Binder Phenotype (Maxillonasal Dysplasia)

Congenital hypoplasia of the premaxilla and nasal complex, with a short, flat and vertical nose, absent or hypoplastic anterior nasal spine and a tendency to class III malocclusion; a malformation pattern of heterogeneous aetiology, which includes isolated forms, X-linked chondrodysplasia punctata (ARSL), embryopathies due to vitamin K antagonists or vitamin K deficiency, maternal autoimmune disease, genetic defects of the vitamin K cycle and several chromosomal and monogenic syndromes.

Literature and regulatory information updated: 29 October 2026.

0. Initial Reference Table

The Binder phenotype, also called Binder syndrome, maxillonasal (or nasomaxillary) dysplasia and maxillonasal dysostosis, is defined by Orphanet as a rare developmental anomaly characterised by midfacial hypoplasia that mainly affects the anterior part of the maxilla (premaxilla) and the nasal complex (ORPHA:1248; OMIM 155050) [1]. There is no dedicated GeneReviews chapter; the reference chapter for the main identified genetic cause, X-linked chondrodysplasia punctata (CDP) type 1 (CDPX1), is that of Braverman and colleagues [2]. Table 0A brings together the identifiers of the entity and of the causes whose most constant facial manifestation is the Binder phenotype; Table 0B summarises the quick-reference data.

Table 0A. Identifiers of the Binder phenotype and of the main identifiable causes

Table 0B. Quick-reference data

1. Introduction

1.1. Founding descriptions

The first description of a face with these features is attributed to Zuckerkandl, in 1882, but the entity was named after the German orthodontist K. H. Binder, who in 1962 described three patients under the name dysostosis maxillo-nasalis and established the features that still define it today: a short nose with a flat nasal root, absence or hypoplasia of the anterior nasal spine and of the columella, an acute nasolabial angle with marked convexity of the upper lip, maxillary hypoplasia with a tendency to class III malocclusion, mild hypertelorism and atrophy of the nasal mucosa [5, 8]. According to the review by Andrietti and colleagues, the nasolabial angle in these patients lies between 76° and 88°, compared with 103° to 117° in the reference population [5].

In 1980, Delaire, Tessier, Tulasne and Resche noted that, although fewer than 40 cases had been published since 1962, they had seen 37 patients in eight years, and described the signs that allow immediate clinical recognition: small nose, a groove under the columella, crescent-shaped nostrils, absence of the nasal spine and projection of the chin [8]. The same authors and Resche reported craniospinal and cervical anomalies in 15 of 28 patients studied radiologically (53.5%) and proposed the name “nasomaxillovertebral syndrome” [8, 10]. Greenberg counted 127 new cases published between 1980 and 1991, which led to the expression “rarely common disorder” [19].

1.2. The Swedish school: pathological anatomy, cephalometry and inheritance

Between 1984 and 1989, Olow-Nordenram and Thilander, in Gothenburg, studied the craniofacial morphology of 97 individuals with maxillonasal dysplasia compared with orthognathic controls matched for age and sex, followed treated and untreated children longitudinally, documented cervical malformations in 44.2% of 43 patients and analysed the pedigrees of 50 patients, with a familial link in 36% [11, 20, 21]. In 1986, Holmström, also in Gothenburg, described in 50 patients the skeletal substrate of the low nose — a palpable depression in the anterior nasal floor, the prenasal fossa, and maxillary hypoplasia localised to the alar base — and proposed that the lack of a secondary ossification centre in the canine region would explain the localised hypoplasia of the floor and walls of the piriform aperture [9].

1.3. From the concept of syndrome to that of phenotype

From the late 1980s, the association with chondrodysplasia punctata (CDP) and with prenatal exposure to vitamin K antagonists showed that the Binder face does not correspond to a single cause. Sheffield and colleagues, after reviewing 103 cases of CDP seen in Melbourne over 20 years, concluded that Binder syndrome should be classified as a mild form of CDP, and noted that most patients seek care in adolescence, when the stippling has already disappeared, though they may still show hypoplasia of the terminal phalanges in some digits and irregular distortion of the vertebrae, a remnant of the vertebral clefts [22]. In 1990, Quarrell, Koch and Hughes concluded that the picture does not represent a single nosological entity, considered the terms “syndrome” and “dysplasia” inappropriate and suggested treating it as an “association”; the term “Binder phenotype” is now dominant in the genetics and fetal medicine literature [22–24]. Roy-Doray and colleagues, reporting an affected mother and son, concluded that the pattern of anomalies does not represent a causally defined entity [25]. The Australian Craniofacial Unit, after 30 years of experience with 72 patients, 12 of whom had CDP, considered Binder to be more an “association” than a syndrome or an entity [26]. In 2019, Mazzone and colleagues posed the same question in the title of a letter: “a phenotype, and not a definitive diagnosis?” [27]. The Oxford Desk Reference records the debate between an autonomous entity and the adult phenotype of mild forms of CDP and classifies the inheritance as uncertain [12, 28].

1.4. Milestones in aetiological understanding

The cloning of the sulfatase gene cluster at Xp22.3, in 1995, identified the arylsulfatase E gene (ARSE, now ARSL) as the cause of X-linked recessive CDP and showed that the enzyme's activity is inhibited by warfarin in vitro, which explains the phenotypic overlap between CDPX1 and warfarin embryopathy [2, 29, 30]. In 1997, Menger and colleagues described three infants with stippled calcifications, nasal hypoplasia and vertebral anomalies, born to mothers with malabsorption that had required parenteral nutrition, and defined embryonic vitamin K deficiency as a third vitamin K-related mechanism, alongside warfarin embryopathy and epoxide reductase deficiency [31]. Howe and Webster reproduced maxillonasal hypoplasia in rats with warfarin combined with vitamin K1 (selective extrahepatic deficiency) and attributed it to calcification of the septal cartilage due to a lack of carboxylated matrix Gla protein (MGP) [32]. Associations followed with maternal autoimmune disease, hyperemesis gravidarum, Crohn's disease, cholelithiasis and bariatric surgery [33–36] and, in the sequencing era, with variants in GGCX, KMT2D and GNPTAB and with partial trisomies of chromosome 5 [13, 37–39].

1.5. Definition and terminology

The term “Binder phenotype” denotes the facial pattern described, regardless of cause, and “Binder syndrome” is reserved, by historical usage, for cases in which the pattern is isolated and no cause is identified. Keppler-Noreuil and Wenzel list six features of the phenotype: arhinoid face, abnormal position of the nasal bones, intermaxillary hypoplasia with malocclusion, reduced or absent anterior nasal spine, atrophy of the nasal mucosa and absence of the frontal sinus [3]. In the prenatal period, Bosco and colleagues define a triad — flattened nose, verticalised nasal bones and maxillary retrusion [6]. Lane and colleagues propose distinguishing the isolated Binder phenotype (nasal hypoplasia only) from the Binder phenotype with CDP (nasal hypoplasia with stippled epiphyses) [7]. The chondrodysplasias punctata and warfarin embryopathy enter the differential diagnosis.

2. Molecular Genetics and Pathophysiology

The Binder phenotype is a common end point of distinct mechanisms that converge on the same anatomical target and the same developmental window: growth of the cartilaginous nasal septum and ossification of the premaxillary region and the piriform aperture in the first trimester. Most of the identified causes act on the vitamin K pathway and on cartilage mineralisation; a fraction of cases have a chromosomal or monogenic cause with no known relation to that pathway; and in many patients no cause is found.

2.1. Anatomy of the defect and embryonic window

Holmström located the skeletal deformity of the low nose in a depression of the anterior nasal floor, the prenasal fossa, accompanied by maxillary hypoplasia confined to the alar base; in 6% of the 50 patients there was a slope (prenasal groove) instead of a fossa, and in one patient a rudimentary fossa [9]. The author related the defect to the development of the premaxilla and to the appearance of an external trabecular bone network in the canine region, a secondary ossification centre whose inhibition would explain the localised hypoplasia of the floor and walls of the piriform aperture, the retracted columella–lip junction and the lack of the normal triangular widening of the columellar base [9, 15]. Gewalli and colleagues consider bilateral prenasal fossae pathognomonic and stress that there is no real soft-tissue deficit; the problem is the skeletal framework around the piriform aperture [40]. Holmes and colleagues describe, by contrast, a constricted nasal soft-tissue envelope, which conditions the surgical strategy [41].

The timing of the defect was clarified by studies of human embryos and fetuses. Howe, Hawkins and Webster showed, in sagittal sections of fetuses at 6 to 9 weeks, that prenatal growth of the nasal septum is maximal in this period and establishes the facial profile that is maintained until birth; this window coincides with the exposure period that produces warfarin embryopathy, and cephalometry of a child with untreated embryopathy showed a short anterior cranial base and a short maxilla, with marked maxillary retrusion [42]. Katsube and colleagues, using magnetic resonance imaging (MRI) and geometric morphometrics of 56 specimens, estimated that the shape of the anterior nasal spine matures at around 12 weeks and that of the nasal septum at around 14 weeks, and that anteroposterior growth of the septum up to 14 weeks is decisive for nasal projection and for formation of the spine [43]. Smith's Recognizable Patterns places the critical period of warfarin embryopathy between 6 and 9 weeks of gestation, and the Oxford Desk Reference between 6 and 12 weeks [12, 29].

2.2. Vitamin K cycle, Gla proteins and cartilage mineralisation

Vitamin K is a cofactor of gamma-glutamyl carboxylase (encoded by GGCX), which converts glutamate residues into gamma-carboxyglutamate (Gla) in coagulation proteins (factors II, VII, IX and X, proteins C, S and Z) and in extrahepatic proteins such as MGP, an inhibitor of cartilage calcification; vitamin K epoxide reductase (VKOR, encoded by VKORC1) regenerates the reduced form of the cofactor and is the target of coumarin antagonists [7, 29, 44]. Because the vitamin K-dependent clotting factors are not yet present at 6–9 weeks, the embryopathy must result from a lack of carboxylation of other Gla proteins [29]. In the Howe and Webster model, rats treated from the first day of life with sodium warfarin (100 mg/kg/day) and vitamin K1 (10 mg/kg/day), a regimen that creates extrahepatic deficiency while preserving hepatic carboxylation, developed maxillonasal hypoplasia with an 11–13% reduction in nasal bone length, extensive calcification of the septal cartilage and calcium bridges in the epiphyseal cartilages; the authors attributed the hypoplasia to reduced longitudinal growth of the calcified septum due to a lack of functional MGP [32]. The 2025 ESC guideline describes vitamin K antagonist (VKA) embryopathy as related to interference with embryonic ossification [17].

