file into the commenting box. Close the box by clicking on ‘x’ in the top right-hand corner. It can be deleted by right clicking (for the PC, ctrl-click on the Mac) on it and selecting ‘Delete’. x

Replace text

Click the ‘Text Edits’ button on the Commenting toolbar. To highlight the text to be replaced, click and drag the cursor over the text. Then simply type in the replacement text. The replacement text will appear in a commenting box. You may also cut-and-paste text from another file into this box. To replace formatted text (an equation for example) please Attach a file (see below). x

Remove text

Click the ‘Text Edits’ button on the Commenting toolbar. Click and drag over the text to be deleted. Then press the delete button on your keyboard. The text to be deleted will then be struck through.

HIGHLIGHT TEXT/MAKE A COMMENT Click on the ‘Highlight’ button on the commenting toolbar. Click and drag over the text. To make a comment, double click on the highlighted text and simply start typing.

ATTACH A FILE Click on the ‘Attach a file’ button on the commenting toolbar. Click on the figure, table or formatted text to be replaced. A window will automatically open allowing you to attach a file. To make a comment, go to ‘General’ and then ‘Description’ in the ‘Properties’ window. A graphic will appear indicating the insertion of a file.

LEAVE A NOTE/COMMENT Click on the ‘Note Tool’ button on the commenting toolbar. Click to set the location of the note on the document and simply start typing. Do not use this feature to make text edits.

REVIEW To review your changes, click on the ‘Show’ button on the commenting toolbar. Choose ‘Show Comments List’. Navigate by clicking on a correction in the list. Alternatively, double click on any mark-up to open the commenting box.

UNDO/DELETE CHANGE To undo any changes made, use the right click button on your mouse (for PCs, Ctrl-Click for Mac). Alternatively click on the ‘Edit’ in the main Adobe menu and then ‘Undo’. You can also delete edits using the right click (Ctrl-Click on the Mac) and selecting ‘Delete’.

SEND YOUR ANNOTATED PDF FILE BACK TO WILEY VIA [email protected] Save the annotations to your file and return as an e-mail. Before returning, please ensure you have answered any questions raised on the Query form that you have inserted all the corrections: later inclusion of any subsequent corrections cannot be guaranteed. Note: Comprehensive instructions are provided within your PDF file: to access these instructions please click on the Comments and Markup menu in the main tool bar, or click on Help.

AJMA, e-proof: C1/Wiley-Liss

1 1 1 R IVER S TREET, HOBOKEN, N J 0 7 0 3 0 ***IMMEDIATE RESPONSE REQUIRED*** Your article will be published online via Wiley's EarlyView® service (www.interscience.wiley.com) shortly after receipt of corrections. EarlyView® is Wiley's online publication of individual articles in full text HTML and/or pdf format before release of the compiled print issue of the journal. Articles posted online in EarlyView® are peer-reviewed, copyedited, author corrected, and fully citable. EarlyView® means you benefit from the best of two worlds--fast online availability as well as traditional, issuebased archiving. READ PROOFS CAREFULLY • This will be your only chance to review these proofs. • Please note that the volume and page numbers shown on the proofs are for position only. ANSWER ALL QUERIES ON PROOFS (Queries for you to answer are attached as the last page of your proof.) • Mark all corrections directly on the proofs. Note that excessive author alterations may ultimately result in delay of publication and extra costs may be charged to you. CHECK FIGURES AND TABLES CAREFULLY (Color figures will be sent under separate cover.) • Check size, numbering, and orientation of figures. • All images in the PDF are downsampled (reduced to lower resolution and file size) to facilitate Internet delivery. These images will appear at higher resolution and sharpness in the printed article. • Review figure legends to ensure that they are complete. • Check all tables. Review layout, title, and footnotes. COMPLETE REPRINT ORDER FORM • Fill out the attached reprint order form. It is important to return the form even if you are not ordering reprints. You may, if you wish, pay for the reprints with a credit card. Reprints will be mailed only after your article appears in print. This is the most opportune time to order reprints. If you wait until after your article comes off press, the reprints will be considerably more expensive.

