Micrognathia

Micrognathia may result from limitation of mandibular growth caused by constraints acting during late gestation. Compression of the chin against the chest can lead to pressure indentation or necrosis on the superior aspect of the anterior thorax (Gorlin et al. 2001a). As for other extrinsically determined congenital deformations, catch-up growth is usually observed postnatally once the constraining fetal environment has ceased, resulting in restoration of normal mandibular size. A small mandible can also result from an inherent bone growth defect in the absence of intrauterine environmental problems. Mi-crognathia occurs in a variety of dysmorphic syndromes, either genetic or drug-induced, and in association with other anomalies that constitute ill-defined malformation phenotypes. The mandible may be entirely hypoplastic or hypoplasia may be predominantly unilateral.

Because of lack of uniform agreement concerning the definition of Robin sequence (see subsequent discussion), the list of disorders associated with either

Submucous Cleft Palate Definition

Fig. 1.43 a-c. Robin sequence. a, b In a 15-year-old boy note a severe micrognathia and b cleft palate. (From Lee et al. 2003) c In this 5-month-old baby boy the lateral radiogram shows retromicrognathia micrognathia or Robin sequence has varied among investigators (Shprintzen 1992; Cohen 1999).

The Robin sequence is a combination of severe mi-crognathia, glossoptosis, and cleft palate (Fig. 1.43a-c). Looser definitions include cases with only one symptom of the triad or with the submucous type of cleft palate (Rintala et al. 1984). As a result, estimates of the incidence of the sequence, like the list of disorders in which it occurs, have varied considerably (Bush and Williams 1983; Poswillo 1968). The pathogenesis of Robin sequence is complex and probably not uniform (Cohen 1979). The 'deforma-tional' hypothesis explains the findings in the light of intrauterine mandibular constraint due to oligohy-dramnios or amniotic bands, resulting in failure of the tongue to descend so that it impacts on the forming palate, with consequent cleft palate (Poswillo 1968; Latham 1966; Marques et al. 1998). Other cases of Robin sequence can be explained by an intrinsic bone growth defect producing either micrognathia and cleft palate individually, or micrognathia and secondary cleft palate owing to impaction of the un-descended tongue. These cases are often associated with chromosomal imbalances, in which universal growth deficiency is usually present. Moreover, this mechanism can be at work in connective tissue disorders, such as Stickler syndrome (Schrander-Stumpel et al. 1991). Finally, mandibular hypoplasia may result from lack of proper fetal movements caused by a neuromuscular disorder (Sher 1992). The face of newborns with Robin sequence is striking, with a small, symmetrically receding mandible. The palatal cleft is usually U-shaped, but it can also be V-shaped (Gorlin et al. 2001b). While the latter occurs as a primary defect not associated with mandibular involvement, the wider U-shaped variety of palatal cleft is thought to result from impaction of the displaced tongue on the developing palate. Respiratory difficulties are commonly present in newborns with Robin sequence and consist in labored breathing, periodic cyanotic attacks, recession of sternum and ribs, stridor and, occasionally, suffocation. They are usually related to downward and backward fall of the tongue (glossoptosis), which acts as a ball valve permitting air flow during expiration but not during inspiration. Retrodisplacement of the tongue and pressure on the posterior wall of the pharynx can stimu-

