The importance of a differential diagnosis between true hemifacial microsomia and pseudo-hemifacial microsomia in the post-surgical long-term prognosis

Journal of Cranio-Maxillo-Facial Surgery 39 (2011) 10e16

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The importance of a differential diagnosis between true hemifacial microsomia and pseudo-hemifacial microsomia in the post-surgical long-term prognosis Maria C. Meazzini a, *, Roberto Brusati a, Patrik Diner b, Ennio Giannì c, Faustina Lalatta d, Alice S. Magri e, Arnaud Picard b, Enrico Sesenna e a

Department of Maxillofacial Surgery, Cleft lip and palate Center, University of Milano, Italy Department of Plastic Surgery, Trousseau Hospital, Paris, France Department of Orthodontics, Dental School, University of Milano, Italy d Medical Genetic Unit, Fondazione IRCCS Foundation, Cà Granda Hospital Maggiore Policlinico, Italy e Department of ENTeDentaleOphtalmologic and Cervico-Facial Sciences, Maxillofacial Surgery Unit, University of Parma, Italy b c

a r t i c l e i n f o

a b s t r a c t

Article history: Paper received 13 July 2009 Accepted 9 March 2010

Long-term results after surgical treatment of the mandibular asymmetry in growing children with hemifacial microsomia (HFM), whether with osteotomies or distraction osteogenesis, have mostly shown a tendency towards the recurrence of the asymmetry. In contrast, in the literature we find sporadic case reports where the long-term post-surgical follow-up of patients diagnosed as HFM, are surprisingly stable. All these reports refer to patients who have substantially no soft tissue involvement, but only severe mandibular ramus and condyle deformities. The phenotypes of these cases are unexpectedly similar. The authors suggest, that it is possible that all of these cases might be isolated hemimandibular hypoplasias, misdiagnosed as HFM, which present a normal functional matrix and, therefore, tend to grow towards the original symmetry. Differential diagnosis between true HFM and this HFM-like isolated hemimandibular hypoplasia (pseudo-HFM) is of great importance given the very different prognosis and it is possible through the collaboration between not only surgeons and orthodontists, but also of geneticists and dysmorphologists. Ó 2010 European Association for Cranio-Maxillo-Facial Surgery.

Keywords: Hemifacial microsomia Condylar fractures Functional appliances Condylar growth Early mandibular surgery Distraction osteogenesis Mandibular asymmetry

1. Introduction Aetiologic diagnosis is possibly the most difficult, but also the most important step in the treatment of facial deformities. Hemifacial microsomia (HFM) is a relatively common craniofacial anomaly with a birth prevalence of at least 1/5600, characterized by the asymmetric underdevelopment of structures originating from the Ist & IInd branchial arches. Deformities may involve the ear and the mandible, as well as the maxilla, the zygomatic arch, the temporal bone, the V & VII cranial nerves, the cervical spine, and facial muscles. In patients affected by HFM the face may be strikingly asymmetrical because of the hypoplastic changes in the mandible and the dysplastic changes and displacement of the ear. The degree of ear involvement is markedly variable and cleft lip or cleft palate may be associated (Jones, 2005).

* Corresponding author. Via Appiani n.7 20121 Milano, Italy. Tel./fax: þ39 02 29010303. E-mail address: [email protected] (M.C. Meazzini).

A condition analogous to HFM has been induced in the mouse by causing a local haemorrhage from the embryonic stapedial artery during the 30the40th day of foetal development, a critical period of neural crest cell migration (Poswillo, 1974). Although the haemorrhage model could account for much of the observed variability, embryological research has increased significantly our knowledge on HFM. It is known that HFM is aetiologically heterogeneous. Many chromosome abnormalities have been recorded, but also environmental causes which include thalidomide, primidione and retinoic acid administered during the organogenesis. The phenotype has also been noted in infants born to diabetic mothers. A recent model, based on a mutation of a locus on chromosome 10, appears to support the hypothesis that HFM anomalies have partly a genetic causation (Cousley et al., 2002; Dabir and Morrison, 2006). So far, evidence for genetic involvement, include family history of HFM phenotype and rare familial cases that exhibit autosomal dominant inheritance (Robinow et al., 1986; Brady et al., 2002). From the embryological point of view, HFM is one of four conditions defined as otofacial malformations, which are Neurocristopathies, which share a major involvement of neural crest cells,

1010-5182/$ e see front matter Ó 2010 European Association for Cranio-Maxillo-Facial Surgery. doi:10.1016/j.jcms.2010.03.003