RETURN

PROOFS REPRINT ORDER FORM CTA (If you have not already signed one)

RETURN IMMEDIATELY AS YOUR ARTICLE WILL BE POSTED IN ORDER OF RECEIPT. QUESTIONS?

Christopher Sannella, Production Editor Phone: 201-748-5949 E-mail: [email protected] Refer to journal acronym and article production number (i.e., AJMA 00-0001 for American Journal of Medical Genetics ms 000001).

COPYRIGHT TRANSFER AGREEMENT Date:

Contributor name:

Contributor address: Manuscript number (Editorial office only): Re: Manuscript entitled (the “Contribution”) for publication in published by

(the “Journal”) (“Wiley-Blackwell”).

Dear Contributor(s): Thank you for submitting your Contribution for publication. In order to expedite the editing and publishing process and enable Wiley-Blackwell to disseminate your Contribution to the fullest extent, we need to have this Copyright Transfer Agreement signed and returned as directed in the Journal’s instructions for authors as soon as possible. If the Contribution is not accepted for publication, or if the Contribution is subsequently rejected, this Agreement shall be null and void. Publication cannot proceed without a signed copy of this Agreement.

A. COPYRIGHT 1. The Contributor assigns to Wiley-Blackwell, during the full term of copyright and any extensions or renewals, all copyright in and to the Contribution, and all rights therein, including but not limited to the right to publish, republish, transmit, sell, distribute and otherwise use the Contribution in whole or in part in electronic and print editions of the Journal and in derivative works throughout the world, in all languages and in all media of expression now known or later developed, and to license or permit others to do so. 2. Reproduction, posting, transmission or other distribution or use of the final Contribution in whole or in part in any medium by the Contributor as permitted by this Agreement requires a citation to the Journal and an appropriate credit to Wiley-Blackwell as Publisher, and/or the Society if applicable, suitable in form and content as follows: (Title of Article, Author, Journal Title and Volume/Issue, Copyright © [year], copyright owner as specified in the Journal). Links to the final article on Wiley-Blackwell’s website are encouraged where appropriate.

B . R E TA I N E D R I G H T S Notwithstanding the above, the Contributor or, if applicable, the Contributor’s Employer, retains all proprietary rights other than copyright, such as patent rights, in any process, procedure or article of manufacture described in the Contribution.

C. PERMITTED USES BY CONTRIBUTOR 1. Submitted Version. Wiley-Blackwell licenses back the following rights to the Contributor in the version of the Contribution as originally submitted for publication: a. After publication of the final article, the right to self-archive on the Contributor’s personal website or in the Contributor’s institution’s/employer’s institutional repository or archive. This right extends to both intranets and the Internet. The Contributor may not update the submission version or replace it with the published Contribution. The version posted must contain a legend as follows: This is the pre-peer reviewed version of the following article: FULL CITE, which has been published in final form at [Link to final article]. b. The right to transmit, print and share copies with colleagues. 2. Accepted Version. Re-use of the accepted and peer-reviewed (but not final) version of the Contribution shall be by separate agreement with WileyBlackwell. Wiley-Blackwell has agreements with certain funding agencies governing reuse of this version. The details of those relationships, and other offerings allowing open web use, are set forth at the following website: http://www.wiley.com/go/funderstatement. NIH grantees should check the box at the bottom of this document.

