*Department of Gynecology, Hôpital Félix Guyon, 97400 Saint-Denis, Ile de la Réunion, France. ** Echography' office, Route de Moufia, 97400 Saint-Denis, Ile de la Réunion, France. *** Department of Cytogenetic, Hôpital Félix Guyon, 97400 Saint-Denis, Ile de la Réunion, France. Tel: 0262 90 55 22. Fax: 0262 90 77 30.

Synonyms: Maxillo-nasal dysplasia. Maxillo-nasal dysostosis. Naso-maxillo-vertebral syndrome. Binder syndrome (Binder syndrome).

Definition: Binder syndrome or maxillo-nasal dysplasia or maxillo-nasal dysostosis is an uncommon developmental anomaly affecting primarily the anterior part of the maxilla and nasal complex. The characteristic findings are failure of development in the premaxillary area with associated deformities of the nasal skeleton (a flat, vertical nose), abnormal development (dysplasia) of the nasal and upper jaw (naso-maxillary) regions and the overlying soft tissues1. Affected individuals typically have an unusually flat, underdeveloped midface (midfacial hypoplasia), with an abnormally short nose and flat nasal bridge, underdeveloped upper jaw, relatively protruding lower jaw (mandible) and/or a "reverse overbite†(or class III malocclusion)^2-3-4.

A case of Binder syndrome was diagnosed at 24 weeks of gestation using two and three-dimensional ultrasound. The first sign was an isolated flattened fetal nose in the mid-sagittal plane. Further ultrasound 3D imaging showed the absence of the naso-frontal angle, giving impression of flat forehead and small fetal nose.

Case report: A 20-year-old para 1, gravida 0, presented for a routine screening at 24 weeks of gestation. She had no relevant past medical, obstetric of family of note, in particular there was no history of Warfarin exposure, alcohol abuse or vit K deficiency. Gestational age had been previously confirmed during the first trimester by crown-rump length measurement at 13 weeks of gestation. Nuchal translucency was normal but maternal risk for trisomy 21 was not made. The biometry was found to be normal for 24-week gestation including the intra-orbital diameter and the external orbital diameter. Nevertheless, nasal hypoplasia with reduced naso-frontal angle was noted.

Sagittal and coronal section of the fetal face at 24 weeks of gestation demonstrating an abnormal profile with flattened nose and abnormally positioned maxilla:

This facial finding was confirmed using a Kretz Technik Voluson ultrasound machine . 3D surface rendered image of the fetal face at 26 weeks of gestation suggesting flat mid-face

As a chromosomal abnormality could not be excluded, an amniocentesis was performed (46 XX). Discussions with the geneticists and neonatologists concluded that Binder syndrome was the most likely diagnosis but evidently, we could not confidently exclude another underlying syndrome. Nevertheless, 4p deletion (Wolf-Hirschhorn syndrome) was eliminated. The parents decided to continue this pregnancy. At 32 weeks of gestation, a brain RMI was done and the brain was normal. At 37 weeks of gestation, the baby born normally. The congenital abnormalities found were facial dysmorphism, flat mid-face.

Photography of the fetal face after birth

An intact arched palate was present without atresia of choana. There was no other malformation and no other pathology. Radiography confirmed the anomalies with hypotrophy of the bone of the nose. However, a hypotrophy of the distal phalanx was noted (brachytelephalangy) but there was not epiphyseal punctation. This young baby has a Binder anomaly.

