Unilateral coronal craniosynostosis and Down syndrome

Report of 2 cases

Full access

There is no known correlation between Down syndrome and craniosynostosis. The authors report 2 infants with trisomy 21 and right unilateral coronal craniosynostosis. Both patients were clinically asymptomatic but displayed characteristic craniofacial features associated with each disorder. One patient underwent a bilateral fronto-orbital advancement and the other underwent an endoscopically assisted strip craniectomy with postoperative helmet therapy. Both patients demonstrated good cosmesis at follow-up.

There is no known correlation between Down syndrome and craniosynostosis. The authors report 2 infants with trisomy 21 and right unilateral coronal craniosynostosis. Both patients were clinically asymptomatic but displayed characteristic craniofacial features associated with each disorder. One patient underwent a bilateral fronto-orbital advancement and the other underwent an endoscopically assisted strip craniectomy with postoperative helmet therapy. Both patients demonstrated good cosmesis at follow-up.

Craniosynostosis refers to the premature fusion of cranial sutures. This condition occurs with an incidence of 1:2500 live births and can be present in isolation or as a component of various syndromes. Some forms of syndromic craniosynostosis are caused by discrete genetic mutations (for example, FGFR, Twist, and EFNB) that impact suture patency. Nevertheless, the molecular basis for many forms of syndromic and nonsyndromic craniosynostosis are unknown. Identification of additional associations may offer further clues about the complex biology of bone growth and the pathology of premature suture fusion.

There is no known association between craniosynostosis and Down syndrome, despite the latter condition's having well-described craniofacial anomalies. We describe 2 patients with trisomy 21 Down syndrome and single-suture craniosynostosis. These are the first descriptions in the literature to our knowledge.

Case Reports

Case 1

A 22-month-old girl born at 39 weeks' gestation, in whom a prenatal diagnosis of trisomy 21 Down syndrome had been made, was referred to our clinic for evaluation of forehead asymmetry, with right frontal flattening (Fig. 1). She had no symptoms of increased intracranial pressure. Her head circumference was about the 60th percentile. Head CT scanning confirmed a right unilateral coronal craniosynostosis (Fig. 2). The patient underwent a frontal orbital advancement and placement of autologous bone graft. She tolerated the procedure well and was discharged without incident. She has had an uneventful recovery and frontal symmetry was excellent almost 1 year after surgery.

Fig. 1.
Fig. 1.

Case 1. Preoperative photographs of a 22-month-old girl with Down syndrome showing frontal asymmetry with right frontal flattening, consistent with right unilateral coronal craniosynostosis.

Fig. 2.
Fig. 2.

Case 1. Preoperative head CT reconstruction demonstrating right unilateral coronal craniosynostosis.

Case 2

A 4-month-old boy, born at term, also with a prenatal diagnosis of trisomy 21 Down syndrome, was examined for right forehead asymmetry (Fig. 3). Head CT scanning was significant for a right unilateral coronal craniosynostosis (Fig. 4). He was otherwise asymptomatic, and his head circumference was in the 30th percentile. Again, there were no examination findings to support syndromic craniosynostosis. The patient underwent an endoscopically assisted strip craniectomy of the fused right coronal suture and tolerated the procedure well. He was fitted with a cranial molding orthosis shortly after the procedure and underwent postoperative helmet therapy to direct cranial growth. The patient had excellent phenotypic improvement almost 1 year after surgery.

Fig. 3.
Fig. 3.

Case 2. Preoperative photographs of a 4-month-old boy with Down syndrome showing frontal asymmetry with right frontal flattening, consistent with right unilateral coronal craniosynostosis.

Fig. 4.
Fig. 4.

Case 2. Preoperative head CT reconstruction demonstrating right unilateral coronal craniosynostosis.