The second proposed pathway involves arylsulfatase E. The activity of the arylsulfatase encoded by ARSL is inhibited in vitro by warfarin, and the similarity between CDPX1, warfarin embryopathy, pseudoembryopathy due to VKOR deficiency and embryopathies due to maternal deficiency — all with nasal hypoplasia, brachytelephalangy and axial stippling — supports the hypothesis of a common metabolic aetiology [2, 12, 29]. The atlas by Spranger and colleagues formulates the same model: warfarin interferes competitively with ARSE activity through inhibition of vitamin K reductase [45]. The physiological substrate of the enzyme remains to be identified [2].

Jin and colleagues studied a patient with congenital deficiency of the vitamin K-dependent factors and compound heterozygous GGCX variants, c.1760A>G p.(His587Arg) and c.1787del p.(Pro596fs) in the authors' notation; oral vitamin K improved the coagulopathy but did not correct the calcification abnormalities, and functional assays showed that the p.His587Arg variant impairs carboxylation of extrahepatic proteins, including MGP, more than that of hepatic proteins [44]. These data, preclinical and from a single patient, help to explain why the skeletal and facial phenotype of VKCFD does not respond to vitamin K as the bleeding does.

2.3. ARSL and X-linked chondrodysplasia punctata type 1

The ARSL gene (formerly ARSE), at Xp22.33, encodes arylsulfatase L, a sulfatase located in Golgi membranes which, like all sulfatases, depends on post-translational activation by the SUMF1 enzyme [2]. The disease results from loss of function: most of the missense variants studied have negligible activity in expression systems, and patients with deletions, nonsense or missense variants have indistinguishable phenotypes [2]. According to Human Gene Mutation Database (HGMD) data gathered in GeneReviews, 88% of pathogenic variants are detectable by sequencing and 12% by deletion and duplication analysis; these figures are proportions of variants detected by each method, not clinical sensitivity [2]. ARSL has a pseudogene on the Y chromosome, which may hinder detection of deletions of some exons [2]. No genotype–phenotype correlations have been identified [2].

Terminal or interstitial Xp22.3 deletions and X;Y translocations that remove ARSL together with contiguous genes add ichthyosis (due to steroid sulfatase deficiency), hypogonadotrophic hypogonadism with anosmia (Kallmann syndrome due to KAL1 deletion), cataracts, intellectual disability, autism and, when SHOX is included, short stature and Madelung deformity [2, 45]. Keppler-Noreuil and Wenzel included an Xp22.3 deletion with CDP among the eight Iowa patients with a strict Binder phenotype [3].

Franco and colleagues cloned in 1995 a cluster of three sulfatase genes at Xp22.3 (ARSD, ARSE/ARSL and ARSF), showed that the arylsulfatase activity produced by ARSE expression is thermolabile and inhibited by warfarin, and found point variants in 5 of 27 men with CDPX1; the mature 68 kD protein is located in the Golgi, and the ARSD and ARSE genes escape X inactivation and have truncated pseudogenes on the Y [30]. In the prospective Collaboration, Education and Test Translation programme (CETT, 2008–2010), only 17 of 29 boys with brachytelephalangic CDP (BCDP; 58%) had ARSE variants, all without relevant enzyme activity, showing that a substantial fraction of male BCDP cases corresponds to phenocopies or other causes [30]. The most frequent variant in patients with an identified variant is the nonsense NM_000047.3:c.1743G>A p.(Trp581Ter) (NC_000023.11:g.2934859C>T), described in the literature with the historical numbering “2045G>A” (W581X) in four unrelated patients [30, 46]. A girl with CDPX1 due to homozygosity for a maternal variant resulting from segmental uniparental disomy has also been described, with a milder phenotype than her brother's [30]. A recent example of a normalised intragenic variant is ARSL NM_000047.3 (MANE Select transcript, Matched Annotation from NCBI and EMBL-EBI):c.1442C>T p.(Thr481Met), NC_000023.11:g.2935160G>A, described in 2026 in an infant with severe CDPX1, with prenatal detection of a flat profile, absent nasal root and narrow sacrum [46, 47]. In the older literature, GeneReviews cites the variant p.Gly137Ala, identified in a proband and in the unaffected maternal grandfather, and a deletion of exons 7 to 10 in a proband and in the asymptomatic maternal grandfather; because the signs of CDPX1 attenuate with age, it is not clear whether these cases represent non-penetrance [2]. Female carriers have no described disease, although some are shorter than expected [2]. Spranger and colleagues record, however, that not all cases of BCDP have ARSE deficiency, that there are affected women with a picture identical to that of the X-linked form and an affected brother–sister pair, allowing autosomal transmission in some cases [45].

2.4. GGCX and VKORC1: combined deficiency of vitamin K-dependent factors

Combined deficiency of the vitamin K-dependent factors enters the differential diagnosis. Biallelic variants in GGCX (VKCFD1, OMIM 277450) and VKORC1 (VKCFD2, OMIM 607473) cause an inherited deficiency of factors II, VII, IX and X and of proteins C, S and Z, with autosomal recessive inheritance, with nasal hypoplasia among the non-haemorrhagic manifestations [2]. Mathonnet and colleagues described the first prenatal diagnosis of VKCFD: a male fetus with BCDP, absent nasal bone, growth restriction and ventriculomegaly at 18 weeks, whose autopsy showed a Binder phenotype, hypoplastic distal phalanges, stippled epiphyses and brain changes suggestive of haemorrhage, with two pathogenic GGCX variants inherited one from each parent [48]. Grammatopoulos and colleagues reported, in 2025, a 4-month-old infant with a congenital Binder phenotype admitted for a large subdural haematoma, with prothrombin time prolonged by deficiency of the vitamin K-dependent factors and an undescribed pathogenic GGCX variant, in a familial context [13]. Keppler-Noreuil and Wenzel included a patient with vitamin K epoxide reductase deficiency among the eight Iowa cases [3]. The observation, by Pauli and colleagues, of features of warfarin embryopathy (nasal hypoplasia, hypoplasia of the distal phalanges and stippling in infancy) in a patient with VKCFD was interpreted as proof that the embryopathy results from inhibition of carboxylation of vitamin K-dependent bone proteins [49].

2.5. Non-genetic causes converging on the vitamin K pathway

Exposure to coumarin antagonists (warfarin, acenocoumarol, phenprocoumon) in the first trimester is the established teratogenic cause [17, 29]; Harrod and Sherrod described two siblings exposed to warfarin with signs of CDP and a third, from a pregnancy without warfarin, without abnormalities [50]. Maternal vitamin K deficiency produces a clinically indistinguishable phenocopy [12]: it has been described in severe hyperemesis gravidarum, Crohn's disease, small bowel obstruction, short bowel after resection, untreated coeliac disease, jejunoileal bypass, pancreatitis, cholelithiasis, hepatic fibrosis due to transfusional iron overload and after bariatric surgery with malabsorption [2, 31, 34–36]. The deficiency was documented in the laboratory in only three cases, one of them described by Alessandri and colleagues with a Binder phenotype and BCDP, and was presumed in the others [2, 51]. The Oxford Desk Reference also includes phenytoin among the exposures associated with CDP, and Jaillet and colleagues mention phenytoin-induced vitamin K deficiency as an established aetiology of Binder phenotype [12, 35].

Maternal autoimmune disease — systemic lupus erythematosus (SLE), mixed connective tissue disease and scleroderma — is associated with CDP, sometimes with rhizomelic shortening, and with a fetal Binder phenotype [2, 24, 33]. Colin and colleagues found no specific maternal autoantibody associated with the phenotype [33]; the mechanism, transplacental passage of antibodies or interference with the vitamin K pathway, is not established in the sources consulted.

2.6. Chromosomal and monogenic causes with no known relation to vitamin K

In the Iowa registry, chromosome analysis of the 24 cases initially identified with a Binder phenotype revealed trisomy 21, trisomy 18 and mosaic trisomy 18; among the eight patients meeting strict criteria there were also Stickler syndrome, Robinow syndrome and cases of unknown aetiology [3]. Levaillant and colleagues found, among eight fetuses, one case of infantile sialic acid storage disease and one probable case of Keutel syndrome (gene MGP, autosomal recessive) [52]. Hadzsiev and colleagues described a girl with a small supernumerary ring chromosome, de novo, containing the pericentromeric region 5p14.1q11.1 (20,950 kb) and, reviewing seven overlapping cases, proposed a causal relationship between trisomy of this region and the Binder phenotype; in 2026 another girl with a chromosome 5 duplication and a palatal epulis was described [39, 53]. Kabuki syndrome (de novo KMT2D variant) can produce severe prenatal midfacial hypoplasia suggestive of CDP [37]. In an exome series of 50 fetuses, GNPTAB variants (the mucolipidosis II/III gene) were found in two unrelated cases, a new association [38]. A case with a SPIN4 variant and fetal overgrowth has also been described [54].

