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Second Family with the Bostontype Craniosynostosis Syndrome: Novel Mutation and Expansion of the Clinical Spectrum

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Second Family with the Bostontype Craniosynostosis Syndrome: Novel Mutation and Expansion of the Clinical Spectrum CLINICAL REPORT Second Family With the Boston-Type Craniosynostosis Syndrome: Novel Mutation and Expansion of the Clinical Spectrum Alexander Janssen,1 Mohammad J. Hosen,2 Philippe Jeannin,3 Paul J. Coucke,2 Anne De Paepe,2 and Olivier M. Vanakker2* 1Department of Neurosurgery, Ghent University Hospital, Ghent, Belgium 2Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium 3Department of Pediatrics, Jan Palfijn Hospital, Ghent, Belgium Manuscript Received: 11 January 2013; Manuscript Accepted: 3 May 2013 Craniosynostosis, caused by early fusion of one or more cranial sutures, can affect the coronal or lambdoid sutures, or include How to Cite this Article: premature fusion of the sagittal (scaphocephaly) or metopic Janssen A, Hosen MJ, Jeannin P, Coucke suture (trigonocephaly). Often occurring as isolated finding, PJ, De Paepe A, Vanakker OM. 2013. their co-existence in a craniosynostosis syndrome is infrequent. Second family with the Boston-type We describe a four-generation family with variable expression of craniosynostosis syndrome: Novel mutation a craniosynostosis phenotype with scaphocephaly and a partic- and expansion of the clinical spectrum. ularly severe trigonocephaly. Molecular analysis revealed a mis- sense mutation in the MSX2—associated with the Boston-type Am J Med Genet Part A 161A:2352–2357. craniosynostosis syndrome—affecting the same amino-acid res- idue as in the original Boston family. Besides unique features such as the cranial sutures involved, minor limb abnormalities isolated sagittal synostosis, accounting for more than half of all and incomplete penetrance, our patients share with the original reported cases. Premature fusion of the sagittal suture results in family autosomal dominant inheritance and the presence of decreased width and inverse elongation of the anteroposterior axis multiple endocranial erosions on CT imaging. Though these of the cranium, also known as scaphocephaly. Recent studies findings appear to be important diagnostic clues for MSX2- demonstrated metopic synostosis, resulting in trigonocephaly, to related craniosynostosis, it is noteworthy that the first affected be almost as frequent as sagittal synostosis [Selber et al., 2008]. generation in this family presented merely with isolated sagittal Coronal synostosis (plagiocephaly or brachycephaly) was identified or unicoronal craniosynostosis and cutaneous syndactyly. Mo- as the third most common form, while multiple, apparently non- lecular analysis of MSX2 should therefore be considered in syndromal synostoses formed a smaller, but still substantial fourth patients with isolated scaphocephaly/unicoronal synostosis, es- group. Lambdoid synostosis, causing posterior plagiocephaly, was pecially in the presence of a family history for craniosynostosis or reported in very low frequencies [Kolar, 2011]. syndactyly. Ó 2013 Wiley Periodicals, Inc. Syndromic craniosynostosis can be associated with various dysmorphic features involving the face, skeleton, or nervous system Key words: Boston-type craniosynostosis; MSX2 and may be accompanied by developmental delay. Secondary effects include vision problems and increased intracranial pressure. More than 180 syndromes have been reported with craniosynosto- sis, and for many the molecular basis is known. Common clinical INTRODUCTION Craniosynostosis is a defect of the skull caused by premature fusion Alexander Janssen and Mohammad J. Hosen contributed equally to this of one or more cranial sutures [Johnson and Wilkie, 2011]. It is one work. Conflict of interest: none. of the most common craniofacial anomalies, affecting three to five à Correspondence to: individuals per 10,000 live births. Besides classification according to Olivier Vanakker, M.D., Ph.D., Center for Medical Genetics, Ghent the type of suture involved, craniosynostosis can be categorized as University Hospital, De Pintelaan 185, B-9000 Ghent, Belgium. syndromic or nonsyndromic [Johnson and Wilkie, 2011]. E-mail: [email protected] Nonsyndromic craniosynostosis is usually an isolated defect, Article first published online in Wiley Online Library classified according to the involved suture(s). Early studies of the (wileyonlinelibrary.com): 5 August 2013 epidemiology of simple craniosynostosis noted a predominance of DOI 10.1002/ajmg.a.36077 Ó 2013 Wiley Periodicals, Inc. 2352 JANSSEN ET AL. 2353 entities include Apert (OMIM# 101200), Crouzon (OMIM# formed using Alamut, Polyphen, Benin, and SIFT software. Pres- 123500), Muenke (OMIM# 602849), and Saethre-Chotzen syn- ence of variants in the general population was also evaluated drome (OMIM# 101400) [Johnson and Wilkie, 2011]. through the data available from the 1000 genomes project Among the less common syndromic craniosynostosis pheno- (http://www.1000genomes.org) and the NHLBI Exome Sequenc- types, the so-called Boston type of craniosynostosis (OMIM# ing Project (http://evs.gs.washington.edu/EVS/). 