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Table 1 Differential diagnosis chart to help distinguish between true hemifacial microsomia and pseudo-HFM (misdiagnosed as HFM). HFM

Pseudo-HFM

Clinical history

Mostly diagnosed at birth

Clinical examination

Soft tissue defects (may be very mild): Ear defects, pre-auricular tags Possible facial nerve involvement Masseter muscle hypoplasia Deviation of the chin on the affected side, associated with flatness on the affected cheek Mild deviation to the affected side during opening Hypoplasia of the ramus and condyle and coronoid processes up to absence of the condyle and temporal fossa

Not diagnosed at birth Seldom history of trauma No soft tissue defects: Normal ears, no pre-auricular tags No nerve deficit Well-developed masseter Deviation of the chin on the affected side, associated with fullness on the affected cheek Significant deviation to the affected side during opening Hypoplasia of the ramus and condyle and coronoid processes which are typically collapsed one on the other. There is a typically V-shaped sigmoid notch. The temporal fossa is always present

Panoramic X-ray (or CT)

Fig. 1. a: Type II Pruzansky HFM ramal deformity. b: Misdiagnosed ramal deformity. c: Tracing of a Type II Pruzansky HFM ramal deformity. d: Tracing of a misdiagnosed Type II Pruzansky HFM ramal deformity. Note the typical shape, visible in all cases, where the condyle is short and collapsed against the coronoid process. The sigmoid notch is very deep. e: Mandibular facial contour in a Type II Pruzansky HFM ramal deformity. Note the transverse hypoplasia of the gonial area as well as vertical on the affected side. f: Mandibular facial contour in misdiagnosed Type II Pruzansky HFM ramal deformity. Note the fullness of the cheek on the affected side.

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together with DiGeorge Syndrome, Retinoic Acid Syndrome and Treacher Collins Syndrome (Charrier et al., 2001; Mooney and Siegel, 2002). Neural crest cells are a migratory cell population that give rise to the majority of the cartilage, bone, connective tissue and sensory ganglia in the head and play an integral part in facial morphogenesis. Just before the neural fold fuses to form the neural tube, neuroectodermal cells adjacent to the neural plate migrate into the facial region, where they form the skeletal and connective tissue of the face: bone cartilage, fibrous connective tissue, and all dental tissues except enamel (Engleka et al., 2008). In view of the aim of this paper, it is very important to remind that the neural crest cells which migrate into the first branchial arch, carry the pattern of information needed for proper morphogenesis of mesodermal derivates such as cranial muscles (Ericsson et al, 2004; Olsson et al, 2005). Extirpation of the mandibular neural crest stream leads to severe alterations of mandibular muscles patterning. While Meckel’s, palatoquadrate, suprarostral and infrarostral cartilages can be severely malformed or missing, all muscles of the levator mandibulae group will also be similarly affected (Olsson et al., 2001). Therefore, although HFM may be very variable in terms of phenotype, mandibular deformity is always proportionate to the associated muscular deformity.

1.1. Treatment of HFM Under the diagnosis of HFM, there is a great deal of variability (Rune et al., 1981; Figueroa and Pruzansky, 1982), thus, treatment varies. Orthodontic functional appliance therapy during growth has been suggested in HFM cases with minor mandibular and soft tissue involvement obtaining a good dento-alveolar correction and some mild improvement in the skeletal asymmetry (Vargervik et al., 1986), but there is no consensus about the actual skeletal effect of such treatment (AAO Council on Scientific Affairs, 2005). Functional treatment has also been recommended in more severe cases prior to and after surgery to improve muscle function and to stimulate growth of the soft and hard tissues (Harvold, 1975), although Vargervik demonstrated that functional appliances improved the short-term results after costo-chondral grafting, but, nevertheless, there was a return of the asymmetry during subsequent growth (Vargervik et al., 1986). Likewise, it was recently shown that functional therapy associated to distraction osteogenesis (DO) only slows down the return to the original asymmetry of HFM (Meazzini et al., 2008). In contrast to this scientific evidence, in the literature we find a large number of case reports describing very successful pure orthopaedic treatment in patients diagnosed as moderate to severe forms of HFM (Melsen et al., 1986;

Fig. 2. Male patient mislabelled as HFM, treated with unilateral mandibular osteotomy. a: Frontal facial photograph pre-surgery. b: Frontal facial photograph immediately postsurgery. c: Frontal facial photograph 29 years post-surgery. d: Tomographic X-ray of the affected side pre-surgery. e: Panoramic X-ray immediately post-surgery. f: Panoramic X-ray 29 years post-surgery.