2.7. Inheritance of forms without an identified cause

In the isolated forms most cases are sporadic [3, 25]. Holmström found a hereditary link in 16% of 50 patients, and Olow-Nordenram and Valentin in 36% of 50 patients who sought orthodontic or surgical treatment, in a study extended to 60 families; the authors did not exclude a genetic origin and considered two hypotheses, autosomal recessive inheritance with incomplete penetrance or a multifactorial threshold trait [9, 20, 21]. Roy-Doray and colleagues counted, in the literature, recurrence in second- or third-degree relatives in six families, recurrence in siblings with unaffected parents in seven and, rarely, parent-to-child transmission, as in the mother and son they described; Gross-Kieselstein and colleagues reported an affected mother and daughter and suggested dominant inheritance [25, 55]. In the formal genetic analysis by Olow-Nordenram and Valentin, segregation ratios were low [22]. Munroe and colleagues suggested that Binder might be an allelic variant of Keutel syndrome, caused by MGP variants, a hypothesis that the sources consulted do not confirm [22]. A transgenic mouse model with the TTR Val30Met variant (historical numbering, = NM_000371.4:c.148G>A p.(Val50Met)) (“Nax” line) showed a maxillonasal malformation with autosomal dominant transmission, a preclinical finding without established human correspondence [22]. Orphanet therefore records three possible patterns (autosomal dominant, autosomal recessive and multifactorial), and the Oxford Desk Reference describes the inheritance as uncertain [1, 28]. Part of the familial aggregation may correspond to undiagnosed mild CDP (including CDPX1 transmitted through the maternal line) or to repeated maternal exposures, which can only be clarified case by case [12, 24].

Table 2. Mechanisms and causes of the Binder phenotype

3. Clinical Spectrum and Manifestations by System

3.1. Face and nasomaxillary skeleton

The nose is short, flat and vertical, with a flattened tip and alae, a short columella and crescent-, comma- or triangle-shaped nostrils; the upper lip is convex, the nasolabial angle acute and the perialar region depressed [8, 24, 28, 56]. There may be a groove under the columella and, in CDPX1, vertical grooves in the alae [2, 8]. The anterior nasal spine is absent or hypoplastic, the nasal septum is short and the frontal sinuses are frequently absent [3, 24]. The face may appear arhinencephalic, but the brain and the sense of smell are normal [24]. In the Orphanet annotations, maxillary hypoplasia, depressed nasal root and bridge, short columella, short nose, midface retrusion and flat face are very frequent (80–99%) [1].

Cephalometry documents the nature of the defect. In a cross-sectional study of 97 Swedish individuals compared with orthognathic controls, the differences were concentrated in the variables linked to maxillary retrognathia [20]. In 14 untreated patients at the Royal Children's Hospital in Melbourne, the anteroposterior lengths of the anterior cranial base and of the maxilla were reduced and most had a class III skeletal relationship, although overjet and overbite were within the limits of the normal population [57]. Holmström found class III malocclusion in 54% of 50 patients [9]. Eliasson and Holmström, using a theoretical midfacial ratio validated in 90 adults (correlation with the sella–nasion–A point angle, SNA, with an adjusted R² of 82.7%), found that fewer than half of 35 adults with Binder had maxillary retrognathia and that most had an orthognathic or even prognathic maxilla, which makes it necessary to individualise the treatment plan [58]. In the most severe cases of the Swedish series, maxillary retrognathia was aggravated by a class III type of mandibular morphology [20].

3.2. Dentition and occlusion

In addition to class III malocclusion and open bite, Orphanet annotates microdontia and tooth agenesis as frequent (30–79%) and mandibular prognathism as occasional (5–29%) [1]. Akeredolu and colleagues described a 20-year-old Nigerian woman with complete absence of the premaxilla, nasal bone and septum, whose main complaint was the absence of the incisors, rehabilitated with a removable maxillofacial prosthesis [59]. Agenesis of the anterior incisors has also been the subject of reports of orthodontic and prosthetic treatment [60]. The dentofacial manifestations of warfarin embryopathy were studied with cephalometry in an 8-year-old boy [61]. In another child with warfarin embryopathy followed up to 8 years, there were caries, delayed eruption of the upper incisors, a high palate, mouth breathing and a short upper lip [62].

3.3. Airway and feeding in the newborn

Severe nasal hypoplasia narrows the upper airway. In the Washington series, the Binder phenotype predicted some degree of respiratory difficulty in five of six live births with nasomaxillary hypoplasia, and was absent in the only case with a normal profile; four had mild and one severe difficulty, with intubation, two required nasal dilatation for nostril stenosis and four had feeding difficulties [24]. In Marseille, among 13 fetuses with Binder, two (18%) had perinatal respiratory difficulty; the fetus with polyhydramnios and laryngeal calcifications was one of them [63]. In the systematic review of 47 prenatal cases, there was respiratory distress syndrome in 12 newborns, and the authors associate the phenotype, on its own, with a higher risk of respiratory and feeding difficulty [6]. Blumenfeld and colleagues reported three cases with immediate respiratory compromise [64]. Ventilatory difficulty may also result from laryngeal or tracheobronchial calcifications and from central hypoventilation due to cervical stenosis, and may be severe even with patent nostrils and trachea [2, 24]. Tessier and colleagues mention the need, in the newborn, for endonasal and gastric tubes for respiratory and feeding problems [65].

3.4. Cervical spine

Cervical spine anomalies are the most relevant extrafacial skeletal association. Resche and colleagues found craniospinal and cervicospinal malformations in 15 of 28 patients (53.5%), and Olow-Nordenram and Rådberg, in 43 patients, minor or major cervical malformations in 44.2%, including six cases of vertebral body dysplasia due to persistence of the notochord, with no correlation with the severity of the face or of the malocclusion and without symptoms at early ages [10, 11, 20]. Andrietti and colleagues summarise the literature as about 50% with cervical anomalies, mainly defects of the anterior and posterior arches of the atlas, vertebral fusions and persistence of the notochord [5]. In CDPX1, 10 of 16 patients had significant cervical changes (vertebral dysplasia or hypoplasia, anterior C1–C2 subluxation, kyphosis, spinal cord compression, canal stenosis), with instability sometimes of late onset [2]. A systematic review of 44 patients with CDP or coumarin embryopathy with cervical involvement found hyperreflexia (21%) and weakness (21%) as the most frequent presentations, neurological complications in 21% of those treated conservatively and two deaths, one with conservative treatment and the other surgical [66]. In 2026, an infant with CDPX1 and movement-triggered cardiorespiratory arrests attributed to dynamic cervical spinal cord compression was described; the arrests decreased temporarily with neck stabilisation [47].

3.5. Hearing, eyes, heart and development

Mixed conductive and sensorineural hearing loss occurred in 13 of 18 patients with CDPX1, and in the Washington series two infants had profound unilateral hearing loss [2, 24]. Delaire and colleagues observed convergent strabismus in two of 37 patients, and the prenatal series report an occasional association with heart disease [5, 8]. Scoliosis and vertebral clefts appear as frequent in the Orphanet annotations [1]. Intellectual disability does not appear to be part of the isolated Binder phenotype; when present, it points to a syndromic cause (chromosomal disorder, Xp22.3 deletion, Kabuki) or to associated brain injury (second-trimester VKA exposure, fetal haemorrhage, cortical dysplasia) [2, 5, 29, 39].

3.6. Manifestations according to cause

CDPX1. Nasomaxillary hypoplasia is present in all patients in the reference series, with epiphyseal stippling (mainly ankles and distal phalanges, disappearing by 2–3 years) and brachytelephalangy; Table 3 shows the frequencies [2]. Most have little morbidity and improve with age, but some have airway stenosis due to tracheobronchial calcifications, cervical instability, hearing loss and cognitive delay [2].

Table 3. Frequency of findings in CDPX1 (series of Nino 2008 and Matos-Miranda 2013, possibly biased towards severe cases)

Source: [2].

Vitamin K antagonist embryopathy. Exposure between 6 and 9 weeks produces nasal hypoplasia with a depressed root, often with a deep groove between the alae and the tip, stippling of the uncalcified epiphyses mainly of the axial skeleton (vertebrae, pelvis), proximal femurs and calcanei, which disappears after the first year, hypoplastic distal phalanges shaped like an inverted triangle, and low birth weight with later catch-up [29]. Occasional features are choanal atresia, cleft lip and palate, pulmonary hypoplasia, severe rhizomelia, scoliosis, congenital heart disease, vertebral anomalies, asplenia, renal agenesis, hypospadias and structural brain defects [29]. Exposure between 14 and 20 weeks is associated with microcephaly, hydrocephalus, Dandy-Walker malformation, agenesis of the corpus callosum, midline cerebellar atrophy, seizures, spasticity, intellectual disability, optic atrophy, cataracts, microphthalmia, Peters anomaly and growth restriction, attributed mainly to fetal haemorrhage [29]. Most children with the classic embryopathy have normal cognitive development and retain the nasal malformation; upper airway obstruction is relieved by an oropharyngeal tube, and cervical instability has led in some cases to severe neurological dysfunction and sudden death [29]. Basu and colleagues described four cases with warfarin below 5 mg/day, one with Dandy-Walker malformation and another with laryngotracheomalacia and patent ductus arteriosus [67].

Maternal vitamin K deficiency. The three infants of Menger and colleagues had stippled calcifications, nasal hypoplasia and spinal anomalies, with cup-shaped ears in two and, in one each, Dandy-Walker malformation with hydrocephalus, congenital cataracts and peripheral pulmonary artery stenosis [31]. The eight patients of Toriello and colleagues, with a Binder phenotype with or without CDP, shared known or suspected maternal deficiency (hyperemesis, Crohn's disease), and brachytelephalangy was common [34]. Cortical dysplasia has been described in two infants with BCDP due to maternal deficiency, one of them with late-onset complex partial seizures, and grey matter heterotopias after hyperemesis [2]. In the review by Lane and colleagues, most newborns with embryopathy due to hyperemesis had only cosmetic consequences [7]. Severe maternal vitamin K deficiency can also cause fetal intracranial haemorrhage, as after gastric band slippage with prolonged vomiting [68]. The children of women with biliopancreatic diversion described by Onesimo and colleagues had a different picture, with psychomotor delay, microphthalmia, growth restriction and hearing loss, attributed mainly to vitamin A deficiency [69].

Maternal autoimmune disease. In the series of Chitayat and colleagues, cited by Blask, eight children with CDP born to mothers with SLE had nasal hypoplasia not detected prenatally; there were two in utero deaths, one death at 6 months and five survivors, three with respiratory symptoms, and a 9-year-old child developed autoimmune and neuropsychiatric disease, unilateral cataract and unilateral sensorineural hearing loss [24].