Discussion

Large cohort studies have found genetic abnormalities in 21% of patients with craniosynostosis, of which 86% and 15% were attributed to single gene and chromosomal abnormalities, respectively.23 A key clinical distinction is the diagnosis of craniosynostosis in the setting of a syndrome, as it can be associated with other anomalies. Genetic studies of the so-called syndromic craniosynostoses, which may account for approximately 15% of patients,9,23 have provided key insights into the physiology of suture formation and its premature closure.15 Familial linkage studies have implicated genetic roles for FGFR family, TWIST-1, MSX-2, EFNB-1, and RAB-23.4,16,17

The contemporaneous occurrence of these 2 conditions raises the question of a possible causal association. Down syndrome occurs in 1 in 690 live births and is the most common chromosomal condition.6,7,25 The incidence of unilateral coronal synostosis is less well defined but is estimated to occur in roughly 1 in 10,000 live births.10,11 Thus, the likelihood of both diagnoses occurring randomly together is around 1 in 6.9 million live births. If there were a causal link, the incidence would be higher. Although it is difficult to conclusively extrapolate, the lack of prior descriptions seems to suggest that the concurrence in our patients might be random. Nevertheless, it is intriguing that the fusion involved the coronal suture in both patients instead of the more commonly fused sagittal or metopic sutures. A more esoteric causal link, possibly related to epigenetic influences, cannot be excluded.

The biology of cranial suture fusion is complex, and thus the root cause of any phenotypic aberrancy is likely to be multifactorial. The cranial sutures are made up of undifferentiated mesenchymal tissue composed of highly proliferative osteoprogenitors, which respond to a multitude of signaling molecules that promote transdifferentiation into osteoblasts to induce skull growth and subsequent suture fusion.14 It is likely that only a subset of key mediators has been elucidated, with additional mediators that remain unidentified. In support of this is the lack of a clear genetic basis for many individuals initially diagnosed with nonsyndromic craniosynostosis, and it may likely be a phenotypic manifestation of multiple genetic and environmental factors.5,22 Subsequent studies of nonsyndromic patients have identified genetic and chromosomal abnormalities in up to 5% of cases.12,18,21 The identification of other associations with craniosynostosis can provide additional insights.

While patients with trisomy 21 exhibit characteristic craniofacial abnormalities,20 an association with craniosynostosis is unknown. Trisomy 21 has been theorized to promote a generalized genetic imbalance. Recently, several candidate genes on chromosome 21 were identified that regulate bone development. DSCR1 and DYRK1A are genes located in the Down syndrome critical region and act to synergistically inhibit nuclear translocation of NFAT,1 a transcription factor important in normal skeletal development.8 Some studies have shown that NFAT inhibition results in increased osteoblast activity,13,26 while other studies have pointed to a more stimulatory role.24 The disparity may lie in timing of the expression, but it does underscore a genetic basis for overexpression of effectors found in chromosome 21 that modulate bone development and could increase the risk of craniosynostosis.

An additional candidate gene located on chromosome 21 is COL18A1, whose cleavage product is endostatin. It has been shown to affect osteoblast activity.19 Additionally, endostatin can inhibit Wnt signaling, which has been implicated in the development of a craniosynostosis phenotype in animal models.2,3 Further characterization of this pathway is necessary to determine the role in the human phenotype.

Conclusions

The association between trisomy 21 and craniosynostosis remains to be elucidated. While the paucity of described cases refutes the possibility of a direct causal link, the fact that both of our patients had fusion of a single coronal suture suggests that a less direct molecular interaction may be operative.

Disclosure

The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.

Author contributions to the study and manuscript preparation include the following. Conception and design: Magge, Rogers. Acquisition of data: Siu. Analysis and interpretation of data: Magge, Siu, Rogers, Khalsa, Keating. Drafting the article: Magge, Siu, Rogers, Khalsa. Critically revising the article: all authors. Reviewed submitted version of manuscript: all authors. Approved the final version of the manuscript on behalf of all authors: Magge. Statistical analysis: Siu. Study supervision: Magge, Rogers.

This article contains some figures that are displayed in color online but in black-and-white in the print edition.

References

  • 1

    Arron JRWinslow MMPolleri AChang CPWu HGao X: NFAT dysregulation by increased dosage of DSCR1 and DYRK1A on chromosome 21. Nature 441:5956002006

    • Search Google Scholar
    • Export Citation
  • 2

    Behr BLongaker MTQuarto N: Craniosynostosis of coronal suture in twist1 mice occurs through endochondral ossification recapitulating the physiological closure of posterior frontal suture. Front Physiol 2:372011

    • Search Google Scholar
    • Export Citation
  • 3

    Behr BLongaker MTQuarto N: Differential activation of canonical Wnt signaling determines cranial sutures fate: a novel mechanism for sagittal suture craniosynostosis. Dev Biol 344:9229402010