late vomiting, causing weight loss and cachexia if it remains unrecognized. Both respiratory and feeding difficulties can contribute to the somatic growth deficiency that occasionally accompanies Robin sequence. Approximately 25% of affected infants die within the first few postnatal months, and about 25% of them have associated heart defects (Williams et al. 1981; Sheffield et al. 1987). Robin sequence can occur in isolation (40%), as one manifestation of distinct syndromes (25%), or associated with other anomalies (35%) (Hanson and Smith 1975). The most common genetic disorder associated with Robin sequence is Stickler syndrome, and the second most common is velo-cardio-facial syndrome. Additional syndromes and/or associations in which Robin sequence occurs include campomelic dysplasia, Catel-Manzke syndrome, cerebro-costo-mandibular syndrome, myotonic dystrophy, diastrophic dysplasia, Larsen syndrome, mandibulofacial dysostosis, Nager acrofacial dysostosis, oto-palato-digital syndrome II, popliteal pterygium syndrome, postaxial acrofacial dysostosis, spondyloepiphyseal dysplasia congenita, CHARGE association, Möbius sequence, chromosomal deletion syndromes (4q-, 6q-, 11q-), amniotic band sequence, teratogenically induced fetopathies, Weissenbacher-Zweymuller syndrome, and several others (Hanson and Smith 1975; Cohen 1997; Carey et al. 1982). Velo-cardio-facial syndrome (Shprint-zen syndrome, OMIM 192430) is characterized by typical facies (long face, narrow receding forehead, prominent tubular nose, hypoplastic alae nasi, narrow, upward slanting palpebral fissures, epicanthal folds, small ears), retruding mandible, cleft palate, cardiovascular anomalies, and learning disabilities (Shprintzen et al. 1978). Inheritance is autosomal dominant with variable expressivity (Shprintzen et al. 1981; Williams et al. 1985). Hypernasal speech is often the presenting symptom when children are first brought for medical attention (Lipson et al. 1991). Platybasia occurs in 85% of cases, whereas microcephaly is found in about 40% and the Robin sequence, in about 15%. Ophthalmologic problems (small optic disc, tortuous retinal vessels, bilateral cataracts) occur in approximately 70% of cases (Fitch 1983). Cardiac anomalies are found in about 80% of cases, and include ventricular septal defect (65%), right-sided aortic arch (35%), tetralogy of Fallot (20%), and aberrant subclavian artery (20%) (Young et al. 1980; Jedele et al. 1992). Additional manifestations include slender hands and digits (63%), umbilical hernia (23%), hypospadias in males (10%), neonatal hypocalcemia, renal anomalies, immune defect, anal anomalies, and conductive hearing loss (Goldberg et al. 1993; Ryan et al. 1997; Worthington et al. 1997). Learning disabilities are present in virtually all patients, consisting primarily in difficulty in dealing with abstract concepts, reading comprehension, and mathematics. Overall, mild intellectual impairment is present in about 40%, whereas an overt psychiatric disorder (bipolar spectrum disorders, attention deficit) is found in approximately 10% (Carlson et al. 1997). I.Q. generally ranges from 70 to 90 (Golding-Kushner et al. 1985; Swillen et al. 1997). There is a wide clinical overlap between velo-cardio-facial syndrome and DiGeorge syndrome, both these conditions being caused by microdeletions of chromosome 22q11.2 (Scambler et al. 1992; Kelly et al. 1993). It is likely that several genes located at 22q11.2, notably the human homologs of the TBX1 (Jerome and Papioannou 2001) and VEGF genes in the mouse (Stalmans et al. 2003), contribute to the phenotype (Sirotkin et al. 1996). This region may also be critical for the development of schizophrenia (Karayiorgou et al. 1995). Möbius syndrome (OMIM 157900,601471, 604185) consists in a congenital paresis or paralysis of the VIth (abducens) and VIIth (facial) cranial nerves, frequently accompanied by dysfunction of other cranial nerves (Möbius 1888). Orofacial features include expressionless face,impaired eye movements, ptosis, strabismus, broad nasal bridge, small mouth, unilateral tongue hypoplasia, and mild to moderate micrognathia. Additional abnormalities include limb malformations (clubfoot, various degree of reduction deformities, polydactyly, syndacty-ly, joint contractures, congenital hip dislocation), defects of the musculoskeletal system (hypo-/aplasia of the pectoralis major muscle, scoliosis), and mild mental retardation (Henderson 1939). Almost all reported cases have been sporadic, although familial recurrence has been observed (van der Wiel 1957; Krueger and Friedrich 1963; MacDermot et al. 1991). Autosomal dominant, autosomal recessive, and X-linked recessive modes of inheritance have been suggested. A number of additional oromandibular-limb hypogenesis syndromes show overlapping features with Möbius syndrome, including hypoglossia-hypo-dactyly syndrome, Hanhart syndrome, glossopala-tine ankylosis syndrome, limb deficiency-splenogo-nadal fusion syndrome, and Charlie M. syndrome (Gorlin et al. 2001c).

Mandibular hypoplasia is a striking feature of several other syndromes. Severe micrognathia, sometimes requiring tracheostomia, is a constant feature of cerebro-costo-mandibular syndrome (rib-gap syndrome, OMIM 117650), a rare disorder of growth deficiency, variable rib-gap defects, bell-shaped thorax,

Cerebro Costo Mandibular Syndrome

Fig. 1.44 a, b. Goldenhar syndrome in a 22-week male fetus (same subject as in Fig. 9.36a, b). a Lateral projection. Note severe micrognathia. b Frontal projection. Mandibular hypopla-sia is unilateral, involving the right mandibular ramus and condyle. Striking asymmetry of the facial bones is observed, with hypoplasia/aplasia involving the right maxilla, orbital process, and petrous pyramid. Additional findings include right radial aplasia and multiple segmentation defects involving the vertebrae and ribs

Fig. 1.44 a, b. Goldenhar syndrome in a 22-week male fetus (same subject as in Fig. 9.36a, b). a Lateral projection. Note severe micrognathia. b Frontal projection. Mandibular hypopla-sia is unilateral, involving the right mandibular ramus and condyle. Striking asymmetry of the facial bones is observed, with hypoplasia/aplasia involving the right maxilla, orbital process, and petrous pyramid. Additional findings include right radial aplasia and multiple segmentation defects involving the vertebrae and ribs cleft palate, and respiratory distress (Smith et al. 1966). In Treacher-Collins syndrome (mandibulofacial dysostosis, OMIM 154500) the mandibular condyle and coronoid process are symmetrically hy-poplastic or aplastic, the ramus is deficient, and the mandibular angle is obtuse. Antegonial notching may be striking (Arvystas and Shprintzen 1991; Herring et al. 1979). In Goldenhar syndrome (oculo-auriculo-vertebral spectrum, OMIM 164210) unilateral hypoplasia or aplasia of the mandibular ramus and condyle may contribute to facial asymmetry, a typical feature of the syndrome (Figueroa and Pruzansky 1982) (Fig. 1.44a,b). Progressive osteolysis of the mandibular body and ramus, resulting in microg-nathia with antegonial notching, is a prominent finding in mandibuloacral dysplasia (OMIM 248370), an autosomal recessive disorder (Cavallazzi et al. 1960; Hall and Mier 1985).

Otocephaly (agnathia, OMIM 202650) is a lethal disorder characterized by either agenesis or severe hypogenesis of the mandible, microstomia or asto-mia, microglossia of extreme degree, ventrally placed ears with or without fusion, and persistence of the buccopharyngeal membrane (Hinojosa et al. 1996;

Ibba et al. 2000). Dysgnathia is thought to result from a defect in the development of the first branchial arch. The relationship between isolated agnathia and dysgnathia complex (agnathia-holoprosencephaly, OMIM 202650), in which agnathia is associated with alobar holoprosencephaly, agenesis of the corpus cal-losum, cyclopia, and frontal proboscis (Ozden et al. 2000), is not clear. A common genetic basis for non-syndromic dysgnathia and agnathia-holoprosen-cephaly is likely (Erlich et al. 2000).

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