VKCFD. Coagulopathy is the distinguishing element: the infant of Grammatopoulos and colleagues presented with a subdural haematoma at 4 months [13].

3.7. Evolution with age

Flattening of the profile attenuates with growth and becomes less evident at around 5 to 8 months, according to the Blask series [24]. Stippling is no longer visible after 2 to 3 years, when the epiphyses ossify, which leads the Oxford Desk Reference to recommend requesting the early radiographs when an adult is referred [2, 12]. In the Swedish longitudinal study of 13 untreated children, all linear dimensions grew in parallel with normal but at a different level, and the differences present at early ages persisted to the end of growth [20]. Hosenfeld and Wiedemann illustrate the course into adulthood: a 32-year-old man with disproportionate short stature and facial dysmorphism, diagnosed in childhood with CDP considered autosomal dominant, turned out to be a case of embryopathy due to phenprocoumon given to his mother between 8 and 15 weeks of gestation in 1953 [70].

4. Clinical Recognition and Red Flags

4.1. Prenatal period

Suspicion arises in the presence of a flat fetal profile in the midsagittal plane, with absence or reduction of the angle between the forehead and the nose, a verticalised nasal bone and a small nose [52, 71, 72]. Assessment of the profile is part of the second-trimester anomaly scan according to the International Society of Ultrasound in Obstetrics and Gynecology (ISUOG) guidance cited by Andrietti and colleagues, and the phenotype has been identified at 13 weeks and 2 days (with confirmation at 17 weeks and 4 days), at 14 weeks and at 14.5 weeks [5, 7, 33]. In the presence of a flat profile, the maternal history should look for exposure to VKAs or phenytoin, severe hyperemesis with weight loss, inflammatory bowel disease, coeliac disease, intestinal or bariatric surgery, cholelithiasis and autoimmune disease, because these causes change the prognosis and counselling [7, 24, 33, 35]. The presence of other findings (short long bones, epiphyseal or vertebral stippling, cervical kyphosis, growth restriction, polyhydramnios, cardiac or brain anomalies) points to a syndromic cause or to CDP [6, 24, 63].

4.2. Newborn and infant

In the newborn, the combination of a flat, short nose, short columella and crescent-shaped nostrils should lead to examination of the distal phalanges (brachytelephalangy, short nails), skeletal radiographs before the stippling disappears, measurement of prothrombin time (PT) and review of the maternal history [2, 12, 13, 24]. In a boy, severe nasal hypoplasia with short distal phalanges suggests CDPX1 or a phenocopy [12, 45]. In a newborn with Binder phenotype and bleeding (including intracranial haemorrhage), VKCFD or acquired vitamin K deficiency should be considered [12, 13].

4.3. Older child, adolescent and adult

Many patients present to orthodontics or plastic surgery with the cosmetic complaint of a flat nose, anterior crossbite or missing incisors [21, 59]. In these patients, the diagnosis of CDP can no longer be made from stippling, but brachytelephalangy persists in the fingers and the neonatal radiographs, where they exist, should be retrieved [2, 12]. The adult seeking counselling may be unaware of the history of their own mother's pregnancy, which should be actively sought [12, 70].

4.4. Emergency signs

Table 4. Red flags and emergency signs

4.5. Newborn screening

There is no newborn screening directed at the Binder phenotype or its genetic causes. Universal vitamin K prophylaxis at birth, provided for in the summary of product characteristics (SmPC) of phytomenadione, is not intended to diagnose VKCFD, and Grammatopoulos and colleagues recommend a coagulation study in all newborns with a Binder phenotype [13, 73].

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Clinical criteria

There are no validated formal diagnostic criteria. Diagnosis of the phenotype is clinical and radiological, based on the six features of Keppler-Noreuil and Wenzel (arhinoid face, abnormal position of the nasal bones, intermaxillary hypoplasia with malocclusion, reduced or absent anterior nasal spine, atrophy of the nasal mucosa and absence of the frontal sinus) and, in the adult, on the palpable prenasal fossa and maxillary hypoplasia localised to the alar base [3, 9]. The Australian Craniofacial Unit draws attention to the frequent error of diagnosing a CDP as Binder syndrome [26]. Andrietti and colleagues point out that, even after testable causes have been excluded, some families are left with diagnostic uncertainty [5].

5.2. Prenatal ultrasound criteria

Cook and colleagues described, at 21 weeks, the flattened fetal nose in the midsagittal plane and the virtual absence of the nasofrontal angle, which gave the impression of a flat forehead and a small nose [71]. Levaillant and colleagues defined the Binder profile as a flat profile without nasal eminence, with nasal bones of normal length but verticalised, and abnormal convexity of the maxilla; according to the description reproduced by Andrietti, the nasofrontal angle lies between 150° and 160°, the convexity of the maxillary alveolar arch decreases in the transverse plane with an increase in width (calculated by the Rotten formula, MX = 0.75 × gestational age + 7.41, with a mean of 23 mm at 21 weeks) and, in the coronal plane, the philtrum disappears and there is mild hypertelorism [5, 52]. In a study of 195 normal fetuses between 18 and 21 weeks, the nasofrontal angle ranged between 110° and 143°, with a mean of 128°; Andrietti and colleagues therefore use the 143° threshold [5]. Blask and colleagues, with another normative reference (126° ± 7° between 14 and 39 weeks), retrospectively measured 135° to 162° in seven fetuses with Binder phenotype [24].

Table 5A. Prenatal imaging parameters of the Binder phenotype

5.3. Diagnostic algorithm

Table 5B. Stepwise approach to a Binder phenotype

5.4. Biomarkers

Prothrombin time and the international normalised ratio (INR) are prolonged in vitamin K deficiency mainly through the effect on factor VII; PIVKA-II rises before changes in global coagulation tests and is preferred to direct measurement of vitamin K; Lane and colleagues propose PT as screening and PIVKA-II as confirmation [7]. In the pregnant woman described by these authors, serum vitamin K at 21 weeks, already on enteral feeding, was 245 pg/mL (reference 80–1160 pg/mL) [7]. In the pregnant woman with cholelithiasis described by Jaillet and colleagues, factors II, VII and X were decreased and PT was abnormal at 11 weeks [35]. In CDPX1, PT, activated partial thromboplastin time and factors II, VII, IX and X are normal, which distinguishes it from VKCFD [2]. In the other CDPs, erythrocyte plasmalogens (RCDP) and plasma 8(9)-cholestenol and 8-dehydrocholesterol (CDPX2) are discriminating [2, 12].

5.5. Molecular tests and their limits

Detection of a pathogenic hemizygous ARSL variant in a boy with compatible findings establishes CDPX1; a variant of uncertain significance (VUS) neither confirms nor excludes the diagnosis, and enzyme activity assay is not available in clinical practice [2]. Sequencing detects small variants but not, in general, deletions of exons or of the whole gene, so a negative result should be followed by deletion/duplication analysis; the Y-chromosome pseudogene may complicate detection of deletions of some exons [2]. Xp22.3 deletions are detected by microarray [2]. The yield of exome with copy number variant (CNV) analysis was 4 of 50 fetuses with a pathogenic or likely pathogenic variant (8%), with relevant VUS in a further six [38]. In a series of 13 fetuses, fetal CT identified calcifications compatible with CDP in 10 (83%), compared with 5 (38%) by ultrasound, and hyoid calcifications in 3 (25%) [63]. Epiphyseal stippling was seen on ultrasound in 2 of 8 fetuses in the Washington series and in 6 on postnatal radiographs, MRI did not show it, and brachytelephalangy, present in 6 of 8 after birth, was not detected prenatally [24]. A negative exome does not exclude a genetic cause, and absence of stippling after 2–3 years does not exclude CDP [2, 38].

The molecular report should state the gene, the reference transcript with version (for ARSL, NM_000047.3, MANE Select), the variant in HGVS nomenclature, the zygosity (hemizygosity in males) and the classification according to the American College of Medical Genetics and Genomics and Association for Molecular Pathology (ACMG/AMP) criteria; testing the mother clarifies segregation and recurrence risk [2, 46].

5.6. Prenatal and preimplantation diagnosis

When the family's ARSL variant is known, prenatal diagnosis and preimplantation genetic testing are possible [2]. Outside this context, prenatal diagnosis relies on imaging (Table 5A) and on cytogenetic and molecular studies of amniotic fluid. Bosco and colleagues recommend, in a fetus with an apparently isolated Binder phenotype in the second trimester, microarray and FISH for ARSE (ARSL) deletion, reserving exome for cases with other signs or a family history [5, 6]. Fetal MRI helps to confirm the nostrils (excluding arhinia), the absence of fluid in the anterior nasopharynx and the shape of the alveolar ridge, and may show cervical kyphosis and C1 stenosis [24]. Fetal CT complements ultrasound in the search for calcifications [63]. Fetal autopsy confirmed the diagnosis in all terminated cases and fetal deaths in the Genoa series [5].

6. Differential Diagnosis

The differential diagnosis has two levels. The first is aetiological: in the presence of a Binder phenotype, it is important to identify the causes with implications for prognosis and recurrence (CDPX1, Xp22.3 deletions, VKCFD, maternal exposures and diseases, chromosomal and monogenic syndromes). The second is morphological: distinguishing the Binder nose from other nasal or midfacial hypoplasias. More than 50 conditions can present with a flat fetal profile, most with other anomalies [5].

6.1. Comparative table

Table 6. Differential diagnosis of the Binder phenotype

6.2. CDP and phenocopies of the vitamin K pathway

Maroteaux, describing BCDP in 1989, noted the similarity of the facial dysmorphism to Binder's “maxillofacial dysostosis” and stressed that the phalangeal anomaly allows diagnosis after the second year [78]. The most important distinction is between isolated Binder syndrome and the mild forms of CDP, because stippling disappears in the first years and some patients are seen only in adolescence [12, 24]. In the Washington series, seven of eight fetuses with confirmed CDP had a Binder phenotype, and the authors consider that the phenotype may exist in almost all aetiologies of CDP [24]. In Marseille, fetal CT identified CDP in 83% of fetuses with Binder phenotype [63], and in the review by Bosco, cited by Andrietti, 40% of prenatal cases had hereditary CDP, mainly CDPX1 [5]. Spranger and colleagues summarise the practical rules: warfarin embryopathy has the same phenotype as CDPX1; maternal SLE and maternal vitamin K deficiency are excluded by the maternal history; vitamin K-dependent coagulation defects are excluded by coagulation studies; the Conradi-Hünermann form has heteromorphic vertebrae, asymmetrical stippling, cataracts, ichthyosis and sparse hair and occurs in girls; RCDP has severe shortening of the humeri and femurs, coronal vertebral clefts and a severe course [45].