604757) represents an extremely rare entity first described by Warman et al. [1993] who reported a three-generation family CLINICAL REPORTS originating from Boston suffering from a fully penetrant though The male proband (Fig. 1A, IV-2), born at 38 weeks after an highly variable craniosynostosis with frontal bossing, turribrachy- uneventful pregnancy, was the second child of nonconsanguineous cephaly and cloverleaf skull anomaly. Hypoplasia of the supraor- parents. Anthropometric measurements at birth were normal: bital ridges was noted. Interestingly, the severity of the skull defect weight 2,600 g, length 46.6 cm. Clinically, he presented with pre- increased from one generation to the next. Though intelligence was mature fusion of the sagittal and metopic suture, resulting in normal, several patients had seizures, severe headaches, and/or scaphocephaly and trigonocephaly (Fig. 1B). Besides the scapho- ocular refraction errors (myopia/hyperopia). One patient had a cephaly, a prominent bony mass on the forehead, several centi- cleft palate. Besides a short first metatarsal in three individuals and a meters in height and width, was noted, in addition to bilateral triphalangeal thumb in one, no skeletal anomalies could be noted. proptosis. There was no sunset phenomenon. He had a prominent The craniosynostosis phenotype in this family was shown to be and wide glabella and bulbous nose tip with mild anteversion of the caused by a gain-of-function mutation in MSX2 (Muscle Segment nares. The trunk and limbs were normal with the exception of mild Homeobox, Drosophila Homolog of 2, OMIM# 123101) [Warman clinodactyly. Hearing and vision were normal. At 4 months of age, et al., 1993; Jabs et al., 1993; Ma et al., 1996]. MSX2, a homeodomain surgical correction of the synostosis was performed. During sur- transcription factor, is a regulator of osteocalcin expression and has gery, the affected bone was noted to be very thin and fragile, a central role in craniofacial development and limb formation complicating the surgical repair. At age 6 months normal develop- [Liu and Lee, 2012]. MSX2 mutations have been associated with ment and growth parameters could be observed. autosomal dominant parietal foramina (OMIM# 168500) with Family history revealed that the father (Fig. 1A, III-5), his sister or without cleidocranial dysplasia (OMIM# 168550) [Wilkie (III-7), and paternal half-sister (III-3) presented with an isolated et al., 2000; Wuyts et al., 2000; Garcia-Minaur et al., 2003; Spruijt single suture craniosynostosis. The father (III-5) was born at term et al., 2005; Ghassibe´ et al., 2006]. Since the initial report of Warman after an uneventful pregnancy. Anthropometric measurements et al. [1993], no other families or sporadic cases with the Boston- were normal. At birth he presented with premature fusion of the type of craniosynostosis due to MSX2 mutations have been sagittal suture which was surgically corrected at age 12 months. reported. There was no evidence of syndactyly. Neuromotor developmental Here we present on a four-generation family with an unusual was normal and presently he has normal cognition. craniosynostosis associated with variable hand and skeletal anom- The paternal aunt (III-7) presented with isolated premature alies, resulting from a MSX2 missense mutation, affecting the same fusion of the sagittal suture and underwent surgical correction at amino-acid residue as in the original Boston family. The over- age 4 months. She had bilateral complete cutaneous syndactyly of lapping characteristics with the original family provide useful the 3rd and 4th ray. Neurological development was normal. diagnostic clues while a number of unique features broaden the The father’s half-sister (III-3) was born with mild craniosynos- clinical spectrum of the Boston-type craniosynostosis. tosis of the left coronal suture in association with mild facial asymmetry, flattening of the left forehead, ipsilateral uplifting of MATERIALS AND METHODS the eyebrow, and slightly forward position of the ear. She also had proptosis of the right eye and bilateral complete cutaneous syndac- Direct sequencing of the coding region and intron–exon bound- tyly of the 3rd and 4th ray. There were no associated developmental aries of MSX2 was initially performed in patient IV-2 (Ref. seq ID: problems. ENSG00000120149). Subsequently, presence of the mutation was The paternal grandfather (Fig. 1A, II-4) had neither craniofacial assessed in other family members (II-4, III-3, III-5, and III-7) and in anomalies nor syndactyly. The paternal great grandfather (I-2) was 200 control alleles. Enrichment
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