    • Search Google Scholar
    • Export Citation
  • 4

    Bellus GAGaudenz KZackai EHClarke LASzabo JFrancomano CA: Identical mutations in three different fibroblast growth factor receptor genes in autosomal dominant craniosynostosis syndromes. Nat Genet 14:1741761996

    • Search Google Scholar
    • Export Citation
  • 5

    Boyadjiev SA: Genetic analysis of non-syndromic craniosynostosis. Orthod Craniofac Res 10:1291372007

  • 6

    Canfield MAHonein MAYuskiv NXing JMai CTCollins JS: National estimates and race/ethnic-specific variation of selected birth defects in the United States, 1999–2001. Birth Defects Res A Clin Mol Teratol 76:7477562006

    • Search Google Scholar
    • Export Citation
  • 7

    Carothers ADHecht CAHook EB: International variation in reported livebirth prevalence rates of Down syndrome, adjusted for maternal age. J Med Genet 36:3863931999

    • Search Google Scholar
    • Export Citation
  • 8

    Chen WZhang XSiu RKChen FShen JZara JN: Nfatc2 is a primary response gene of Nell-1 regulating chondrogenesis in ATDC5 cells. J Bone Miner Res 26:123012412011

    • Search Google Scholar
    • Export Citation
  • 9

    Cohen MMMacLean RE: Craniosynostosis: Diagnosis Evaluation and Management ed 2New YorkOxford University2000

  • 10

    Collett BRAylward EHBerg JDavidoff CNorden JCunningham ML: Brain volume and shape in infants with deformational plagiocephaly. Childs Nerv Syst 28:108310902012

    • Search Google Scholar
    • Export Citation
  • 11

    Di Rocco CPaternoster GCaldarelli MMassimi LTamburrini G: Anterior plagiocephaly: epidemiology, clinical findings, diagnosis, and classification. A review. Childs Nerv Syst 28:141314222012

    • Search Google Scholar
    • Export Citation
  • 12

    Justice CMYagnik GKim YPeter IJabs EWErazo M: A genome-wide association study identifies susceptibility loci for nonsyndromic sagittal craniosynostosis near BMP2 and within BBS9. Nat Genet 44:136013642012

    • Search Google Scholar
    • Export Citation
  • 13

    Koga TMatsui YAsagiri MKodama Tde Crombrugghe BNakashima K: NFAT and Osterix cooperatively regulate bone formation. Nat Med 11:8808852005

    • Search Google Scholar
    • Export Citation
  • 14

    Lenton KANacamuli RPWan DCHelms JALongaker MT: Cranial suture biology. Curr Top Dev Biol 66:2873282005

  • 15

    Passos-Bueno MRSerti Eacute AEJehee FSFanganiello RYeh E: Genetics of craniosynostosis: genes, syndromes, mutations and genotype-phenotype correlations. Front Oral Biol 12:1071432008

    • Search Google Scholar
    • Export Citation
  • 16

    Rice DP: Craniofacial sutures. Development, disease and treatment. Preface. Front Oral Biol 12:xi2008

  • 17

    Senarath-Yapa KChung MTMcArdle AWong VWQuarto NLongaker MT: Craniosynostosis: molecular pathways and future pharmacologic therapy. Organogenesis 8:1031132012

    • Search Google Scholar
    • Export Citation
  • 18

    Seto MLHing AVChang JHu MKapp-Simon KAPatel PK: Isolated sagittal and coronal craniosynostosis associated with TWIST box mutations. Am J Med Genet A 143:6786862007

    • Search Google Scholar
    • Export Citation
  • 19

    Sipola ASeppinen LPihlajaniemi TTuukkanen J: Endostatin affects osteoblast behavior in vitro, but collagen XVIII/endostatin is not essential for skeletal development in vivo. Calcif Tissue Int 85:4124202009

    • Search Google Scholar
    • Export Citation
  • 20

    Starbuck JMCole TM IIIReeves RHRichtsmeier JT: Trisomy 21 and facial developmental instability. Am J Phys Anthropol 151:49572013

    • Search Google Scholar
    • Export Citation
  • 21

    Ursitti FFadda TPapetti LPagnoni MNicita FIannetti G: Evaluation and management of nonsyndromic craniosynostosis. Acta Paediatr 100:118511942011

    • Search Google Scholar
    • Export Citation
  • 22

    Wilkie AOBochukova EGHansen RMTaylor IBRannan-Eliya SVByren JC: Clinical dividends from the molecular genetic diagnosis of craniosynostosis. Am J Med Genet A 143A:194119492007