6.3. Nasal hypoplasia in other syndromes

Acrodysostosis shares maxillary hypoplasia with prognathism and transient neonatal stippling, but brachydactyly with cone-shaped epiphyses, advanced bone age and resistance to hormones acting through cyclic AMP (parathyroid hormone, thyroid-stimulating hormone, gonadotrophins) distinguish it; the PDE4D form has more severe maxillonasal hypoplasia and intellectual disability [75]. In Stickler syndrome, the flat nasal root of the infant grows well during childhood, there is no stippling and myopia with congenital vitreous anomaly is the discriminating sign; the face may, however, resemble that of CDP [12, 28]. In Keutel syndrome, maxillonasal hypoplasia and short phalanges may result from reduced growth secondary to abnormal calcification, and life expectancy appears normal [79]. Keutel syndrome should be considered in a child with tracheobronchial calcifications, midfacial hypoplasia and stippled epiphyses [56]. In the acrocephalosyndactylies, maxillary hypoplasia is accompanied by shallow orbits, proptosis and craniosynostosis, and the nasal flattening characteristic of Binder is absent [24]. In the prenatal period, identification of fluid-filled nostrils excludes arhinia [24]. Andrietti and colleagues also include, among the conditions with low nasal bones, Apert, Aarskog, Rüdiger and Robinow syndromes and trisomies 21 and 18 [5].

7. Treatment and Risk Management Strategies

7.1. General principles

There is no pharmacological treatment for the Binder phenotype. The approach combines resolution of neonatal complications (airway, feeding, coagulation), surveillance of associated features (cervical spine, hearing) and orthodontic and surgical correction of the face, adapted to age and cause [2, 14, 65]. A 2022 systematic review, registered in PROSPERO, included 24 studies (14 on surgical techniques and 10 on clinical features); 12 of the 14 surgical studies dealt with rhinoplasties and 2 with maxillary osteotomies, only 3 compared techniques, and the authors concluded that there is no optimal surgical plan [14]. The Australian Craniofacial Unit and the Gothenburg school recommend joint planning between orthodontists and maxillofacial and plastic surgeons, in a multidisciplinary setting [26, 80].

7.2. Neonatal period

Andrietti and colleagues advise, following a prenatal diagnosis, routine obstetric care with delivery in a tertiary centre prepared for possible immediate intubation, and Blask and colleagues mention the proposal of an otorhinolaryngologist in the delivery room [5, 24]. Nasal obstruction in the newborn may require an oropharyngeal tube, endonasal and gastric tubes, nasal or choanal stents and oxygen; in cases with extensive tracheobronchial calcifications, tracheostomy and tracheal reconstruction have been necessary [2, 29, 65]. In the Washington series, two infants required nasal dilatation for nostril stenosis and one intubation [24]. Silveira and colleagues treated upper airway obstruction due to narrowing of the nasal fossae, in a child with warfarin embryopathy, with a graft, Z-plasty and osteotomies of the piriform aperture [62]. Coagulation studies and correction of a deficiency of vitamin K-dependent factors are part of this phase [13].

7.3. Orthodontics and dentofacial orthopaedics

Tessier and colleagues propose treating the child's occlusal problems and orofacial dysfunctions as early as possible with an orthodontic face mask, reserving surgery for adulthood [65]. Evidence on the effect on growth is limited: in the longitudinal series of Olow-Nordenram and Thilander, 15 children treated with conventional orthodontics achieved acceptable dental conditions in 10, but there was no demonstrable influence on craniofacial growth compared with 13 untreated children, and six patients needed surgery as adults [80]. Because fewer than half of adults with Binder phenotype have true maxillary retrognathia, correction of the anterior crossbite may require mandibular setback instead of maxillary advancement [58]. In agenesis of the incisors and premaxilla, removable prosthetic rehabilitation is an option [59].

7.4. Nasal reconstruction

The techniques aim to project the tip and lengthen the dorsum, fill the prenasal region and reconstruct the columella. Table 7A summarises the series with quantified results.

Table 7A. Surgical series of nasomaxillary reconstruction in the Binder phenotype

The Australian Craniofacial Unit operated on 65 of 72 patients (90%), with a mean of 2.4 procedures per patient, 35 (54%) with completed treatment and a maximum follow-up of 18 years; there were postoperative complications in 18 patients (28%): partial necrosis of the maxilla, osteomyelitis of the mandible, neurapraxia of the facial nerve and of the inferior alveolar nerve, exposure of the nasal bone graft and cellulitis [26]. Nasal reconstruction in the Binder phenotype has also been reported in Brazil, at the University of São Paulo [86].

7.5. Skeletal and orthognathic surgery

Posnick and Tompson prospectively followed seven patients aged 16 to 20 years who underwent, between 1986 and 1992, a one-piece Le Fort I osteotomy fixed with four miniplates, with orthodontics, iliac grafting of the premaxilla in five and nasal augmentation with bone in six (four costochondral, one cranial, one iliac): mean maxillary advancement was 6.0 mm, with 5.9 mm maintained at one year; anterior vertical displacement went from 4.2 to 3.1 mm and posterior from 2.8 to 2.2 mm; all maintained positive overjet and overbite; one cranial graft dehisced through the nasal skin and was replaced [16]. Hao and colleagues treated 27 adults with nasomaxillary hypoplasia and class III with orthodontics and orthognathic surgery followed by rhinoplasty with costal cartilage: point A advanced 5.20 ± 1.43 mm, the SNA angle increased by 5.59 ± 2.86° and the nasolabial angle by 16.83 ± 6.65°, without serious complications and without evident graft resorption [87]. Le Fort II osteotomy with distraction osteogenesis was used in a 19-year-old man with Binder phenotype and repaired cleft lip and palate [88]. Delaire, Tessier and colleagues reserve osteotomy for patients whose occlusion remains abnormal after orthodontics; if occlusion is normal, surgery may be limited to repositioning the muscles of the nose and upper lip [65].

7.6. Timing of surgery

There are two strategies. The classic staged approach concentrates orthodontics in childhood and orthognathic surgery and nasal augmentation in adolescence or after the end of growth [16, 65, 80]. The early approach advocates correcting the nose in childhood — with serial tissue expansion and definitive rhinoplasty at the end of growth, or with costal cartilage grafts between 6 and 13 years — citing the psychological benefit without relevant disturbance of facial growth, but accepting more procedures [41, 85]. Bone grafts in children are associated with unpredictable growth and resorption [41]. The lack of direct comparisons precludes an evidence-based recommendation [14].

7.7. Cervical spine

Cervical instability may require a cervical collar or arthrodesis, and stenosis may require decompression; these indications come mainly from CDPX1 and coumarin embryopathy [2, 66]. The review by Vogel and Menezes showed neurological complications in 21% of patients treated conservatively and advocates regular neurological monitoring [66].

7.8. Vitamin K: correction of the deficiency in the child and in the pregnant woman

Phytomenadione (vitamin K1) does not correct the facial phenotype, but it is the treatment of deficiency of vitamin K-dependent factors in the child and of maternal deficiency. In VKCFD, oral vitamin K improves the coagulopathy without correcting the calcification abnormalities [44]. In the pregnant woman with deficiency, no guideline or trial sets a dose: Lane and colleagues report that 10 mg subcutaneously (SC) daily until laboratory correction was used successfully in case reports and that enteral or parenteral nutrition should ensure at least the adequate intake of 90 µg per day; Jaillet and colleagues propose intravenous supplementation as early as possible; Levaillant and colleagues recommend considering early prophylactic supplementation in all suspected acquired deficiency, including intractable vomiting of pregnancy [7, 35, 52]. This use for preventing embryopathy is extrapolated from the approved indications for hypoprothrombinaemia due to malabsorption and has no demonstrated efficacy on nasal development. The Portuguese SmPC of Kanakion MM® notes that vitamin K1 crosses the placenta poorly and does not recommend it in pregnant women for prophylaxis of haemorrhagic disease of the newborn, allowing use in pregnancy when the maternal benefit outweighs the risk [89]. The label approved by the US Food and Drug Administration (FDA) states that phytomenadione should be given to a pregnant woman only if clearly needed, because of the lack of animal reproduction studies and of data on fetal harm [90].

Table 7B. Phytomenadione: label doses for the relevant situations (no specific guideline for the Binder phenotype)

Table 7C. Regulatory status of phytomenadione

7.9. Prevention of vitamin K antagonist embryopathy

The 2025 ESC guideline on cardiovascular disease and pregnancy estimates the risk of embryopathy in the first trimester at between 0.6% and 12%, and that of fetopathy (central nervous system anomalies, intracranial haemorrhage) in later stages at between 0.7% and 2%; with low-dose warfarin, two systematic reviews found 0.45% to 0.9% embryopathy [17]. It defines low dose as that needed for the target INR with 5 mg/day or less of warfarin, 2 mg/day or less of acenocoumarol or 3 mg/day or less of phenprocoumon [17]. Smith's Recognizable Patterns cites an estimated incidence of 6.4% of fetal complications among exposed live births [29]. The ESC practical guidance for prevention is as follows [17]:

Table 7D. Anticoagulation in pregnancy and prevention of embryopathy (ESC 2025)

The guideline points out that no dose is safe for the fetus and that, with LMWH, neither embryopathy nor fetopathy has been described, but thromboembolic complications in mechanical prostheses are more frequent (8.7% with LMWH, 5.8% with unfractionated heparin and 2.7% with VKAs) [17]. The Portuguese case of Sousa and colleagues shows the limit of the low-dose strategy: a woman with mechanical mitral and aortic prostheses on warfarin 5 mg/day, who stopped the drug without medical advice between weeks 8 and 10 without other anticoagulation, had a newborn with signs of embryopathy and a ventricular septal defect [92]. Basu and colleagues described four cases with less than 5 mg/day [67]. The class and level of evidence of each recommendation are in the guideline tables, which were not extracted in text format.

