Predictive Factors for Perinatal Outcomes of Infants Diagnosed With Micrognathia Antenatally.

INTRODUCTION: Advances in fetal imaging have allowed us to identify abnormalities previously not appreciated. With this study, we hope to identify factors predicting a difficult airway at birth and review the perinatal outcomes of these patients. METHODS: Sixteen patients with antenatally diagnosed micrognathia were reviewed from a tertiary care hospital database from 2011 to 2016. Jaw index (JI), amniotic fluid index (AFI), glossoptosis, gastric size, and oropharynx obliteration were assessed. The airway support required at birth, specialist team involvement, and outcomes were evaluated. RESULTS: Nine (56.3%) of 16 patients had JI <5th percentile, 3 (33.3%) of 9 had difficult intubation, 2 (22.2%) of 9 needed an emergency tracheostomy, and 1 (11.1%) of 9 died. Seven patients had polyhydramnios, 2 (28.6%) of 7 had difficult intubation, 2 (28.6%) of 7 required tracheostomy, and 1 (14.3%) of 7 died. Twelve patients had either JI <5th percentile or abnormal AFI, 5 (41.7%) of 12 had difficult intubation, 2 (16.7%) of 12 required tracheostomy, and 1 (8.33%) of 12 died. For the group without otolaryngology consultation, 8 (50%) of 16, 1 (12.5%) of 8 had difficult intubation and 1 (12.5%) of 8 died because airway was not secured after 45 minutes of resuscitation. CONCLUSION: Jaw index <5th percentile or abnormal AFI predicts a difficult airway. A multidisciplinary approach with otolaryngology involvement for airway intervention may be required at birth.

Prenatal indices for mandibular retrognathia/micrognathia.

OBJECTIVE: Micro- and retrognathia of mandibular origin may lead to life-threatening respiratory problems in connection with glossoptosis immediately after birth. Prenatal screening for this malformation is therefore increasingly important. Today this is accomplished by predominantly subjective standards. Objective criteria have been proposed but have not become established. We therefore made an effort to develop indices that would identify major skeletal discrepancies or micrognathia in as straightforward a fashion as possible during routine prenatal sonography. MATERIALS AND METHODS: Series of fetal jaw sonograms (Toshiba Aplio MX®) were obtained in 313 women with normal pregnancies from weeks 19-29 of gestation. Upper- and lower-jaw landmarks were interactively located on screen and evaluated for reproducibility. Linear parameters representative of maxillary and mandibular length (SpA'-SpP' and Rami-SymMe) were measured and related to femur length and gestational age. Based on these data, indices for maxillary, and mandibular length were derived and analyzed. RESULTS: High correlations were identified for mandibular length both with gestational age (R = 0.845; R(2) = 0.713) and with femur length (correlation coefficients (R) = 0.839; coefficients of determination (R(2)) = 0.704). For maxillary length, the respective correlation coefficients were 0.691 (R(2) = 0.477) and 0.656 (R(2) = 0.430). Estimates of mandibular and maxillary length based on gestational age and femur length were obtained by regression analysis. The mean bimaxillary length ratio was 0.628 ± 0.043. CONCLUSION: Maxillary and mandibular growth can be objectively evaluated via indices. It is conceivable to develop this approach into a sensitive and reliable method of prenatal jaw screening for major skeletal anomalies and congenital malformations.

Noninvasive Prenatal Diagnosis of Hypohidrotic Ectodermal Dysplasia by Tooth Germ Sonography.

