Pathogenesis of Cleft Palate in Robin Sequence: Observations From Prenatal Magnetic Resonance Imaging.

PURPOSE: The etiology of the palatal cleft in Robin sequence (RS) is unknown. The purpose of this study was to assess the position of the fetal tongue at prenatal magnetic resonance imaging (MRI) and to suggest a potential relation between tongue position and development of the cleft palate seen in most patients with RS. MATERIALS AND METHODS: This is a retrospective case-and-control study including fetuses with prenatal MRIs performed in the authors' center from 2002 to 2017. Inclusion criteria were 1) prenatal MRI of adequate quality, 2) liveborn infant, and 3) postnatal diagnosis of RS (Robin group) or cleft lip and palate (CLP group). Patients with postnatal RS without a palatal cleft were excluded. A control group with normal facial morphology was matched by gestational age. The outcome variable was tongue position at fetal MRI, described as within the cleft, along the floor of the mouth (normal), other, or indeterminate. RESULTS: One hundred twenty-two patients with mean gestational age at MRI of 25.8 ± 4.9 weeks were included (Robin, n = 21 [17%]; CLP, n = 47 [39%]; control, n = 54 [44%]). The tongue was visualized within the palatal cleft in 76.2% of the Robin group and 4.3% of the CLP group. The tongue was found along the floor of the mouth (normal) in the remainder of the Robin and CLP groups and in 100% of the control group. CONCLUSION: These findings suggest a relation between in utero tongue position and the development of cleft palate in RS.

[Cleft lip and palate]. / Lippen-Kiefer-Gaumen-Spalten.

BACKGROUND: Cleft lip and palate (CLP) represents a group of malformations of unknown etiology but similar phenotypes. This implies consequences for the diagnostics, therapy, prevention, prognosis and risk estimation. OBJECTIVE: Definition of CLP subtypes and the embryonic development, clarification of correlations and differences between entities using epidemiological data, overview of the present state of genetic analyses, correlation to syndromes, sequences and associations and resulting consequences for clinical practice. MATERIAL AND METHODS: Update on embryological development of the face, summary of epidemiological and genetic studies and considerations on pedopathological and forensic aspects. RESULTS: Syndromic and non-syndromic CLP exhibit different and highly variable etiologies, therapeutic needs and prognosis. A thorough understanding is mandatory to distinguish between the different subgroups. In addition to specific aspects of CLP for the pediatric (forensic) pathologist this article provides an overall view of the topic which aims to help understand these malformations.

Dislocated Tongue Muscle Attachment and Cleft Palate Formation.

In Pierre Robin sequence, a retracted tongue due to micrognathia is thought to physically obstruct palatal shelf elevation and thereby cause cleft palate. However, micrognathia is not always associated with palatal clefting. Here, by using the Bmp7-null mouse model presenting with cleft palate and severe micrognathia, we provide the first causative mechanism linking the two. In wild-type embryos, the genioglossus muscle, which mediates tongue protrusion, originates from the rostral process of Meckel's cartilage and later from the mandibular symphysis, with 2 tendons positive for Scleraxis messenger RNA. In E13.5 Bmp7-null embryos, a rostral process failed to form, and a mandibular symphysis was absent at E17.5. Consequently, the genioglossus muscle fibers were diverted toward the lingual surface of Meckel's cartilage and mandibles, where they attached in an aponeurosis that ectopically expressed Scleraxis. The deflection of genioglossus fibers from the anterior-posterior toward the medial-lateral axis alters their direction of contraction and necessarily compromises tongue protrusion. Since this muscle abnormality precedes palatal shelf elevation, it is likely to contribute to clefting. In contrast, embryos with a cranial mesenchyme-specific deletion of Bmp7 (Bmp7:Wnt1-Cre) exhibited some degree of micrognathia but no cleft palate. In these embryos, a rostral process was present, indicating that mesenchyme-derived Bmp7 is dispensable for its formation. Moreover, the genioglossus appeared normal in Bmp7:Wnt1-Cre embryos, further supporting a role of aberrant tongue muscle attachment in palatal clefting. We thus propose that in Pierre Robin sequence, palatal shelf elevation is not impaired simply by physical obstruction by the tongue but by a specific developmental defect that leads to functional changes in tongue movements.

Disruption of the ERK/MAPK pathway in neural crest cells as a potential cause of Pierre Robin sequence.