7.10. Prevention and correction of maternal vitamin K deficiency

Deficiency should be considered in every pregnant woman admitted for hyperemesis, with inflammatory bowel disease or coeliac disease, intestinal or bariatric surgery, cholelithiasis or parenteral nutrition; screening with PT and, if prolonged, PIVKA-II is a reasonable approach, and nutritional support should include sufficient vitamin K, with the involvement of a dietitian [7, 35, 68]. Lane and colleagues cite the American College of Obstetricians and Gynecologists (ACOG) recommendation to correct ketosis and vitamin deficiencies in pregnant women with hyperemesis who need intravenous hydration [7]. After bariatric surgery with food intolerance, early vitamin replacement is indicated [68]. The possibility of preventing or attenuating the Binder phenotype with vitamin K supplementation has been raised, but the sources consulted do not describe studies that have tested it [24].

7.11. Clinical trials and recent developments

There are no clinical trials registered in ClinicalTrials.gov for “Binder syndrome”, “maxillonasal dysplasia” or “Binder phenotype” (search of 29 October 2026), nor drugs in development or regulatory procedures. The developments of the last 12 months are observational studies and case reports:

Table 7E. Developments (November 2025 to October 2026) and level of evidence

The lack of trials reflects the nature of the problem — a malformation pattern of diverse causes, treated surgically — and should not be read as proof that no intervention is under study.

7.12. Agents and circumstances to avoid, anaesthesia, pregnancy and transition

In patients with cervical instability, extreme neck extension and flexion and contact sports should be avoided, and imaging of the cervical spine should be performed before general anaesthesia [2]. This precaution is particularly relevant in the Binder phenotype, in which many patients undergo several facial operations and the prevalence of cervical anomalies is about 50% [5, 10, 26]. In women with a Binder phenotype who become pregnant, the recurrence risk and diagnostic options depend on the cause (Section 8); if they take VKAs, the ESC rules apply [17]. Transition to adult care often coincides with the phase of orthognathic surgery and definitive rhinoplasty, and requires continuity of the craniofacial team [16, 80].

8. Reproductive Options and Family Counselling

8.1. Recurrence risk according to cause

Counselling depends entirely on the identified cause, and the first task is to look for it, including in the parents, who should be carefully examined [28]. If the cause of the stippling or of the phenotype remains unknown, the Oxford Desk Reference recommends considering mildly affected parents (whose adult radiographs no longer show stippling but may show irregular bone growth), investigating the mother for malabsorption and SLE, and remembering that the adult consultand may be unaware of the history of their own mother's pregnancy [12].

Table 8. Recurrence risks by cause

In CDPX1, all mothers tested of boys with a detectable variant were carriers, and no de novo case has yet been described; carriers have no described disease [2]. Possible non-penetrance in carrier maternal grandfathers and the improvement of signs with age make careful examination of male relatives on the maternal side necessary [2].

8.2. Cascade testing and carrier detection

In CDPX1, testing of at-risk female relatives is most informative when the proband's variant is known; in its absence, sequencing followed by deletion/duplication analysis is performed [2]. At-risk male relatives, even if asymptomatic, benefit from genetic clarification for cervical, cardiac, ophthalmological and hearing surveillance [2]. Carrier detection is also possible by radiology or biochemistry in the CDPs for which markers exist [12].

8.3. Prenatal and preimplantation diagnosis and reproductive decision-making

With the familial ARSL variant known, prenatal diagnosis and preimplantation genetic testing are possible [2]. In pregnancies at risk because of maternal medication or SLE, ultrasound of the epiphyses and limb biometry complement surveillance [12]. Ultrasound shows the phenotype from the second trimester, but only very marked nasal hypoplasia is predicted with confidence, and in CDPX1 nasal hypoplasia and abnormal vertebral curvature were identified in the second and third trimesters [2, 28].

In the prenatal series, the decision to terminate the pregnancy was frequent: three of seven in the Genoa series, one of eight in Washington and 55% of the 50 fetuses in the exome series, where seven of 31 families who waited for the result terminated despite a negative or uncertain result; the decisions depended on the genetic findings, ultrasound severity, recurrence and previous experiences [5, 24, 38]. Bosco and colleagues stress that, when isolated, the Binder phenotype has good obstetric and neonatal outcomes, information that should be part of counselling [6]. Couples should receive counselling from a multidisciplinary team and emotional support, because part of the diagnostic uncertainty persists even after complete investigation [5].

8.4. Women of reproductive age on anticoagulation

Women with mechanical valve prostheses or other indications for VKAs should be counselled before conception about the teratogenic risk and the alternatives, according to the ESC [17]. The case of Hosenfeld and Wiedemann shows the weight of a correct diagnosis: a man with phenprocoumon embryopathy, wrongly classified as autosomal dominant CDP, believed he had a high risk of transmission and fathered a healthy son [70].

8.5. Minors

Counselling on the risk to offspring and reproductive options should be offered to young adult women who are affected, carriers or at risk, ideally before pregnancy [2]. In at-risk boys, early clarification is justified by cervical surveillance [2].

9. Special Considerations: Population Diversity and Epidemiology

9.1. Prevalence and what each number measures

There is no validated prevalence estimate; Orphanet classifies it as unknown [1]. The only population-based figure in the sources consulted comes from the Iowa (USA) active-surveillance registry, between 1998 and 2008: 24 cases with a Binder phenotype were identified, of which 8 met the specific criteria, corresponding to an incidence of about 1 per 18,000; the figure depends on the definition used and includes cases of known cause [3]. The frequency of “less than 1 per 10,000 live births” repeated in surgical and prenatal reviews has no identified population study in the sources [4, 5]. The remaining figures describe case series from specialist centres, not prevalences: 37 patients in 8 years in the series of Delaire and colleagues, 72 patients in 30 years at the Australian Craniofacial Unit, 92 patients operated on between 1972 and 1995 in Gothenburg, 33 patients at the Royal Children's Hospital in Melbourne and seven fetuses in 22 months at a prenatal diagnosis centre in Genoa, between 2021 and 2023 [5, 8, 15, 26, 57]. The Genoa authors acknowledge that this cluster may result from chance, greater attention from specialists or environmental factors, and point out that there is no evidence of an increase in congenital anomalies after COVID-19 infection or vaccination in the first trimester [5]. The number of published cases grew from fewer than 40 up to 1980 to a further 127 between 1980 and 1991 [8, 19].

As for the distribution of causes, the review of 47 prenatal cases, cited by Andrietti and colleagues, found 12.8% isolated cases without other postnatal anomalies, 19% possibly associated with non-hereditary maternal conditions (hyperemesis, autoimmune disease) and 40% with hereditary CDP, mainly CDPX1 [5, 6]. These proportions describe prenatally diagnosed cases, biased towards the more visible forms. CDPX1 has an unknown prevalence, estimated in one study at 1 per 500,000 and probably more frequent [2].

9.2. Sex, ancestry and founder populations

At the Australian Craniofacial Unit, 40 of the 72 patients were male and 32 female [26]. CDPX1 affects boys, whereas isolated Binder syndrome and the phenocopies affect both sexes [2, 12]. The sources consulted describe no founder variants or differences in frequency between ethnic groups. The published series come from Sweden, France, the United Kingdom, Italy, Germany (Fulda), Australia, the USA, China, India, Egypt, Nigeria and Brazil, showing a worldwide distribution with no known geographical pattern [3, 5, 20, 26, 38, 52, 59, 83, 85–87].

9.3. Portugal and Brazil

The sources consulted contain no epidemiological data on the Binder phenotype in Portugal or Brazil. From Portugal there are reports of warfarin embryopathy in children of women with valve prostheses, one of them with low-dose warfarin stopped without medical advice between weeks 8 and 10 [92, 94]. From Brazil there is an 8-year follow-up of a child with warfarin embryopathy in Porto Alegre and a report of nasal reconstruction in the Binder phenotype in São Paulo [62, 86]. In both countries, phytomenadione is available (Kanakion MM® in Portugal; Kavit®, Eskavit® and Vikatron® with active registration in Brazil) [89, 91].

9.4. Special populations

Pregnant women with severe hyperemesis, inflammatory bowel disease, coeliac disease, intestinal or bariatric surgery, cholelithiasis, transfusional iron overload, autoimmune disease or VKA anticoagulation make up the groups in which the phenotype may be preventable or in which its detection should change management [2, 7, 17, 35, 68]. Hyperemesis gravidarum affects 0.5% to 2% of pregnancies, and nausea and vomiting of pregnancy 70% to 85%, according to the references cited by Lane [7]. In low- and middle-income countries, the lower availability of anti-Xa assays, mentioned by the ESC, conditions the choice between VKAs and LMWH in women with mechanical prostheses [17].

9.5. European reference networks and patient associations

The relevant network is ERN CRANIO, dedicated to rare and/or complex craniofacial anomalies and ear, nose and throat disorders, including clefts and orodental anomalies [18]. In cases with CDP, ERN BOND, for rare bone diseases, is the reference network. Among associations, Headlines Craniofacial Support (United Kingdom) supports people with rare craniofacial conditions, and GeneReviews lists for CDPX1 the CDPX1 Family Support Group, Little People of America, the Human Growth Foundation, the MAGIC Foundation and the International Skeletal Dysplasia Registry of the University of California, Los Angeles [2, 95].