PURPOSE: Hypohidrotic ectodermal dysplasia, a potentially life-threatening heritable disorder, may be recognized already in utero by characteristic features such as oligodontia and mandibular hypoplasia. As therapeutic options and prognosis depend on the time point of diagnosis, early recognition was attempted during routine prenatal ultrasound examinations. SUBJECTS AND METHODS: Fetuses of nine pregnant women (one triplet and eight singleton pregnancies) with family histories of hypohidrotic ectodermal dysplasia were investigated by sonography between the 20th and 24th week of gestation. RESULTS: In 4 male and 2 female fetuses reduced amounts of tooth germs were detected, whereas 5 fetal subjects showed the normal amount. Three-dimensional ultrasound evaluation revealed mandibular hypoplasia in 5 of the 6 fetuses with oligodontia. Molecular genetic analysis and/or clinical findings after birth confirmed the prenatal sonographic diagnosis in each subject. CONCLUSION: In subjects with a family history of hypohidrotic ectodermal dysplasia, the diagnosis of this rare condition can be established noninvasively by sonography in the second trimester of pregnancy. Early recognition of the disorder may help to prevent dangerous hyperthermic episodes in infancy and may allow timely therapeutic interventions.

Successful ex utero intrapartum treatment procedure for prenatally diagnosed severe micrognathia: a case report.

We present a case of fetal severe micrognathia in which successful airway stabilization was achieved by an ex utero intrapartum treatment procedure. In this case, it was anticipated that the infant would have a vulnerable airway at birth based on in utero sonographic findings, including an extremely hypoplastic jaw, worsening polyhydramnios and absence of stomach visualization. Early sonographic recognition was helpful in preparing the parents and physicians for the possibility of airway emergencies during the perinatal period. When a severely hypoplastic mandible accompanied by polyhydramnios and absent stomach visualization is noted on ultrasound, clinicians should consider the indication for ex utero intrapartum treatment. A multidisciplinary team with technically skilled medical providers should be coordinated to perform the procedure.

Absent mandibular gap in the retronasal triangle view: a clue to the diagnosis of micrognathia in the first trimester.

OBJECTIVE: To describe a new ultrasound technique that may be useful for the diagnosis of micrognathia in the first trimester of pregnancy. METHODS: The retronasal triangle (RNT) view is a technique that captures the coronal plane of the face in which the primary palate and the frontal processes of the maxilla are visualized simultaneously. Normal first-trimester fetuses display a characteristic gap between the right and left body of the mandible in this view (the 'mandibular gap'). The presence or absence of this gap was evaluated and measured prospectively during real-time scanning (n = 154) and retrospectively by analyzing three-dimensional (3D) datasets (n = 50) in normal first-trimester fetuses undergoing screening for aneuploidy at 11-13 weeks' gestation. 3D datasets from 12 fetuses with suspected micrognathia were also collected and examined retrospectively for the same features. RESULTS: The mandibular gap was identified in all 204 normal fetuses and increased linearly with increasing crown-rump length (y = 0.033x + 0.435; R(2) = 0.316), with no statistically significant differences between measurements obtained by two-dimensional ultrasound and 3D offline analysis. Among fetuses with suspected micrognathia, three 3D datasets were excluded from analysis because of poor image quality in one and the diagnosis of a normal chin in two. In the remaining nine fetuses, the mandibular gap was absent and was replaced by a bony structure representing the receding chin in seven (77.8%) cases and was not visualized due to severe retrognathia in the remaining two (22.2%) cases. All fetuses with micrognathia had associated anomalies, including seven with aneuploidy and two with skeletal dysplasia. CONCLUSIONS: The RNT view may be a helpful technique for detecting micrognathia in the first trimester. The absence of the mandibular gap or failure to identify the mandible in this view is highly suggestive of micrognathia and should prompt a targeted ultrasound scan to assess for other anomalies. Further research is needed to determine the false-positive and false-negative rates of this technique.

Frontomaxillary and mandibulomaxillary facial angles at 11 + 0 to 13 + 6 weeks in fetuses with trisomy 18.