Disrupted ERK1/2 signaling is associated with several developmental syndromes in humans. To understand the function of ERK2 (MAPK1) in the postmigratory neural crest populating the craniofacial region, we studied two mouse models: Wnt1-Cre;Erk2(fl/fl) and Osr2-Cre;Erk2(fl/fl). Wnt1-Cre;Erk2(fl/fl) mice exhibited cleft palate, malformed tongue, micrognathia and mandibular asymmetry. Cleft palate in these mice was associated with delay/failure of palatal shelf elevation caused by tongue malposition and micrognathia. Osr2-Cre;Erk2(fl/fl) mice, in which the Erk2 deletion is restricted to the palatal mesenchyme, did not display cleft palate, suggesting that palatal clefting in Wnt1-Cre;Erk2(fl/fl) mice is a secondary defect. Tongues in Wnt1-Cre;Erk2(fl/fl) mice exhibited microglossia, malposition, disruption of the muscle patterning and compromised tendon development. The tongue phenotype was extensively rescued after culture in isolation, indicating that it might also be a secondary defect. The primary malformations in Wnt1-Cre;Erk2(fl/fl) mice, namely micrognathia and mandibular asymmetry, are linked to an early osteogenic differentiation defect. Collectively, our study demonstrates that mutation of Erk2 in neural crest derivatives phenocopies the human Pierre Robin sequence and highlights the interconnection of palate, tongue and mandible development. Because the ERK pathway serves as a crucial point of convergence for multiple signaling pathways, our study will facilitate a better understanding of the molecular regulatory mechanisms of craniofacial development.

Experimental aspects of the pathogenesis of Robin sequence.

OBJECTIVE: The Pierre Robin Sequence (PRS) is a good example of disturbed embryonic development of the secondary palate involving insufficient mandibular growth, failed forward tongue movement, and, in the case of a cleft, impeded fusion of the secondary palate. Discussion continues regarding which of the involved pathogenetic factors is the primary cause of the induced cascade of signs: insufficient mandibular growth or failed descent of the tongue. DESIGN: Forty-five randomly selected, 18-day-old formalin-fixed A/WySn mouse fetuses were investigated. The strain is known to have a basic genetic defect and as much as 44% clefts in the offspring. Twenty-four fetuses in the group had a cleft palate. Mandible position was measured relative to the head and to the presence or absence of a cleft. Cleft width and tongue position were also determined. Thirty-eight NMRI mouse fetuses of the same age served as controls. RESULTS: All A/WySn fetuses showed marked mandibular retrognathia, which was more severe in the cleft group (p < .05), but there was no correlation between the degree of retrognathia and cleft width. The median cleft width was 3.4 mm (1.6 through 6.3 mm). The tongue was in the cleft in all 12 fetuses with wide clefts (>3.4 mm wide), and free in the oral cavity in the other 12. Tongue position did not influence the degree of retrognathia (p < .05). Moreover, the tongue was free in all fetuses with severe retrognathia. CONCLUSION: The results support the primary role of retroposition of the mandible in the development of cardinal symptoms of Pierre Robin Sequence.

Pierre Robin sequence in Denmark: a retrospective population-based epidemiological study.

OBJECTIVE: To give an epidemiological description of the clinical entity given the name Pierre Robin sequence, defined by retro- and micrognathia, cleft palate, and respiratory distress and describe other malformations and possible intrauterine impairment. METHODS: Using the inclusion criteria of micrognathia, cleft palate, and neonatal respiratory distress, a retrospective population-based study of all Danish live births during 1990 through 1999 were carried out. We found 50 children, 25 boys and 25 girls, fulfilling the inclusion criteria, giving an incidence of 1 in 14,000 live births. RESULTS: Two-thirds (n = 33) of the children had the classical U-shaped cleft palate. More than one-third (n = 19) had one or several other malformations, and in five patients the triad of Pierre Robin was a minor feature of a complex syndrome. The most common noncomplex syndrome was the Stickler syndrome found in 6 of the 50 patients. More than one-fourth (n = 17) had some kind of intrauterine impairment, with no specific obstetric diagnosis predominant. Consistent with this, the average birth weight was well below normal. CONCLUSIONS: Several authors have stated that the triad of Pierre Robin is not a nosological entity, in that it has diverse etiology and diverse pathogenesis. We conclude that the triad of Pierre Robin still can be regarded as a clinical entity, readily defined at birth, experiencing the same neonatal problems in varying degrees and hence the possibility of designing treatment protocols for later scientific evaluation.

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.

The infant with Pierre Robin sequence: review and implications for nursing practice.