10. Illustrative Clinical Case

10.1. Binder phenotype due to vitamin K deficiency in hyperemesis gravidarum, detected at 14 weeks

Lane and colleagues, in Greenville (South Carolina, USA), described a 21-year-old African-American primigravida with nausea and vomiting from 7 weeks, with ketosis and weight loss of more than 5%, a diagnosis of hyperemesis gravidarum and no response to intravenous fluids, ondansetron, promethazine and metoclopramide [7]. She was referred to maternal–fetal medicine at 14 weeks, when her weight reached its nadir, with a loss of 17 kg (18% of pre-pregnancy weight). Gastroenteritis, hepatitis, appendicitis, pancreatitis, pyelonephritis and diabetic ketoacidosis were excluded; amylase, lipase, transaminases, creatinine and electrolytes were normal and there was marked ketonuria. She had no inflammatory bowel disease, coeliac disease, bulimia, bariatric surgery or chronic pancreatitis, and was not taking warfarin derivatives or vitamins A or E. The 14-week ultrasound showed a prominent forehead and flattened facial profile (Figure 1), without maternal bleeding diathesis [7].

At 15 weeks, because of worsening, she was admitted and a percutaneous endoscopic gastrojejunostomy tube was placed for enteral feeding with a supplement containing vitamin K; she also received correction of hypokalaemia and daily intravenous multivitamins, thiamine and folate [7]. The 21-week anomaly scan confirmed nasal hypoplasia, a flat profile and a prominent forehead, without other anomalies (Figure 3, three-dimensional reconstruction). She declined amniocentesis; cell-free fetal DNA screening indicated a male fetus at low risk for trisomies 21, 18 and 13. Serum vitamin K at that time was 245 pg/mL (reference 80–1160 pg/mL), interpreted as repletion of stores by enteral feeding [7].

At birth, the newborn had a hypoplastic nose, a high palate without cleft and a flattened face, without feeding difficulties on occupational therapy assessment; he passed newborn hearing screening and was discharged on the third day [7]. The paediatric geneticist confirmed the diagnosis of vitamin K deficiency embryopathy (Figure 4, profile at 2 months); radiographs of the hands, legs, hips and skull showed no CDP and, given the history, pedigree, examination and imaging, no other genetic tests were requested. The authors considered the long-term prognosis favourable and identified, in a literature search between 1997 and March 2015, eight previous cases of hyperemesis-related Binder phenotype, this being the ninth, the earliest and the first with ultrasound images [7].

Interpretation of the case. The case illustrates three points: severe hyperemesis with marked weight loss is a recognisable risk factor; the phenotype may be visible at the end of the first trimester, before the usual anomaly scan; and the absence of CDP on postnatal radiographs does not exclude an aetiology of vitamin K deficiency [7]. The replacement strategy used (enteral feeding with vitamin K) and the authors' suggestion of 10 mg of vitamin K SC daily derive from case reports; no guideline establishes them, and the diagnosis rested on clinical exclusion without molecular study, which today would include at least the exclusion of CDPX1 in a male fetus [6, 7].

10.2. Isolated Binder phenotype with a family history, Genoa series

In the series of Andrietti and colleagues, a 25-year-old primigravida with chronic hypertension, a previous admission for cholelithiasis and severe hyperemesis gravidarum, on ursodeoxycholic acid, labetalol and acetylsalicylic acid 150 mg, was referred at 21 weeks and 1 day for facial abnormalities on the anomaly scan; first-trimester combined screening had been low risk and nuchal translucency normal [5]. Targeted ultrasound, with three-dimensional reconstruction, showed a flat profile with a nasofrontal angle of 152.18° (threshold 143°), with no other structural anomalies and a normal fetal echocardiogram (Figure 1) [5]. There was a family history of craniofacial anomaly; the couple declined amniocentesis and continued the pregnancy. Fetal growth was normal; at 40 weeks and 3 days, because of diet-controlled gestational diabetes and hypertension, labour was induced, with vaginal delivery of a boy weighing 3210 g, Apgar scores 9 and 10, and confirmation of the facial dysmorphism [5]. The combination of hyperemesis, cholelithiasis and family history illustrates the overlap of maternal factors and possible genetic predisposition, which the study could not separate.

11. Prognosis and Long-term Follow-up

11.1. Prognosis

Prognosis depends on the cause and on the associated anomalies [5, 38]. When the phenotype is isolated, obstetric and neonatal outcomes are generally good, intellectual development is normal and the main problem is cosmetic and occlusal, with surgical and orthodontic treatment [5, 6]. Even in the isolated forms there is an increased risk of respiratory and feeding difficulty in the neonatal period, and the cervical spine has anomalies in about half of patients [5, 6, 10, 11]. In CDPX1, most patients have a normal life expectancy and signs that improve with age, but some have severe morbidity or early death due to respiratory compromise, cervical stenosis or instability [2]. In classic warfarin embryopathy, most children have normal cognitive development and retain the nasal deformity, but cervical instability has caused severe neurological dysfunction and sudden death in some cases, and second-trimester exposure is associated with brain lesions with intellectual disability [29]. In hyperemesis embryopathy, most newborns described had only cosmetic consequences [7]. In VKCFD, the risk of bleeding dominates the immediate prognosis [13]. In maternal autoimmune disease, the Chitayat series, cited by Blask, had two in utero deaths and one death at 6 months among eight cases [24].

The cosmetic results of surgery are durable in several series, with improvement of the facial convexity angle and nasolabial angle maintained for more than 5 years and stable maxillary advancement at one year, but they involve on average 2.4 procedures and secondary corrections in 19–25% [15, 16, 26, 40].

11.2. Surveillance

There is no specific surveillance protocol for the Binder phenotype. Table 11 combines the GeneReviews recommendations for CDPX1, applicable to the forms with CDP, with the recommendations of the Binder series for the cervical spine and craniofacial follow-up.

Table 11. Recommended surveillance

Resche and colleagues recommend examination of the skull and cervical spine in all patients with a Binder phenotype and regular surveillance of those with vertebral malformations, to detect neurological injury early [10].

12. Summary and Concluding Remarks

The Binder phenotype is a malformation pattern of the premaxilla and nasal complex — short, flat and vertical nose, short columella, absent anterior nasal spine, prenasal fossa and maxillary hypoplasia with a tendency to class III — that forms between 6 and 14 weeks, during growth of the nasal septum and ossification of the piriform aperture region [9, 42, 43]. The designation “syndrome” gave way to “phenotype” once its aetiological heterogeneity had been demonstrated [23, 24].

Most of the identifiable causes converge on the vitamin K pathway and cartilage mineralisation: CDPX1 due to ARSL and Xp22.3 deletions, vitamin K antagonist embryopathy, maternal vitamin K deficiency (hyperemesis, malabsorption, intestinal or bariatric surgery, cholelithiasis), VKCFD due to GGCX or VKORC1, and maternal autoimmune disease [2, 13, 29, 31, 33, 34]. Other causes, chromosomal and monogenic, have no known relation to that pathway [3, 37–39]. Many cases remain without a cause, with familial aggregation in a minority and unclarified inheritance [21, 25].

The diagnostic approach relies on the maternal history, skeletal radiological study before the stippling disappears, PT in the newborn, microarray and, in boys, ARSL testing, reserving exome for cases with other anomalies [6, 12, 13]. Prenatally, an increased nasofrontal angle, verticalised nasal bones and a widened maxillary arch allow diagnosis from the second trimester, sometimes in the first, and fetal MRI and CT help to look for CDP [5, 24, 63].

Treatment is mainly surgical and orthodontic, staged throughout growth, with no established optimal plan, with stable results in series with long follow-up and with a non-negligible rate of complications and reoperations [14, 15, 26]. Surveillance of the airway in the newborn and of the cervical spine at all ages, especially before anaesthesia, is the main safety measure [2, 10]. Possible prevention involves management of anticoagulation in pregnancy according to the 2025 ESC guideline and the detection and correction of maternal vitamin K deficiency [7, 17]. The recurrence risk is that of the identified cause; when none is found, the uncertainty should be explained.