OBJECTIVE: To define the relative position of the maxilla and mandible in fetuses with trisomy 18 at 11 + 0 to 13 + 6 weeks of gestation. METHODS: A three-dimensional (3D) volume of the fetal head was obtained before karyotyping at 11 + 0 to 13 + 6 weeks of gestation in 36 fetuses subsequently found to have trisomy 18, and 200 chromosomally normal fetuses. The frontomaxillary facial (FMF) angle and the mandibulomaxillary facial (MMF) angle were measured in a mid-sagittal view of the fetal face. RESULTS: In the chromosomally normal group both the FMF and MMF angles decreased significantly with crown-rump length (CRL). In the trisomy 18 fetuses the FMF angle was significantly greater and the angle was above the 95(th) centile of the normal range in 21 (58.3%) cases. In contrast, in trisomy 18 fetuses the MMF angle was significantly smaller than that in normal fetuses and the angle was below the 5(th) centile of the normal range in 12 (33.3%) cases. CONCLUSIONS: Trisomy 18 at 11 + 0 to 13 + 6 weeks of gestation is associated with both mid-facial hypoplasia and micrognathia or retrognathia that can be documented by measurement of the FMF angle and MMF angle, respectively.

The role of integrated imaging techniques for prenatal prediction of phenotype in two cases of facial anomalies.

OBJECTIVES: Fetal face malformations represent one of the most challenging prenatal diagnoses mainly because of the wide range of morphological features involved. We tested an approach based on a combination of conventional two-dimensional ultrasound with the more recent three-dimensional technique plus magnetic resonance imaging, in order to improve parents' understanding of fetal face anomalies, thereby facilitating parent counselling. METHODS: Two cases of fetal facial anomaly were studied using these combined techniques; one had severe micrognathia and malformation of the ears with preauricular tags, while the other had bilateral dacryocystocele and severe hypertelorism. RESULTS: The images generated by three-dimensional ultrasound enabled the parents to visualize their child immediately and helped them to adjust to the diagnosis of facial defects and its clinical consequences. CONCLUSIONS: An approach based on combined use of different imaging techniques was found useful in both cases.

Cerebro-costo-mandibular syndrome presenting as Pierre Robin sequence.

Cerebro-costo-mandibular syndrome is a rare disorder characterized by psychomotor retardation, posterior rib-gap defects, and the orofacial defects of Pierre Robin sequence. Most cases are sporadic, but several familial cases have been reported, many of which support autosomal recessive inheritance. We present a case of autosomal dominant inheritance from father to son; the seventh known case of dominant transmission. We also review the findings, inheritance pattern, and outcomes of Pierre Robin sequence that are useful in managing affected patients.

Clinical, cytogenetic and molecular investigation in a fetus with Wolf-Hirschhorn syndrome with paternally derived 4p deletion. Case report and review of the literature.

Wolf-Hirschhorn (4p-) syndrome (WHS), caused by partial deletion of the short arm of chromosome 4, has been extensively described in children and young adults. Knowledge on fetuses with WHS is still limited due to the small number of published cases. We report on a fetus with prenatally diagnosed severe intrauterine growth retardation, reduced thoracal diameter, clubfeet deformity and midface hypoplasia including slight microretrognathia indicative for fetal karyotyping. Chromosome analysis after amniocentesis revealed a de novo terminal deletion of chromosome 4p [karyotype: 46,XX,del(4) (p16)] which was confirmed by FISH. Analyses of a set of polymorphic markers mapping in 4pter->4p15.3 showed absence of paternal haplotypes. These observations corroborate the preferential paternal origin of the de novo 4p deletion in WHS patients. Furthermore, the distal breakpoint could be narrowed to band 4p16.1. At autopsy, the fetus showed typical craniofacial dysmorphic signs of WHS, severe IUGR and delayed bone age. This report suggests the possibility of recognising the particular phenotype of WHS in utero by prenatal ultrasound and emphasises the importance of karyotyping fetuses with severe IUGR, especially when the amount of amniotic fluid is normal.

Three-dimensional ultrasonographic presentation of micrognathia.