Pierre Robin sequence (PRS) is associated with long-term respiratory, nutritional, and developmental difficulties. Hypoxic complications, including cerebral impairment, cor pulmonale, and failure to thrive may be prevented or minimized with early detection and comprehensive care. This article reviews the embryological development of PRS and outlines the medical and nursing implications for treatment. Partnership with parents and a coordinated community care team are essential for successful management of infants and children with PRS.

[The Pierre-Robin syndrome. Classification and new therapeutic approach]. / Le syndrome de Pierre Robin. Classification et nouvelle approche thérapeutique.

Rhombencephalic failure of the suction-swallowing, excess of central and obstructive ventilatory arrests with hypoxia and hypercapnia, vagal hypertonia and esophagogastric motor abnormalities are the new clinical signs observed in children presenting with the Pierre Robin's syndrome. A therapeutic management adapted to each of the types I, II, III of the syndrome were defined and a good nursery-nursing allowed a reduction in the mortality-rate from 27 to 5%. Still considered by some as a malformative and glossoptosing disorder whose etiology is only bucco-pharyngeal in origin, this syndrome, common to numerous embryopathies, is a precocious embryonal abnormality of the brain stem neurogenesis, expressed by the dramatic failure of the physiological oro-ventilation system. This syndrome appears to be a peculiar form of dysautonomia of the brain stem development with an uncertain future, often transitory, isolated or associated but in the heart of pediatric internal medicine and its multi-disciplinarity.

[Management of Pierre-Robin syndrome]. / La prise en charge du syndrome de Pierre Robin.

Pierre Robin syndrome continuously raises problems of intensive care that are difficult to surmount. A peak has to be overcome, the date of which varies as a function of the severity of the affection, following which the infant remains a neonate at high risk. Intensive care of these infants during the neonatal period involves avoidance of the sequence of disturbances provoked by the disorders of ventilation and deglutition. Surveillance of biological variables, feeding and the fight against glossoptosis are mainly the concern of medical procedures: from orthostatic nipples to continuous gastric feeding, from procubitus to intubation with assisted ventilation, and including pharyngeal catheters and physiotherapy. Surgery is required only exceptionally at this stage, mainly in the form of hyomandibulopexy.

[A new concept of Pierre Robin syndrome and disease: dysneurulation of the rhombencephalon]. / Nouvelle conception de la maladie et du syndrome de Pierre Robin: dysneurulation du rhombencéphale.

Pierre Robin's syndrome, a disorder apparently constituted by peripheral signs, is in fact the result of early major disturbances of ontogenesis of motor and regulatory organization of the fetal rhombencephalon. This is confirmed by the presenting signs in neonates with Pierre Robin's syndrome: --electrophysiological deglutition and sucking disorders as demonstrated on electromyography; --disorders in tone of tongue, pharyngeal and laryngeal muscles; --cardiac and respiratory regulatory disorders as shown by central and obstructive apneas with diminished oxygen pressure and bradycardia of central origin during sleep; and gastro-esophageal reflux. Associated signs indicating that Pierre Robin's syndrome is a separate disease entity are: --evidence of a rhomboencephalic neurocristopathy (malformation of 3rd and 4th aortic arch arteries, thymic and parathyroid hypoplasia) associated with a central rhomboencephalic lesion and resulting in dysneurulation; --mesencephalic lesion as seen in Stickler's syndrome and prosencephalic lesion as in Binder's syndrome, indicating more diffuse cephalic dysneurulation. The common origin of Di George's and Pierre Robin's syndromes is emphasized, the neonatal microretrognathism of the latter syndrome being a bulbar sign. Pierre Robin's syndrome has a poor prognosis, as there is a fatal outcome in one out of four neonates affected, and it appears to be an affection that is the clinical expression of an early major anomaly of cephalic neurulation.

U-shaped palatal defect in the Robin anomalad: developmental and clinical relevance.

The palatal defect in patients with the Robin anomalad was found to be U shaped. This finding is compatible with the hypothesis that the underlying dysmorphic event is usually early mandibular hypoplasia with secondary extrinsic obstruction of palatal closure by a posteriorly displaced tongue. The more common V-shaped defects of palate closure arise by a different mechanism. Unfortunately, available recurrence risk data for cleft palate do not allow for this distinction. Furthermore, physicians should be alert for instances in which the Robin anomalad is but one feature of a broader pattern of malformation. In the current study, 25% of the 28 patients ascertained as having the Robin anomalad had a recognizable syndrome for which specific, but varying, genetic counsel was indicated.