History: Maxillo-nasal dysplasia was first reported by Noyes (1939), while Binder, in 1962 ⁵, described a condition called maxillo-nasal dysostosis (defective ossification), characterized by a short nose with a flat bridge, a short columella, an acute naso-labial angle, perialar flatness, a convex upper lip and a tendency to angle III malocclusion ⁶. He thought the condition was a form of arrhinencephaly, which it is not. Critical features of the syndrome appear to be midfacial hypoplasia, lack of anterior nasal spine and malocclusion. Since this description by Binder, more than 200 cases have been described, but mainly by plastic and reconstructive surgeons1. Noyes reported an example as early as 1939 ¹ and Zuckerkandl in 1982 described a similar malformation. The condition was also been called facies scaphoidea and congenitally flat nose syndrome ⁷. Sheffield et al. (1989) reviewed 103 cases of chondrodysplasia punctata; seen in Melbourne over a 20-year period and they concluded that Binder syndrome should be classified as a mild form of chondrodysplasia punctata ^8-9. Sheffield et al. (1991) pointed out that most patients with Binder syndrome seek medical attention in adolescence. Indeed, by this age, the diagnostic radiologic features of chondrodysplasia punctata have disappeared and the diagnosis is often not considered ⁹. Older patients may show terminal phalangeal hypoplasia of the hand, sometimes only in some digits, and patchy distortion of vertebrae, a residuum of vertebral clefting. However, some of the patients labeled as Binder phenotype had a maternal history of warfarin ingestion during pregnancy ¹⁰. Quarrell et al. (1990) reported a case and reviewed the clinical features, concluding that the disorder does not represent a single nosologic entity and that the use of the word syndrome or the word dysplasia is inappropriate. They suggested that the phenotype be considered an "association†or a "symptom‹¹. Well over 200 examples have been described, including several largest series of cases or reviews ^{12-13-14-15-16-17}. Some authors believed the condition is rather common and some authors do not regard it as a true syndrome, agreeing with Toriello that it is a nonspecific abnormality of the naso-maxillary complex, possibly related in many cases to prenatal deficiency of vitamin K18. The basic significance of Binder anomaly is a surgical entity, not a genetic, nosologic or syndrome entity. It is neither a dysplasia nor a syndrome. Although most cases involve only the naso-maxillary complex, a variety of other anomalies have been recorded including, especially, cervical vertebral anomalies, but also various other skeletal defects, cardiac anomalies, oro-facial clefting, strabismus, mental retardation and other abnormalities. Many of these cases likely have a syndrome of which Binder anomaly is a component manifestation and they have mild chondrodysplasia punctata or possibly warfarin embryopathy ^18-19.

Prevalence: In most cases, the condition appears to occur randomly for unknown reasons (sporadically). Rare familial cases have also been reported. Affected parents and child have been noted thrice and affected sibs have been observed on four occasions ^20-21-22. Consanguinity has been recorded in a few instances. Holmström suggested that 16 % of his sample exhibited "hereditary factorsâ€. Although Binder anomaly is believed to be common, it is often unrecognized in some ethnics groups, such as the japanese ²³.

Etiology: The etiology of Binder syndrome still remains uncertain. In 1962, Binder believed that this patient had a mild form of arrhinencephaly but they had no olfactory anomalies to support the hypothesis. Hopkin in 1963 reported five cases and he supposed that Binder syndrome was the result of development abnormality ²⁴. In 1987, Narcy et al reported a case of Binder syndrome in association with esophageal achalasia and abnormal autonomic reflexes suggesting that the phenotype be the result of an abnormal migration of neural crest cells. The author proposed that Binder syndrome might be a neurocristopathy ^25-26.

Pathogenesis: Noguchi et al. (2002) noted that retinoic acid, a metabolic product of retinol, is essential for cranio-facial morphogenesis, and that transthyretin is a plasma protein delivering retinol to tissues ²³. Nevertheless, the pathogenesis is not really known.

Sonographic findings: The Binder phenotype may be heterogeneous. The pattern of abnormalities seen in this condition does not represent a causally defined entity ¹. Diagnosis of the Binder syndrome is easy when the fetus is born because of its characteristic anomalies of the upper lip and nose: smallness of the nose, a groove under the columnella, a "half-moon" appearance of the nasal apertures, absence of the nasal spine, and projection of the chin. But in addition, we can observed several associated abnormalities as convergent strabismus, labio-maxillo-palatine cleft, and numerous abnormalities of the cervical spine, frequently associated with mandibular prognathism. In view of the frequency of the latter abnormalities. Binder syndrome might well be called a "naso-maxillo-vertebral syndrome′⁷. Nevertheless, the diagnosis in utero is difficult but we can be alerted by the visualization of flat profile with 2D ultrasound. Certainly 3D ultrasound most often supplies better information than that obtained from 2D ultrasound. It will certainly useful for accuracy of the description and study all of cranio-facial dysmorphology ²⁸.