3. Final Published Version. Wiley-Blackwell hereby licenses back to the Contributor the following rights with respect to the final published version of the Contribution: a. Copies for colleagues. The personal right of the Contributor only to send or transmit individual copies of the final published version in any format to colleagues upon their specific request provided no fee is charged, and further-provided that there is no systematic distribution of the Contribution, e.g. posting on a listserve, website or automated delivery. b. Re-use in other publications. The right to re-use the final Contribution or parts thereof for any publication authored or edited by the Contributor (excluding journal articles) where such re-used material constitutes less than half of the total material in such publication. In such case, any modifications should be accurately noted. c. Teaching duties. The right to include the Contribution in teaching or training duties at the Contributor’s institution/place of employment including in course packs, e-reserves, presentation at professional conferences, in-house training, or distance learning. The Contribution may not be used in seminars outside of normal teaching obligations (e.g. commercial seminars). Electronic posting of the final published version in connection with teaching/training at the Contributor’s institution/place of employment is permitted subject to the implementation of reasonable access control mechanisms, such as user name and password. Posting the final published version on the open Internet is not permitted. d. Oral presentations. The right to make oral presentations based on the Contribution. 4. Article Abstracts, Figures, Tables, Data Sets, Artwork and Selected Text (up to 250 words). a. Contributors may re-use unmodified abstracts for any non-commercial purpose. For on-line uses of the abstracts, Wiley-Blackwell encourages but does not require linking back to the final published versions. b. Contributors may re-use figures, tables, data sets, artwork, and selected text up to 250 words from their Contributions, provided the following conditions are met: (i) Full and accurate credit must be given to the Contribution. (ii) Modifications to the figures, tables and data must be noted. Otherwise, no changes may be made. (iii) The reuse may not be made for direct commercial purposes, or for financial consideration to the Contributor. (iv) Nothing herein shall permit dual publication in violation of journal ethical practices.

CTA-A

D. CONTRIBUTIONS OWNED BY EMPLOYER 1. If the Contribution was written by the Contributor in the course of the Contributor’s employment (as a “work-made-for-hire” in the course of employment), the Contribution is owned by the company/employer which must sign this Agreement (in addition to the Contributor’s signature) in the space provided below. In such case, the company/employer hereby assigns to Wiley-Blackwell, during the full term of copyright, all copyright in and to the Contribution for the full term of copyright throughout the world as specified in paragraph A above. 2. In addition to the rights specified as retained in paragraph B above and the rights granted back to the Contributor pursuant to paragraph C above, WileyBlackwell hereby grants back, without charge, to such company/employer, its subsidiaries and divisions, the right to make copies of and distribute the final published Contribution internally in print format or electronically on the Company’s internal network. Copies so used may not be resold or distributed externally. However the company/employer may include information and text from the Contribution as part of an information package included with software or other products offered for sale or license or included in patent applications. Posting of the final published Contribution by the institution on a public access website may only be done with Wiley-Blackwell’s written permission, and payment of any applicable fee(s). Also, upon payment of Wiley-Blackwell’s reprint fee, the institution may distribute print copies of the published Contribution externally.

E. GOVERNMENT CONTRACTS In the case of a Contribution prepared under U.S. Government contract or grant, the U.S. Government may reproduce, without charge, all or portions of the Contribution and may authorize others to do so, for official U.S. Govern-

ment purposes only, if the U.S. Government contract or grant so requires. (U.S. Government, U.K. Government, and other government employees: see notes at end)

F. C O P Y R I G H T N O T I C E The Contributor and the company/employer agree that any and all copies of the final published version of the Contribution or any part thereof distributed or posted by them in print or electronic format as permitted herein will include the notice of copyright as stipulated in the Journal and a full citation to the Journal as published by Wiley-Blackwell.

G . C O N T R I B U T O R ’ S R E P R E S E N TAT I O N S The Contributor represents that the Contribution is the Contributor’s original work, all individuals identified as Contributors actually contributed to the Contribution, and all individuals who contributed are included. If the Contribution was prepared jointly, the Contributor agrees to inform the co-Contributors of the terms of this Agreement and to obtain their signature to this Agreement or their written permission to sign on their behalf. The Contribution is submitted only to this Journal and has not been published before. (If excerpts from copyrighted works owned by third parties are included, the Contributor will obtain written permission from the copyright owners for all uses as set forth in WileyBlackwell’s permissions form or in the Journal’s Instructions for Contributors, and show credit to the sources in the Contribution.) The Contributor also warrants that the Contribution contains no libelous or unlawful statements, does not infringe upon the rights (including without limitation the copyright, patent or trademark rights) or the privacy of others, or contain material or instructions that might cause harm or injury.

