Craniosynostosis And Dental Anomalies

A number sign (#) is used with this entry because of evidence that craniosynostosis and dental anomalies (CRSDA) is caused by homozygous mutation in the IL11RA gene (600939) on chromosome 9p13.

Description

This autosomal recessive disorder is characterized by craniosynostosis, maxillary hypoplasia, and dental anomalies, including malocclusion, delayed and ectopic tooth eruption, and/or supernumerary teeth. Some patients also display minor digit anomalies, such as syndactyly and/or clinodactyly (summary by Nieminen et al., 2011).

Clinical Features

Nieminen et al. (2011) studied 3 consanguineous families of Pakistani origin and 2 families of northern European origin in which affected children had craniosynostosis involving the metopic, coronal, sagittal, and/or lambdoid sutures, maxillary hypoplasia, and variable dental anomalies. In the first Pakistani family ('family 1'), 4 of 6 children were affected, whereas the parents and 2 daughters had normal craniofacial features with no history or signs of supernumerary tooth formation or delayed tooth eruption. The proband, who presented at 11.4 years of age with maxillary hypoplasia, class III malocclusion, and abnormal tooth eruption, was found to have premature fusion of all calvarial sutures. Her 2 brothers had complex synostosis of all calvarial sutures, and a younger sister had fused sagittal and coronal sutures but patent lambdoid sutures. All affected sibs had some degree of midface hypoplasia associated with class III malocclusion, and although their permanent teeth had all developed, eruption was delayed and several teeth erupted ectopically. All 4 sibs also had supernumerary teeth, from 1 to 7 in number, that developed approximately 4 years after the permanent dentition and were located lingually and occlusally to the normal permanent teeth in the incisor, canine, and premolar regions. The syndrome in this family had previously been designated 'Kreiborg-Pakistani syndrome' (Cohen and MacLean, 2000). In the second Pakistani pedigree ('family 2'), a total of 5 affected children were born to 2 consanguineous and closely related couples. The proband was diagnosed at 2 years of age due to severe proptosis and papilledema, with multiple suture synostosis confirmed radiologically; 2 sibs and 2 cousins, who had more subtle clinical findings, were subsequently also diagnosed with craniosynostosis. Dental anomalies in this pedigree consisted of large lateral incisors seen in 2 affected children; additional anomalies included broad first toes with hallux valgus and mild syndactyly of the second and third toes. In the third Pakistani family ('family 3'), the second of 5 sibs was the only affected child; after trigonocephaly was noted on routine examination at 13 months of age, evaluation revealed premature fusion of all calvarial sutures, slight exorbitism, and bilateral papilledema. At 12 years of age, orthodontic assessment due to compacted palate with dental disarray and persisting deciduous teeth revealed maxillary hypoplasia with class III malocclusion, presence of all permanent teeth, and palatal eruption of right maxillary premolars and ectopic eruption of maxillary third molars. In the fourth family, an affected sister and brother were born to unrelated parents of northern European origin. The sister had total vault sutural fusion, mild hypertelorism with prominent eyes, mild papilledema, reduced vision with an enlarged blind spot in the left eye, maxillary hypoplasia, and marked turricephaly. Multiple extractions of deciduous teeth were required to allow eruption of permanent teeth. Her brother was not evaluated in detail but was reported to have a similar skull shape and history of dental problems. The fifth family involved 2 affected brothers born to unaffected nonconsanguineous Dutch parents; 1 of the brothers had synostosis of all cranial sutures, whereas the other had premature fusion of only the sagittal suture. The brothers displayed maxillary hypoplasia but no dental anomalies were reported.

Mapping

In a consanguineous Pakistani family ('family 1') segregating autosomal recessive craniosynostosis and dental anomalies, Nieminen et al. (2011) performed genomewide homozygosity analysis followed by fine mapping and identified a region of shared homozygosity at chromosome 9p21.3-q21.13, from D9S265 to D9S175. Multipoint linkage analysis gave a location score of 3.26, considered to be significant evidence for linkage, over the entire region. Genomewide analysis of a second affected Pakistani family ('family 2') revealed a common haplotype in affected individuals on chromosome 9 between SNPs rs10967436 and rs7044969, overlapping the region of linkage in family 1; a maximum location score of 4.18 was obtained. A third affected Pakistani family ('family 3') showed homozygosity for markers within the candidate regions in families 1 and 2, with a maximum location score of 1.55.

Inheritance

Craniosynostosis and dental anomalies is an autosomal recessive disorder (Nieminen et al., 2011).

Molecular Genetics

In a consanguineous Pakistani family ('family 1') segregating autosomal recessive craniosynostosis and dental anomalies mapping to chromosome 9p21.3-q21.13, Nieminen et al. (2011) sequenced 11 candidate genes and identified homozygosity for a missense mutation in the IL11RA gene (600939.0001) that segregated with disease and was not found in controls. Analysis of IL11RA in DNA samples from 2 more similarly affected Pakistani families and from a cohort of unrelated craniosynostosis-affected individuals revealed homozygosity for 2 additional missense mutations in the 2 Pakistani families (600939.0002 and 600939.0003, respectively) and a nonsense mutation in a family of northern European origin (600939.0004). In 2 Dutch brothers with craniosynostosis, Nieminen et al. (2011) identified homozygosity for a 9-bp duplication in the IL11RA gene (600939.0005).