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Fig. 3. Male patient mislabelled as HFM, treated with unilateral mandibular distraction osteogenesis (DO). a: Frontal facial photograph pre-DO. b: Frontal facial photograph immediately post-DO. c: Frontal facial photograph 8 years post-DO. d: Panoramic X-ray pre-DO. e: Panoramic X-ray immediately post-DO. f: Panoramic X-ray 8 years post-DO.

Fig. 4. Male patient mislabelled as HFM, treated with unilateral mandibular distraction osteogenesis (DO). a: Frontal facial photograph pre-DO. b: Frontal facial photograph immediately post-DO. c: Frontal facial photograph 6 years post-DO. d: Panoramic X-ray pre-DO. e: Panoramic X-ray immediately post-DO. f: Panoramic X-ray 6 years post-DO.

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Fig. 5. Female patient mislabelled as HFM, treated with unilateral mandibular distraction osteogenesis (DO). a: Frontal facial photograph pre-DO. b: Frontal facial photograph immediately post-DO. c: Frontal facial photograph 10 years post-DO. d: Panoramic X-ray pre-DO. e: Panoramic X-ray immediately post-DO. f: Panoramic X-ray 10 years post-DO.

Kaplan, 1989; Silvestri et al., 1996; Sidiropoulou et al., 2003). The patients in these case reports respond to functional treatment, without any surgery, and all have a surprisingly similar clinical and especially radiographical phenotype. Meazzini et al., collected and described in detail a number of these patients, all previously misdiagnosed as HFM, treated with functional appliances only, which have often been used as evidence that it is possible to change with functional treatment the pattern of growth of HFM patients (Meazzini et al., 2008). In the surgical literature we find very similar cases, utilized to justify early intervention on HFM (Kaban and Troulis, 2004), where post-surgical growth is surprisingly symmetrical when compared to the available literature on true HFM (Hollier et al.,1999; Mommaerts and Nagy, 2002, Huisinga-Fisher et al., 2003; Meazzini et al., 2005), where a consistent recurrence of the asymmetry during subsequent growth is demonstrated.

In Figs. 2e5 we describe four cases of pseudo-HFM, previously misdiagnosed as HFM, treated surgically with an excellent longterm follow-up, while in Fig. 6 we show an example of a case of true HFM treated with DO, with the expected return of the asymmetry in the long-term follow-up (Meazzini et al., 2005). Other patients with almost identical phenotype misdiagnosed as HFM can be found in the literature (Melsen et al., 1986; Kaplan, 1989; Silvestri et al., 1996; Sidiropoulou et al., 2003), while other cases already identified as non-HFM can be also found (Figueroa et al, 1984; Harkness and Thorburn, 1989; Leonardi and Barbato, 2007; Meazzini et al., 2008). In order to give a more complete scenery of the response of this type of mandibular deformity, we have included one case (Fig. 7), where functional stimulation alone was able to re-establish symmetry in the long-term. 3. Discussion

2. Objective The aim of this paper is to describe this peculiar type of mandibular asymmetry, frequently misdiagnosed as HFM, where both orthopaedic and surgical treatment have an excellent longterm follow-up, in order not to give false prognosis to true HFM patients. The cases shown share indeed two main characteristics which distinguish them from the more traditional HFM patients (Table 1, Fig. 1): (1) there is no soft tissue involvement, the external ear is present and well formed, the musculature seems to be well developed. Although the chin point deviates to the affected side, the typical flatness of the gonial area seen in HFM patients is not present (Fig. 1b). On the contrary, there is more fullness on the affected side than on the non-affected side (Fig. 1a). (2) The shape of the hypoplastic ramus is very peculiar and extremely similar in all cases. The condyle is very short and collapsed against the coronoid process and the sigmoid notch is extremely deep (Fig. 1c).

Unilateral surgical lengthening of the ramus in growing individuals, through DO, is very successful in the short term (McCarthy et al., 1992), but has been disappointing in the long term. There is a recurrence of the asymmetry with time, together with a consistent tendency towards a return to the original phenotype and facial proportion (Hollier et al., 1999; Mommaerts and Nagy, 2002; Huisinga-Fisher et al., 2003; Meazzini et al., 2005). Such reappearance of the asymmetry is linked to the involvement, not only of the bony segments, but especially of the neuromuscular pattern, which slowly leads back the bony proportions to the original architecture. The first four surgically treated cases shown in this paper on the contrary, have maintained the symmetry in the long term. Getting back to the results of functional treatment, Harkness and Thorburn questioned Kaplan’s orthopaedic results suggesting that the shape of the mandibular hypoplastic side could be related

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Fig. 6. Male patient with left Type II HFM, treated with unilateral mandibular distraction osteogenesis (DO). a: Frontal facial photograph pre-DO. b: Frontal facial photograph immediately post-DO. c: Frontal facial photograph 13 years post-DO. d: Panoramic X-ray pre-DO. e: Panoramic X-ray post-DO after removal of the distraction device. f: Panoramic Xray 13 years post-DO. Note the recurrence of the asymmetry in this case.