OBJECTIVE: To present the variable appearance of micrognathia in fetuses by three-dimensional ultrasonography and to describe practical methods for analysis of these volume data. METHODS: Three-dimensional multiplanar imaging and surface-rendering techniques were used to show various syndromes and diagnostic approaches for the evaluation of fetal micrognathia. RESULTS: Nine cases of fetal micrognathia are presented. Orthogonal multiplanar views were used to obtain a midsagittal facial profile. Examples of micrognathia include 3 cases of Pierre Robin sequence, cerebrocostomandibular syndrome, Cornelia de Lange syndrome, and hypochondrogenesis. Diagnostic pitfalls for micrognathia are also shown. CONCLUSIONS: Three-dimensional multiplanar imaging increases the likelihood that a true midline sagittal view of the facial profile is being analyzed. Surface rendering provides another way to qualitatively evaluate the fetal chin from different viewing perspectives. Three-dimensional ultrasonographic methods are useful adjuncts to the preliminary diagnostic impression from two-dimensional ultrasonography.

Altered mandibular development precedes the time of palate closure in mice homozygous for disproportionate micromelia: an oral clefting model supporting the Pierre-Robin sequence.

BACKGROUND: Development of the human craniofacial anatomy involves a number of interrelated, genetically controlled components. The complexity of the interactions between these components suggests that interference with the spaciotemporal interaction of the expanding tongue and elongating Meckel's cartilage correlates with the appearance of cleft palate. Mice homozygous for the semi-dominant Col2a1 mutation Disproportionate micromelia (Dmm), presenting at birth with both cleft palate and micrognathia, provide the opportunity to test the hypothesis that mandibular growth retardation coincides with formation of the secondary palate as predicted from our understanding of the Pierre Robin sequence. The present study was conducted in embryonic day 14 (E14) mice, 1 day before palate closure, to describe the relationship between growth of the lower jaw/tongue complex versus genotype of the embryo. METHODS: Whole heads, isolated from E14.25, E14.5 and E14.75 wild-type and homozygous mutant embryos, were fixed in Bouin's solution, embedded in paraffin, and serially sectioned. Mid-sagittal sections, stained with toluidine blue, were used to estimate growth of both tongue and lower jaw (Meckel's cartilage length) during a 12-hr period preceding palate closure. RESULTS: In control embryos, the largest increase in Meckel's cartilage length occurred between E14.5 and E14.75. Compared to control, the mean Meckel's cartilage length in the mutant was similar at E14.25, but was significantly less at E14.5 and E14.75. Absolute tongue size in control embryos increased linearly during this period of E14.25 to E14.75. Relative to the rapidly growing Meckel's cartilage, however, relative tongue size in control embryos actually decreased over time. Absolute tongue size in the mutant was not significantly different from that of control at any of the embryonic stages examined, however, relative tongue size in the mutant was significantly greater at E14.75 compared to control. CONCLUSION: Mandibular growth retardation, coupled with relative macroglossia in E14 Dmm/Dmm mice, suggests that the concerted development of the palate and lower jaw complex in the mutant is aberrant. Detection of micrognathia and pseudomacroglossia in homozygotes, before the time of palate closure, supports the hypothesis that a relationship exists between growth retardation of Meckel's cartilage and malformation of the secondary palate, as predicted by the Pierre-Robin sequence.

Effects of irradiation and methyl-triazene on craniofacial development in mouse embryos: a semiautomated morphometric analysis.

OBJECTIVE: The purpose of the present study was a 2D-semiautomated morphometric analysis of craniofacial growth in nuclear magnetic resonance imaged (NMRI) mouse embryos. METHODS: The NMRI mouse embryos were exposed in utero to either a single dose of 2 Gy X-irradiation on day 9 of gestation (113 embryos) or to 1.5 mg methyl-triazene administered orally to their pregnant mothers on gestational day 10.5 (124 embryos). An additional group of 108 embryos was used as controls. Digitized pictures of embryos from gestational days 14 to 17 were taken in lateral right view using a video system. Landmarks were located and digitized for computerized analysis of growth changes in relation to developmental stages of the face. RESULTS: The results revealed that the snout of control embryos lengthens during the developmental period considered. The snout of embryos previously submitted to methyl-triazene displayed micrognathia, and all treated fetuses exhibited macroscopic signs of microcephaly with a reduced mandible. The snouts of irradiated embryos appeared shortened at the 14-day stage and continued to shorten as development proceeded. A shortening of the midface was detected macroscopically in 83% of the cases. CONCLUSION: The results of this morphometric analysis enabled us to trace the developmental progression of the induced dysmorphosis and to assess the differences compared with normal development.