    • Search Google Scholar
    • Export Citation
  • 23

    Wilkie AOByren JCHurst JAJayamohan JJohnson DKnight SJ: Prevalence and complications of single-gene and chromosomal disorders in craniosynostosis. Pediatrics 126:e391e4002010

    • Search Google Scholar
    • Export Citation
  • 24

    Winslow MMPan MStarbuck MGallo EMDeng LKarsenty G: Calcineurin/NFAT signaling in osteoblasts regulates bone mass. Dev Cell 10:7717822006

    • Search Google Scholar
    • Export Citation
  • 25

    Wiseman FKAlford KATybulewicz VLFisher EM: Down syndrome—recent progress and future prospects. Hum Mol Genet 18:R1R75R832009

    • Search Google Scholar
    • Export Citation
  • 26

    Zanotti SSmerdel-Ramoya ACanalis E: Nuclear factor of activated T-cells (NFAT)c2 inhibits Notch receptor signaling in osteoblasts. J Biol Chem 288:6246322013

    • Search Google Scholar
    • Export Citation

If the inline PDF is not rendering correctly, you can download the PDF file here.

Article Information

Address correspondence to: Suresh N. Magge, M.D., 111 Michigan Ave. NW, Washington, DC 20010-2970. email: smagge@cnmc.org.

Please include this information when citing this paper: published online March 21, 2014; DOI: 10.3171/2014.2.PEDS13504.

© AANS, except where prohibited by US copyright law.

Headings

Figures

  • View in gallery

    Case 1. Preoperative photographs of a 22-month-old girl with Down syndrome showing frontal asymmetry with right frontal flattening, consistent with right unilateral coronal craniosynostosis.

  • View in gallery

    Case 1. Preoperative head CT reconstruction demonstrating right unilateral coronal craniosynostosis.

  • View in gallery

    Case 2. Preoperative photographs of a 4-month-old boy with Down syndrome showing frontal asymmetry with right frontal flattening, consistent with right unilateral coronal craniosynostosis.

  • View in gallery

    Case 2. Preoperative head CT reconstruction demonstrating right unilateral coronal craniosynostosis.

References

  • 1

    Arron JRWinslow MMPolleri AChang CPWu HGao X: NFAT dysregulation by increased dosage of DSCR1 and DYRK1A on chromosome 21. Nature 441:5956002006

    • Search Google Scholar
    • Export Citation
  • 2

    Behr BLongaker MTQuarto N: Craniosynostosis of coronal suture in twist1 mice occurs through endochondral ossification recapitulating the physiological closure of posterior frontal suture. Front Physiol 2:372011

    • Search Google Scholar
    • Export Citation
  • 3

    Behr BLongaker MTQuarto N: Differential activation of canonical Wnt signaling determines cranial sutures fate: a novel mechanism for sagittal suture craniosynostosis. Dev Biol 344:9229402010

    • Search Google Scholar
    • Export Citation
  • 4

    Bellus GAGaudenz KZackai EHClarke LASzabo JFrancomano CA: Identical mutations in three different fibroblast growth factor receptor genes in autosomal dominant craniosynostosis syndromes. Nat Genet 14:1741761996

    • Search Google Scholar
    • Export Citation
  • 5

    Boyadjiev SA: Genetic analysis of non-syndromic craniosynostosis. Orthod Craniofac Res 10:1291372007

  • 6

    Canfield MAHonein MAYuskiv NXing JMai CTCollins JS: National estimates and race/ethnic-specific variation of selected birth defects in the United States, 1999–2001. Birth Defects Res A Clin Mol Teratol 76:7477562006

    • Search Google Scholar
    • Export Citation
  • 7

    Carothers ADHecht CAHook EB: International variation in reported livebirth prevalence rates of Down syndrome, adjusted for maternal age. J Med Genet 36:3863931999

    • Search Google Scholar
    • Export Citation
  • 8

    Chen WZhang XSiu RKChen FShen JZara JN: Nfatc2 is a primary response gene of Nell-1 regulating chondrogenesis in ATDC5 cells. J Bone Miner Res 26:123012412011

    • Search Google Scholar
    • Export Citation
  • 9

    Cohen MMMacLean RE: Craniosynostosis: Diagnosis Evaluation and Management ed 2New YorkOxford University2000