Differential diagnosis: Although the facies may appear "arhincephaloidâ€, no brain abnormalities have been observed in this condition. The sense of smell is completely normal. Absent frontal sinuses and relative mandibular prognathism can be associated with a host of conditions and may be seen in otherwise normal individuals. Nasal hypoplasia occurs in pseudohypoparathyroidism, acrodysostosis, Marshall syndrome and Warfarin or Phenytoin embryopathy. Toriello said that Binder anomaly and Keutel syndrome are allelic. Others syndromes with maxillary hypoplasia can easily be excluded.

• Chondrodysplasia: and especially achondroplasia, which includes a saddle nose, skull, bones abnormalities and dwarfism, which are not present in Binder syndrome. The likeness with chondrodysplasia punctata is striking and Sheffield et al hypothesized that Binder phenotype should be the same than the mild type of chondrodysplasia punctata ^8-9.
• Fetal warfarin syndrome: following maternal warfarin uptake during the first trimester of pregnancy. A characteristic includes significant nasal hypoplasia (sometimes resulting in respiratory difficulties), shortness of the neck and fingers, hypoplasia of the terminal phalanges and sometimes, a slight mental retardation, optic atrophy and dysplasia of the nails ⁶.
• In Stickler syndrome: the facies is flat with depressed nasal bridge. Deafness, myopia and spondylo-epiphyseal dysplasia are usual ²⁵.
• Craniostenosis: such as Crouzon syndrome or Apert syndrome which include an ocular subluxation due to orbital hypoplasia and a unique shape of the cranium ²⁵.
• Peripheral dysostosis, nasal hypoplasia and mental retardation: described by Maroteaux is characterized by a flat nose, but the nasal floor is normally horizontal without the groove under columella. These cases are mental retarded, obese and they have short hands and feet ²⁹.
• Robinow syndrome or fetal face syndrome: This is characterized, like Binder syndrome, by a significant maxillo-nasal hypoplasia with a groove under the nares and by vertebral lesions (fusions or hemi-vertebrae). However, in contrast to Binder syndrome, there are usually short fore arms with brachydactyly and often labio-palatal clefts, hypertrophied gingiva and macroglossia ⁷.

Associated anomalies: A variety of other anomalies have been described including, especially, cervical vertebral anomalies, but also various other skeletal defects, cardiac anomalies, oro-facial clefting, strabismus, mental retardation and other abnormalities. Older patients may show terminal phalangeal hypoplasia of the hand, sometimes only in some digits, and patchy distortion of vertebrae, a residuum of vertebral clefting.

Prognosis: The prognosis is good if there is no other problem associated.

Recurrence risk: The etiology and pattern of inheritance and prevalence remain uncertain. Inheritance is uncertain1. Although the majority of cases of maxillo-nasal-dysplasia are sporadic, familial occurrence has been reported by a number of authors. In a formal genetic analysis, Olow-Nordenram and Valentin (1988) found low segregation ratios and suggested that recurrence in their pedigrees could be explained by either autosomal recessive inheritance with reduced penetrance or by multifactorial inheritance ¹⁸. Recurrence in sibs with unaffected parents has been observed seven times but an affected parent and child has been rarely reported ^1-20.

Management: The treatment of Binder syndrome differs with the degree of facial bone abnormalities. When maxillo-nasal dysplasia is observed at birth, it is usually not thought to be important if it presents as a single findings. Individuals may also be seen as children or adolescents by orthodontists or plastic surgeons and their facial features are then diagnosed as Binder syndrome. Orthodontic therapy should be conducted as early as possible; the most severe cases require a Le Fort I or II osteotomy with nasal grafting ^21-24. However, cases with severe malocclusion were treated by a Le Fort I and/or Le Fort II osteotomy when the children were older. When the malocclusion was less severe, interceptive orthodontics have been useful. The nose can be significantly lengthened and enlarged through a frontal craniotomy incision connected with an upper buccal sulcus incision, without any incision on the face ²². Binder syndrome is an uncommon though easily recognizable congenital condition characterized by a retruded mid-face with an extremely flat nose. The facial deficiencies lead to functional as well as psychological problems. Noses can be corrected with inlay of costal cartilage grafts using a combined oral vestibular and external rhinoplasty approach. The technique has been used in children as well as adults with promising results. Since the degree of malformation in Binder syndrome varies significantly, surgical correction needs to be tailored individually based on the principles demonstrated. In all patients, minor malocclusion was first treated by orthodontists. The treatment of these patients is a challenge for every surgeon and needs interdisciplinary cooperation.