[Observation of micrognathic development in mouse fetus induced by sulfadimethoxine].

The purpose of this study was to investigate the process of micrognathic development in mouse fetus induced by Sulfadimethoxine (SDM). SDM of 3,000 mg/kg was administered orally to pregnant ICR mice on days 8, 9, 10, 11, 12, and 13 of gestation. The fetuses were removed on day 15 to analyze the incidence of micrognathia. The incidence of micrognathia was the highest in the treated group on day 10. The fetuses, SDM-treated on day 10, were sacrificed on days 11, 12, 13, 14, 15, and 18 and prepared for histological and morphological analyses. Histomorphological analyses were performed by lateral and horizontal graphic reconstruction using serial frontal sections. It was also performed by clearing and alcian blue-alizarin red double staining. In the treated group, bilateral sigmoid buckling and shortening of Meckel's cartilage became evident after day 14, however, the nasal septal and capsule cartilage were less affected. It was concluded that remarkable hypoplastic and malformed Meckel's cartilage, caused by the administration of SDM, induced mandibular dysmorphogenesis.

[Histological study of micrognathic development in mouse fetus induced by 3,3-dimethyl-1-phenyltriazene].

The purpose of this study was to investigate the influence of 3,3-dimethyl-1-phenyltriazene (DMPT) on development of craniofacial structures in mouse fetus. (1) Pregnant C57BL/6 mice were treated with 30 mg/kg DMPT injection on days 10.5 approximately 13.5 of gestation. The fetuses were analyzed on day 15.0. The incidence of micrognathia was formed 100% in the treated group on days 10.5 and 11.0, and then decreased remarkably after day 11.5. This result suggested that the critical period of micrognathic development is days 10.5 approximately 11.0. (2) The fetuses, injected 30 mg/kg DMPT on day 10.5, were sacrificed on days 11.0 approximately 18.0. Their heads were used for the following histomorphological analyses: 1. clearing and Alcian blue-alizarin red double staining and 2. lateral graphic reconstruction using serial frontal sections. Dysmorphology of the anterior portion of Meckel's and nasal septal cartilage became evident after day 13.0, however, nasal capsule cartilage was hardly affected. It was concluded that hypoplastic Meckel's cartilage, caused by the administration of DMPT, induced mandibular dysmorphogenesis.

Pathogenesis of bromodeoxyuridine-induced cleft palate in mice.

This study was designed to examine the pathogenesis of bromodeoxyuridine-induced (BrdU) clefts of the secondary palate in mice. Intraperitoneal injections of BrdU (500 mg/kg body weight) were given on days 11 and 12 to some pregnant mice and on days 12 and 13, and days 11, 12 and 13 to others. Evaluation of craniofacial relations and palate development in BrdU-treated mice revealed inhibition of vertical development of the palatal shelves, mandibular hypoplasia which led to failure of downward displacement of the tongue and the creation of an obstacle to reorientation of the palatal shelves. The results of this study demonstrate a strong correlation between induction of cleft palate and the presence of structural alterations in the mandible, and the mechanism of BrdU-induced cleft palate resembles the defect in the Pierre Robin anomaly.

Agnathia (severe micrognathia), aglossia and choanal atresia in an infant.

