Solitary median maxillary central incisor (SMMCI) is a rare dental anomaly that has been described as an isolated dental finding or part of the so-called ‘SMMCI syndrome’ (OMIM number 147 250). SMMCI syndrome is a complex, autosomal dominant developmental disorder in which an SMMCI is seen in association with midline nasal cavity defects (choanal atresia, mid-nasal stenosis, nasal pyriform aperture stenosis) and variably holoprosencephaly1. It is one of the presenting microforms of the holoprosencephaly spectrum, and probably results from a developmental field defect of the forebrain, arising from unknown events occurring between the 35th and 38th days in utero2. While prenatal diagnosis of holoprosencephaly is readily made by both fetal ultrasonography and magnetic resonance imaging (MRI), identification of SMMCI with nasal pyriform aperture stenosis is also important owing to the risk of airway obstruction, as neonates are obligate nasal breathers.
A 33-year-old woman, gravida 2 para 1, was referred to the fetal medicine unit at 34 weeks' gestation for consultation regarding possible fetal holoprosencephaly. Her first pregnancy resulted in the spontaneous vaginal delivery of a healthy male infant, birth weight 3570 g, but had been complicated by gestational diabetes requiring insulin therapy. There was a strong maternal family history of both Type 1 and Type 2 diabetes. The couple was of Canadian Caucasian ethnicity and non-consanguineous.
An intrauterine pregnancy with a normal nuchal translucency was confirmed on ultrasound examination at 12 weeks' gestation. Integrated prenatal screening results for Down syndrome and open spina bifida were screen negative. At 20 weeks her anatomical scan was reported as normal. Ultrasonography performed at 29 weeks for the assessment of growth and biophysical profile revealed dilated ventricles with an absent cavum septi pellucidi. These findings were suspicious for holoprosencephaly, therefore fetal MRI was requested. MRI was performed using a 1.5-T magnet (GE Healthcare Technologies, Milwaukee, WI, USA) and showed semilobar holoprosencephaly (Figure 1), mid-nasal stenosis (Figure 2), and a central incisor (Figure 3).
The couple subsequently had consultations with our genetics and neonatology services. Amniocentesis with cytogenetic analysis revealed a normal male karyotype. In view of the cerebral malformation and poor neuro-developmental prognosis, permission for late termination of pregnancy was sought from the ethics committee but was not obtained. Prenatal ascertainment of the poor fetal prognosis, however, facilitated formation of a delivery plan that avoided Cesarean section intervention for non-reassuring fetal status and made provisions for palliative care of the neonate at delivery.
Labor was induced at 40 weeks and 6 days. A stillborn male, birth weight 3908 g, was delivered. Consent for autopsy limited to external examination and X-rays was obtained. Microcephaly, hypotelorism, nasal stenosis and abnormality of the palate and maxillary alveolar ridge (Figure 4) were noted. Holoprosencephaly DNA analysis (TGIF, SIX3, SHH and ZIC2 genes) was negative (GeneDx, Inc., Gaithersburg, MD, USA).
A search of PubMed using the free-text search terms SMMCI syndrome, prenatal diagnosis, MRI and congenital nasal pyriform aperture stenosis (CNPAS) revealed no previous reports of SMMCI syndrome with nasal obstruction, prenatally diagnosed by fetal MRI. The estimated incidence of SMMCI syndrome is 1 : 50 000 live births3, in contrast to the other major traits present in this syndrome, namely choanal atresia (incidence of 1 : 5000 live births4) and holoprosencephaly (1 : 16 000 live births5). Familial aggregation occurs in the form of autosomal dominant inheritance. In patients with SMMCI syndrome without holoprosencephaly or holoprosencephaly-like phenotypes and normal MRIs, known holoprosencephaly genetic mutations (SHH, SIX3, TGIF and ZIC2) have been identified in some, but not all cases. Additionally, deletions on chromosomes 7 and 18 in regions that harbor holoprosencephaly genes have been reported6. Other associations include diabetic pregnancies (14%), preterm labor and low birth weight (37%)7.
Prenatal ultrasonography is safe, accessible and inexpensive and remains the primary imaging method for fetal evaluation, but fetal MRI using ultrafast sequences offers complementary diagnostic information. It is particularly useful in the event of equivocal ultrasound findings or difficult acoustic windows in late pregnancy or an inaccessible fetal position8. MRI offers additional clarification of complex brain malformations9. In the present case, while semilobar holoprosencephaly was suspected at ultrasound, the additional facial and airway anomalies were only identifiable on MRI. Several reports in the literature document postnatal diagnosis using computed tomography (CT). One report documented six cases of CNPAS as a presenting feature of holoprosencephaly, five of which had an SMMCI visualized on postnatal CT10. Another article reported two cases of neonatal nasal obstruction secondary to CNPAS each with an associated SMMCI11. A sibling of one case had SMMCI syndrome with holoprosencephaly and the family pedigree suggested an autosomal dominant form of holoprosencephaly. Recently, three-dimensional CT was recommended as a useful tool for postnatal diagnosis of CNPAS12. In our case, fetal MRI, however, enabled antenatal diagnosis of SMMCI syndrome with semilobar holoprosencephaly and thus ascertainment of poor neurodevelopmental prognosis.
Genetic testing yielded a normal karyotype, absence of genetic deletions or mutations. Of the known holoprosencephaly-associated mutations—SHH, ZIC2, SIX3, TGIF—mutations in the SHH gene have been most predictive of holoprosencephaly in patients with SMMCI1. Autosomal dominant holoprosencephaly was not suspected as parental phenotypic features were normal and both genetic testing and family history were negative. The couple was thus reassured that their risk of recurrence would be approximately 6%.
Diabetes mellitus has been cited as an etiological factor for holoprosencephaly. This patient was diagnosed with gestational diabetes mellitus (GDM) at approximately 20 weeks' gestation. Though we have no formal laboratory evidence of hyperglycemia during the critical period of organogenesis, the possibility of abnormal glucose tolerance exists given the early gestational age at which GDM was diagnosed. Formal glucose tolerance testing at 6 weeks postpartum was advised. Prepregnancy consultation with the fetal medicine unit was recommended prior to a future pregnancy.
In this case of SMMCI syndrome, MRI provided detailed insight into fetal anatomy and pathology, aiding prenatal diagnosis and facilitating parental counseling.