Solitary median maxillary central incisor syndrome: heterozygous pathogenic variant in the SIX3 gene

Introduction

Solitary median maxillary central incisor (SMMCI) syndrome, previously referred to as “solitary median maxillary central incisor, short stature, choanal atresia/midnasal stenosis syndrome,” is a disorder that encompasses a variety of congenital midline defects. Holoprosencephaly is among the most serious presentations of this condition, manifesting in significant craniofacial and neural defects. The diagnosis can be identified with ultrasound prenatally; respiratory distress is the presenting symptom of choanal atresia/midnasal stenosis in infancy. Some patients are diagnosed upon eruption of the single maxillary primary central incisor. Several chromosomal abnormalities have been implicated with this syndrome, including mutations in the SHH gene.

Case Findings

A 4-year-old male presented with a history significant for repaired unilateral cleft lip, developmental delay, and a nasal dermoid cyst. Holoprosencephaly was not identified on brain MRI. His intraoral examination was significant for primary dentition including a single large maxillary midline primary central incisor, and no maxillary labial frenum. The parents deny history of trauma. A maxillary occlusal radiograph revealed a single primary central incisor located in the midline, as well as a single developing permanent central incisor. All other dentition appeared to be developing appropriately.

Results

The patient’s phenotype of unilateral cleft lip, solitary median maxillary primary central incisor, nasal dermoid cyst, and developmental delay are consistent with SMMCI syndrome. The patient was evaluated with chromosomal microarray (negative study) as well as Invitae Holoprosencephaly Panel which identified a heterozygous pathogenic variant in the SIX3 gene. SIX3 gene is observed in autosomal dominant nonsyndromic holoprosencephaly and SIX3 has been implicated in SMMCI syndrome.

Conclusion

SMMCI syndrome is composed of unique congenital abnormalities inherited in an autosomal dominant pattern. The family history may appear negative because of reduced penetrance. The presentation of a single symmetrical large maxillary central incisor should raise concern for congenital midline defects warranting directed genetic testing.