A neonate is reported here, who was born with severe mandibular hypoplasia, complete absence of the tongue, unilateral choanal atresia, contralateral choanal stenosis and developed severe airway obstruction at birth. Arrested development of the ventral first branchial arch most likely underlies the clinical deficits. Most reported cases of agnathia have been lethal but the infant reported here has survived into infancy with a tracheostomy and feeding gastrostomy. Her clinical features, assessment and management are discussed.

Lack of mandibular movement manifested by absent fetal swallowing: a possible factor in the pathogenesis of micrognathia.

This study was performed to assess the association of lack of mandibular movement as manifested by absent fetal swallowing and micrognathia in a nonrestrictive intrauterine environment. Over a 5-year period, 14 fetuses with sonographic findings of polyhydramnios (amniotic fluid index [AFI] more than 20 cm), absent mandibular movement, and a nonvisualized fetal stomach, all consistent with absent fetal swallowing, were followed. A group of 14 fetuses, each with polyhydramnios (AFI more than 20 cm), yet with sonographic detection of fetal swallowing, served as controls. All gravidas in both groups were normoglycemic throughout gestation. Subsequent mandibular development was assessed at delivery or autopsy. Analysis of the data revealed that in the study group, 12 of these infants were liveborn, and two were stillborn. Eleven of the liveborn infants had an early neonatal death. All 14 infants of the study group demonstrated micrognathia. None of the control infants (all of whom survived) had micrognathia. In conclusion, this study supports the concept that normal mandibular growth may depend on the presence of mandibular movement during intrauterine development.

Morphogenesis of isotretinoin-induced microcephaly and micrognathia studied by scanning electron microscopy.

Isotretinoin ingestion during the first trimester of human pregnancy can induce malformations of the skull, ears, face, central nervous system, eyes, palate, lungs, circulatory system, limbs, and digits. A single oral dose of isotretinoin on day 8 of gestation in hamsters induces a similar syndrome of congenital malformation. The present study concerned scanning electron microscopic (SEM) observation of embryonic and fetal hamster craniofacial structures at 4, 8, 12, 24, 48, and 72 hr after administration of an oral dose of 50 mg/kg isotretinoin or an equivalent volume of the vehicle. The variability in development among control embryos recovered 4 hr after treatment precluded objective assessment of pathologic change by SEM at very early time points. Craniofacial damage was obvious within 8-12 hr of isotretinoin treatment, and it included hypoplasia of the maxillary and mandibular processes of the first branchial arch, a rudimentary second arch, and apparent collapse of the forebrain. Equivalent fusion between the lateral nasal process and the maxillary process and between the medial nasal process and the maxillary process in treated and control embryos accounts for the very low incidence of cleft lip observed in fetuses. The terminal microstomia was not associated with excessive merging or overgrowth of the first arch components. Hypoplasia of the first arch can account for retinoid-induced macrostomia and microstomia.

Mandibular skeletal dysmorphology in micrognathic mice.

The primary manifestations of micrognathia were microglossia, midline fusion of the right and left sides of the mandible, total absence of incisor and molar toothbuds and, in many cases, absence or perhaps premature resorption of Meckel's cartilage. In addition, there was altered osteogenesis as evidenced by disrupted trabecular patterns, as well as an overall dimensional reduction of the mandible both antero-posteriorly and laterally. Strikingly similar results were reported by Johnson (1926), who studied the progeny of x-irradiated mice. How specifically our results correlate with this much earlier work is a matter for further analysis. It seems clear that the critical factor in the development of micrognathia is not so much an abnormal formation of the bony mandible, but a deficiency of tongue development, specifically its intrinsic musculature. Thus, mandibular micrognathia involves not only a dysmorphology of the first branchial arch, but also the mesenchymal cell migration from the occipital somites. Taken together, the picture is one that suggests an underlying cause that may have its inception at a much earlier developmental stage, when ectomesenchymal migration from the region of the neural tube occurs. In any event, we can report confidently that spontaneous micrognathia in prenatal mice is not a simple dimensional reduction of the lower jaw, but a more complex morphological phenomenon.