Fig. 7. Male patient mislabelled as HFM, treated with a “Morpho-correcting” Functional appliance (Giannì, 1972). a: Frontal facial photograph pre-treatment. b: Frontal facial photograph at 12 years follow-up. c: Panoramic X-ray pre-treatment. d: Panoramic X-ray at 12 years follow-up.

to a mandibular fracture instead of HFM (Harkness and Thorburn, 1989). Several long-term studies on mandibular condylar fractures show the ability to self-correct (Lund, 1974; Larsen and Nielsen,

1976; Proffit et al., 1980) or a successful correction with orthopaedics (Girthofer and Göz, 2002). The authors of this paper, and in particular the embryologist in the team, suggest that, although with our current knowledge a correct diagnosis of the cases

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described as pseudo-HFM might not be possible, their phenotype suggests that these are not true HFM cases. These patients present a bony defect, but a normal neuromuscular pattern, which is able to remodel the damaged bony structure into a new condyleecoronoid complex, with the help of functional stimulation or to maintain symmetry after surgical correction. The similarity of the phenotype in all of these cases is certainly of great interest. On this basis we believe that it would be crucial to correctly recognize those cases which have been mislabelled as HFM. Given the great heterogeneity of HFM phenotype and the little genetic knowledge on the syndrome, the differences between these two types of hemimandibular hypoplasia are not always obvious. We have attempted to summarize the most important clinical and radiological differences in Table 1 and Fig. 1, which might be of help in the differential diagnosis. True HFM patients, given the very early timing of the offset of the pathology, are more likely to have a bony as well as a neuromuscular deficit, which orthopaedics might help improve, but certainly not correct and which tend to recur after surgical correction with subsequent growth. On the other hand pseudoHFM has an excellent prognosis both after surgery and after functional jaw orthopaedics. The choice of treatment in these cases might depend on patient cooperation, duration of treatment or psychological considerations.

4. Conclusion Cooperation between not only surgeons and orthodontists, but also with the dysmorphologists is crucial in the treatment of craniofacial anomalies. Neuromuscular pattern drives craniofacial growth (Vargervik et al., 1986) and, dictates the recurrence of asymmetry after surgical correction in true HFM patients (Meazzini et al., 2005). However some patients with recognizable condylar deformity, like those we have described in this report, show an excellent follow-up after early surgical correction. It is important to identify these patients, and distinguish them from true HFM patients, in order not to impose ineffective orthopaedic therapy, or surgical treatment with a poor prognosis, to those who have a clear embryological deficit. References AAO Council on Scientific Affairs (COSA): Functional appliances and long-term effects on mandibular growth. Am J Orthod Dentofacial Orthop 128(3): 271e272, 2005 Sep Brady AF, Winter RM, Wilson LC, Tatnall FM, Sheridan RJ, Garrett C: Hemifacial microsomia, external auditory canal atresia, deafness and Mullerian anomalies associated with acro-osteolysis: a new autosomal recessive syndrome? Clin Dysmorphol 11(3): 155e161, 2002 Jul Charrier JB, Bennaceur S, Couly G: Hemifacial microsomia. Embryological and clinical approach. Ann Chir Plast Esthet 46(5): 385e399, 2001 Oct Cousley R, Naora H, Yokoyama M, Kimura M, Otani H: Validity of the HFM transgenic mouse as a model for hemifacial microsomia. Cleft Palate Craniofac J 39 (1): 81e92, 2002 Jan Dabir TA, Morrison PJ: Trisomy 10p with clinical features of facio-auriculo-vertebral spectrum: a case report. Clin Dysmorphol 15(1): 25e27, 2006 Jan Engleka KA, Lang D, Brown CB, Antonucci NB, Epstein JA: Neural crest formation and craniofacial development. In: Inborn errors of development, the molecular basis of clinical disorders of morphogenesis, Oxford University Press, 69e79, 2008

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