Clinical appearance: Binder syndrome is a disorder characterized by naso-maxillary hypoplasia and a 40-50% association of an underdeveloped frontal sinus and cervico-spinal abnormalities. The midfacial retrusion is similar to that in chondrodysplasia punctata, resulting in confusion regarding diagnosis. Although most cases involve only the naso-maxillary complex, a variety of other anomalies has been recorded1. Binder syndrome has a characteristic clinical appearance including midface hypoplasia, flattened nose, convex upper lip, broad philtrum, crescent-shaped nostrils, and a deep fold or fossa between nose and upper lip. The frontal sinuses are often hypoplastic or absent. The naso-frontal angle is absent and the nose is hypoplastic with flattened alae and nasal tip. The nostrils are usually half moon shaped and the upper lip is convex with a high arched palate. The nasal mucosa has been described as atrophic, but the sense of smell is normal. The philtral crest may be bow shaped, rising vertically to the columella without convergence. The incisors may be in crossbite with over angulation of the maxillary incisors, and a Class III occlusion is common ¹¹. The profile does not change with time. There is a palpable depression in the anterior nasal floor and localized maxillary hypoplasia in the alar base region. The overall facial profile gives the appearance of mandibular prognathism associated with an increased gonial angle. Retrognathism is less usual. Mild hypertelorism is usually present as well a malocclusion and a lower overbite. Strabismus and mild mental retardation have been occasionally described, but they probably have no statistical significance. Rarely there is cleft lip or cleft palate. Radiographic features include small or absent anterior nasal spine, thin labial plate over incisor roots, and nasomaxillary hypoplasia ⁴. The frontal sinuses are often hypoplastic or absent. Cephalometric studies have shown increased gonial angle and proclination of the incisors. There are decreased anterior cranial base measurements and a smaller maxilla vertically and antero-posteriorly, although Eliasson have suggested that less than half have maxillary retrognathia. There are various anomalies of the cervical spine, which may be seen, such as separate odontoid process, spina bifida occulta, short posterior arch and block vertebrae. The cervical spine is anomalous in 50 %. The atlas and axis are most frequently involved ²⁴. Various anomalies include short posterior arch, block vertebrae, separate odontoid, spina bifida occulta and persistence either of chorda dorsalis (15 %), isolated or in various combinations. Calcifications extending from the anterior arch of the atlas have been noted as well as mild scoliosis and/or kyphosis ¹. The cervical spine is abnormal in 50 % of the cases. Other features are more inconstant: oro-facial clefting is rarely reported as well as other dental abnormalities than those secondary to malocclusion. Cardiopulmonary anomalies are uncommon. Non-specific congenital heart defects have been found in 5 %. Hearing loss occurs in approximatively 5 %. Retarded growth and mental retardation are unusual. Joint abnormalities (dislocated hips) or limbs abnormalities are described in 11 % of the cases. Minor fingers anomalies have been described ⁷.

Conclusions: Binder syndrome type maxillo-nasal dysplasia is a rare condition characterized by abnormal development of the nasal and upper jaw (nasomaxillary) regions. Affected individuals typically have an unusually flat, underdeveloped midface, with an abnormally short nose and flat nasal bridge, underdeveloped upper jaw, relatively protruding lower jaw and/or a "reverse overbite" (class III malocclusion). Many researchers suggest that Binder syndrome does not represent a distinct disease entity or syndrome, but, rather, is a nonspecific abnormality of the nasomaxillary regions. In most cases, the condition appears to occur randomly for unknown reasons. The Binder phenotype may be heterogeneous and it is clear from the previously mentioned review that the pattern of abnormalities of Binder syndrome does not represent a causally defined entity. That's the reason why many researchers considers that maxillo-nasal dysplasia is not a nosologic or syndromic entity but rather a surgical entity and that Binder syndrome type maxillo-nasal dysplasia does not represent a distinct disease entity or syndrome, but, rather, is a nonspecific abnormality of the naso-maxillary regions. So Quarrel et al suggests the use of Binder "phenotype†or "association†instead of the world "syndromeâ€.

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