CHECK ONE BOX: Contributor-owned work AT TA C H A D D I T I O N A L S I G N AT U R E PA G E S A S N E C E S S A RY

Contributor’s signature

Date

Type or print name and title

Co-contributor’s signature

Date

Type or print name and title

Company/Institution-owned work (made-for-hire in the course of employment)

Company or Institution (Employer-for-Hire)

Date

Authorized signature of Employer

Date

U.S. Government work

Note to U.S. Government Employees A contribution prepared by a U.S. federal government employee as part of the employee’s official duties, or which is an official U.S. Government publication, is called a “U.S. Government work,” and is in the public domain in the United States. In such case, the employee may cross out Paragraph A.1 but must sign (in the Contributor’s signature line) and return this Agreement. If the Contribution was not prepared as part of the employee’s duties or is not an official U.S. Government publication, it is not a U.S. Government work.

U.K. Government work (Crown Copyright)

Note to U.K. Government Employees The rights in a Contribution prepared by an employee of a U.K. government department, agency or other Crown body as part of his/her official duties, or which is an official government publication, belong to the Crown. U.K. government authors should submit a signed declaration form together with this Agreement. The form can be obtained via http://www.opsi.gov.uk/advice/crown-copyright/copyright-guidance/ publication-of-articles-written-by-ministers-and-civil-servants.htm

Other Government work

Note to Non-U.S., Non-U.K. Government Employees If your status as a government employee legally prevents you from signing this Agreement, please contact the editorial office.

NIH Grantees

Note to NIH Grantees Pursuant to NIH mandate, Wiley-Blackwell will post the accepted version of Contributions authored by NIH grant-holders to PubMed Central upon acceptance. This accepted version will be made publicly available 12 months after publication. For further information, see www.wiley.com/go/nihmandate. CTA-A

These proofs have been typeset using figure files transmitted to production when this article was accepted for publication. Please review all figures and note your approval with your submitted proof corrections. You may contact the journal production editor via e-mail at [email protected] if you wish to discuss specific concerns. Because of the high cost of color printing, we can only print figures in color if authors cover the expense. If you have submitted color figures, please indicate your consent to cover the cost on the table listed below by marking the box corresponding to the approved cost on the table. Please note, all color images will be reproduced online in Wiley InterScience at no charge, whether or not you opt for color printing. You will be invoiced for color charges once the article has been published in print. Failure to return this form with your article proofs may delay the publication of your article.

JOURNAL

AMERICAN JOURNAL OF MEDICAL GENETICS PART A

MS. NO.

NO. COLOR PAGES

MANUSCRIPT TITLE AUTHOR(S) No. Color Pages Color Charge No. Color Pages Color Charge No. Color Pages Color Charge 1 5 9 $950 $3400 $5850 2 6 10 $1450 $3900 $6350 3 7 11 $1950 $4400 $6850 4 8 12 $2450 $4900 $7350 ***Contact [email protected] for a quote if you have more than 12 pages of color***

Please print my figures color

Please print my figures in black and white

Please print the following figures in color and convert these figures to black and white

Approved by Billing Address

E-mail Telephone Fax

                   

 

       

Additional reprint and journal issue purchases   

Should you wish to purchase additional copies of your article,   please click on the link and follow the instructions provided:  https://caesar.sheridan.com/reprints/redir.php?pub=10089&acro=AJMGA Corresponding authors are invited to inform their co‐authors of  the reprint options available.    Please note that regardless of the form in which they are acquired,  reprints should not be resold, nor further disseminated in electronic form, nor  deployed in part or in whole in any marketing, promotional or educational  contexts without authorization from Wiley. Permissions requests should be  directed to mailto: [email protected]    For information about ‘Pay‐Per‐View and Article Select’ click on the following  link: http://wileyonlinelibrary.com/ppv