  • 10

    Collett BRAylward EHBerg JDavidoff CNorden JCunningham ML: Brain volume and shape in infants with deformational plagiocephaly. Childs Nerv Syst 28:108310902012

    • Search Google Scholar
    • Export Citation
  • 11

    Di Rocco CPaternoster GCaldarelli MMassimi LTamburrini G: Anterior plagiocephaly: epidemiology, clinical findings, diagnosis, and classification. A review. Childs Nerv Syst 28:141314222012

    • Search Google Scholar
    • Export Citation
  • 12

    Justice CMYagnik GKim YPeter IJabs EWErazo M: A genome-wide association study identifies susceptibility loci for nonsyndromic sagittal craniosynostosis near BMP2 and within BBS9. Nat Genet 44:136013642012

    • Search Google Scholar
    • Export Citation
  • 13

    Koga TMatsui YAsagiri MKodama Tde Crombrugghe BNakashima K: NFAT and Osterix cooperatively regulate bone formation. Nat Med 11:8808852005

    • Search Google Scholar
    • Export Citation
  • 14

    Lenton KANacamuli RPWan DCHelms JALongaker MT: Cranial suture biology. Curr Top Dev Biol 66:2873282005

  • 15

    Passos-Bueno MRSerti Eacute AEJehee FSFanganiello RYeh E: Genetics of craniosynostosis: genes, syndromes, mutations and genotype-phenotype correlations. Front Oral Biol 12:1071432008

    • Search Google Scholar
    • Export Citation
  • 16

    Rice DP: Craniofacial sutures. Development, disease and treatment. Preface. Front Oral Biol 12:xi2008

  • 17

    Senarath-Yapa KChung MTMcArdle AWong VWQuarto NLongaker MT: Craniosynostosis: molecular pathways and future pharmacologic therapy. Organogenesis 8:1031132012

    • Search Google Scholar
    • Export Citation
  • 18

    Seto MLHing AVChang JHu MKapp-Simon KAPatel PK: Isolated sagittal and coronal craniosynostosis associated with TWIST box mutations. Am J Med Genet A 143:6786862007

    • Search Google Scholar
    • Export Citation
  • 19

    Sipola ASeppinen LPihlajaniemi TTuukkanen J: Endostatin affects osteoblast behavior in vitro, but collagen XVIII/endostatin is not essential for skeletal development in vivo. Calcif Tissue Int 85:4124202009

    • Search Google Scholar
    • Export Citation
  • 20

    Starbuck JMCole TM IIIReeves RHRichtsmeier JT: Trisomy 21 and facial developmental instability. Am J Phys Anthropol 151:49572013

    • Search Google Scholar
    • Export Citation
  • 21

    Ursitti FFadda TPapetti LPagnoni MNicita FIannetti G: Evaluation and management of nonsyndromic craniosynostosis. Acta Paediatr 100:118511942011

    • Search Google Scholar
    • Export Citation
  • 22

    Wilkie AOBochukova EGHansen RMTaylor IBRannan-Eliya SVByren JC: Clinical dividends from the molecular genetic diagnosis of craniosynostosis. Am J Med Genet A 143A:194119492007

    • Search Google Scholar
    • Export Citation
  • 23

    Wilkie AOByren JCHurst JAJayamohan JJohnson DKnight SJ: Prevalence and complications of single-gene and chromosomal disorders in craniosynostosis. Pediatrics 126:e391e4002010

    • Search Google Scholar
    • Export Citation
  • 24

    Winslow MMPan MStarbuck MGallo EMDeng LKarsenty G: Calcineurin/NFAT signaling in osteoblasts regulates bone mass. Dev Cell 10:7717822006

    • Search Google Scholar
    • Export Citation
  • 25

    Wiseman FKAlford KATybulewicz VLFisher EM: Down syndrome—recent progress and future prospects. Hum Mol Genet 18:R1R75R832009

    • Search Google Scholar
    • Export Citation
  • 26

    Zanotti SSmerdel-Ramoya ACanalis E: Nuclear factor of activated T-cells (NFAT)c2 inhibits Notch receptor signaling in osteoblasts. J Biol Chem 288:6246322013

    • Search Google Scholar
    • Export Citation

TrendMD

Metrics

Metrics

All Time Past Year Past 30 Days
Abstract Views 0 0 0
Full Text Views 225 213 11
PDF Downloads 285 266 11
EPUB Downloads 0 0 0

PubMed

Google Scholar