13. References

1. Orphanet. Maxillonasal dysplasia (ORPHA:1248) [Internet]. Paris: INSERM; 2026 [cited 2026-10-29]. Available from: https://www.orpha.net/en/disease/detail/1248
2. Braverman NE, Bober MB, Brunetti-Pierri N, Suchy SF. Chondrodysplasia Punctata 1, X-Linked. 2008 Apr 22 [updated 2020 Oct 15]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2026. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1544/
3. Keppler-Noreuil KM, Wenzel TJ. Binder phenotype: associated findings and etiologic mechanisms. J Craniofac Surg. 2010;21(5):1339-45. doi:10.1097/SCS.0b013e3181ef2b71. PMID: 20818242.
4. Barbera G, Raponi I, Nocini R, Della Monaca M, Priore P, Valentini V. Secondary Rhinoplasty in Binder Syndrome: Considerations and Management of Complex Problem With Heterologous Bone Graft. J Craniofac Surg. 2021;32(1):e5-e8. doi:10.1097/SCS.0000000000006789. PMID: 32694479.
5. Andrietti S, Maccarrone A, Gullo G, Billone V, De Paola L, Gaggero C, et al. Prenatal Ultrasound Diagnosis of Binder Phenotype: Case Series of Seven Patients and Literature Review. Reports (MDPI). 2025;8(3). doi:10.3390/reports8030188. PMID: 41003474. PMC12473893.
6. Bosco M, Simonetto C, Loreti S, Grisolia G, Garzon S, Franchi M, et al. Obstetrics and neonatal outcomes of binder phenotype with antenatal diagnosis: A case report and literature review. J Gynecol Obstet Hum Reprod. 2024;53(10):102836. doi:10.1016/j.jogoh.2024.102836. PMID: 39181504.
7. Lane AS, Stallworth JL, Eichelberger KY, Trofatter KF. Vitamin K Deficiency Embryopathy from Hyperemesis Gravidarum. Case Rep Obstet Gynecol. 2015;2015:324173. doi:10.1155/2015/324173. PMID: 26347836. PMC4549487.
8. Delaire J, Tessier P, Tulasne JF, Resche F. Clinical and radiologic aspects of maxillonasal dysostosis (Binder syndrome). Head Neck Surg. 1980;3(2):105-22. doi:10.1002/hed.2890030205. PMID: 7440178.
9. Holmström H. Clinical and pathologic features of maxillonasal dysplasia (Binder's syndrome): significance of the prenasal fossa on etiology. Plast Reconstr Surg. 1986;78(5):559-67. doi:10.1097/00006534-198611000-00001. PMID: 3763743.
10. Resche F, Tessier P, Delaire J, Tulasne JF. Craniospinal and cervicospinal malformations associated with maxillonasal dysostosis (Binder syndrome). Head Neck Surg. 1980;3(2):123-31. doi:10.1002/hed.2890030206. PMID: 7440179.
11. Olow-Nordenram MA, Rådberg CT. Maxillo-nasal dysplasia (Binder syndrome) and associated malformations of the cervical spine. Acta Radiol Diagn (Stockh). 1984;25(5):353-60. doi:10.1177/028418518402500501. PMID: 6507129.
12. Firth HV, Hurst JA. Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. p. 98–100.
13. Grammatopoulos K, Harroche A, Peduto C, Vegas N, Mathonnet A, Baujat G, et al. Familial vitamin K metabolism deficiency responsible for a congenital binder phenotype. Arch Pediatr. 2025;32(6):420-422. doi:10.1016/j.arcped.2025.05.003. PMID: 40562611.
14. Kerbrat A, Ferri J. Surgical Treatment for Patients With Binder Syndrome, Clinical Features and Associated Symptoms: A Systematic Review. J Craniofac Surg. 2022;33(2):530-533. doi:10.1097/SCS.0000000000008325. PMID: 34711759.
15. Holmström H, Gewalli F. Long-term behavior of three different grafts in nasomaxillary reconstruction of binder syndrome: an analysis by digitalized measurements. Plast Reconstr Surg. 2008;122(5):1524-1534. doi:10.1097/PRS.0b013e3181881fde. PMID: 18971737.
16. Posnick JC, Tompson B. Binder syndrome: staging of reconstruction and skeletal stability and relapse patterns after LeFort I osteotomy using miniplate fixation. Plast Reconstr Surg. 1997;99(4):961-73; discussion 974-5. doi:10.1097/00006534-199704000-00004. PMID: 9091941.
17. De Backer J, Haugaa KH, Hasselberg NE, de Hosson M, Brida M, Castelletti S, et al. 2025 ESC Guidelines for the management of cardiovascular disease and pregnancy. Eur Heart J. 2025;46(43):4462-4568. doi:10.1093/eurheartj/ehaf193. PMID: 40878294.
18. European Reference Network for rare and/or complex craniofacial anomalies and ENT disorders (ERN CRANIO) [Internet]. [cited 2026-10-29]. Available from: https://www.ern-cranio.eu/
19. Greenberg SA. Binder's syndrome (nasomaxillary dysplasia): an uncommonly common disorder. J La State Med Soc. 1991;143(3):27-33, 35-8. PMID: 2026926.
20. Olow-Nordenram M. Maxillonasal dysplasia (Binder's syndrome). A study of craniofacial morphology, associated malformations and familial relations. Swed Dent J Suppl. 1987;47:1-38. PMID: 3499673.
21. Olow-Nordenram M, Valentin J. An etiologic study of maxillonasal dysplasia--Binder's syndrome. Scand J Dent Res. 1988;96(1):69-74. doi:10.1111/j.1600-0722.1988.tb01410.x. PMID: 3422508.
22. Online Mendelian Inheritance in Man, OMIM®. %155050 Maxillonasal dysplasia, Binder type [Internet]. Baltimore (MD): Johns Hopkins University [cited 2026-10-29]. Available from: https://omim.org/entry/155050
23. Quarrell OW, Koch M, Hughes HE. Maxillonasal dysplasia (Binder's syndrome). J Med Genet. 1990;27(6):384-7. doi:10.1136/jmg.27.6.384. PMID: 2359101. PMC1017137.
24. Blask AR, Rubio EI, Chapman KA, Lawrence AK, Bulas DI. Severe nasomaxillary hypoplasia (Binder phenotype) on prenatal US/MRI: an important marker for the prenatal diagnosis of chondrodysplasia punctata. Pediatr Radiol. 2018;48(7):979-991. doi:10.1007/s00247-018-4098-8. PMID: 29572747. PMC6365632.
25. Roy-Doray B, Geraudel A, Alembik Y, Stoll C. Binder syndrome in a mother and her son. Genet Couns. 1997;8(3):227-33. PMID: 9327267.
26. Chummun S, McLean NR, Nugent M, Anderson PJ, David DJ. Binder syndrome. J Craniofac Surg. 2012;23(4):986-90. doi:10.1097/SCS.0b013e31824e2683. PMID: 22777437.
27. Mazzone E, Cos Sanchez T, Persico N, Cannie MM, Jani J. Binder syndrome: a phenotype rather than a definitive diagnosis?. Ultrasound Obstet Gynecol. 2019;53(1):131-132. doi:10.1002/uog.19198. PMID: 30084160.
28. Firth HV, Hurst JA. Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. p. 242–244.
29. Jones KL, Jones MC, del Campo M. Smith's Recognizable Patterns of Human Malformation. 8th ed. Philadelphia: Elsevier; 2022. p. 796–797.
30. Online Mendelian Inheritance in Man, OMIM®. *300180 Arylsulfatase L; ARSL [Internet]. Baltimore (MD): Johns Hopkins University; last edited 2023-01-20 [cited 2026-10-29]. Available from: https://omim.org/entry/300180
31. Menger H, Lin AE, Toriello HV, Bernert G, Spranger JW. Vitamin K deficiency embryopathy: a phenocopy of the warfarin embryopathy due to a disorder of embryonic vitamin K metabolism. Am J Med Genet. 1997;72(2):129-34. PMID: 9382132.
32. Howe AM, Webster WS. The warfarin embryopathy: a rat model showing maxillonasal hypoplasia and other skeletal disturbances. Teratology. 1992;46(4):379-90. doi:10.1002/tera.1420460408. PMID: 1412066.
33. Colin E, Touraine R, Levaillant JM, Pasquier L, Boussion F, Ferry M, et al. Binder phenotype in mothers affected with autoimmune disorders. J Matern Fetal Neonatal Med. 2012;25(8):1413-8. doi:10.3109/14767058.2011.636105. PMID: 22082304.
34. Toriello HV, Erick M, Alessandri JL, Bailey D, Brunetti-Pierri N, Cox H, et al. Maternal vitamin K deficient embryopathy: association with hyperemesis gravidarum and Crohn disease. Am J Med Genet A. 2013;161A(3):417-29. doi:10.1002/ajmg.a.35765. PMID: 23404932.
35. Jaillet J, Robert-Gnansia E, Till M, Vinciguerra C, Edery P. Biliary lithiasis in early pregnancy and abnormal development of facial and distal limb bones (Binder syndrome): a possible role for vitamin K deficiency. Birth Defects Res A Clin Mol Teratol. 2005;73(3):188-93. doi:10.1002/bdra.20123. PMID: 15751048.
36. Kang L, Marty D, Pauli RM, Mendelsohn NJ, Prachand V, Waggoner D. Chondrodysplasia punctata associated with malabsorption from bariatric procedures. Surg Obes Relat Dis. 2010;6(1):99-101. doi:10.1016/j.soard.2009.05.004. PMID: 19640801.
37. Gatsis A, Alvanou M, Christidou E, Demertzidou E, Kontou A, Stathopoulou T, et al. Kabuki Syndrome: Case Report of Severe Prenatal Midface Hypoplasia (Binder Phenotype), due to a Novel Variant in the KMT2D Gene. Mol Syndromol. 2025;16(1):38-42. doi:10.1159/000540088. PMID: 39911174. PMC11793879.
38. Gupta S, Kanago D, Tilak P, Reddy BS, Indla G, Gowda M, et al. Binder Phenotype: Evaluating the Utility and Influence of Genetic Results on Parental Decision Making in Antenatally Diagnosed Cases. Am J Med Genet A. 2026;200(5):1055-1061. doi:10.1002/ajmga.70047. PMID: 41521578.
39. Hadzsiev K, Dávid D, Szabó G, Czakó M, Melegh B, Kosztolányi G. Partial trisomy of the pericentromeric region of chromosome 5 in a girl with binder phenotype. Cytogenet Genome Res. 2014;144(3):190-5. doi:10.1159/000369653. PMID: 25531548.
40. Gewalli F, Berlanga F, Monasterio FO, Holmström H. Nasomaxillary reconstruction in Binder syndrome: bone versus cartilage grafts. A long-term intercenter comparison between Sweden and Mexico. J Craniofac Surg. 2008;19(5):1225-36. doi:10.1097/SCS.0b013e31818435aa. PMID: 18812845.
41. Holmes AD, Lee SJ, Greensmith A, Heggie A, Meara JG. Nasal reconstruction for maxillonasal dysplasia. J Craniofac Surg. 2010;21(2):543-51. doi:10.1097/SCS.0b013e3181d024b0. PMID: 20216441.
42. Howe AM, Hawkins JK, Webster WS. The growth of the nasal septum in the 6-9 week period of foetal development--Warfarin embryopathy offers a new insight into prenatal facial development. Aust Dent J. 2004;49(4):171-6. doi:10.1111/j.1834-7819.2004.tb00069.x. PMID: 15762337.
43. Katsube M, Yamada S, Miyazaki R, Yamaguchi Y, Makishima H, Takakuwa T, et al. Quantitation of nasal development in the early prenatal period using geometric morphometrics and MRI: a new insight into the critical period of Binder phenotype. Prenat Diagn. 2017;37(9):907-915. doi:10.1002/pd.5106. PMID: 28675493.
44. Jin DY, Chen X, Wang M, Qi X, Stafford DW, Lewis S, et al. Molecular insights into the comorbidity of vitamin K-dependent clotting factor deficiency and chondrodysplasia punctata. J Thromb Haemost. 2025;23(12):3832-3844. doi:10.1016/j.jtha.2025.08.011. PMID: 40876756. PMC13455504.
45. Spranger JW, Brill PW, Hall C, Nishimura G, Superti-Furga A, Unger S. Bone Dysplasias: An Atlas of Genetic Disorders of Skeletal Development. 4th ed. Oxford University Press; 2018. p. 363–367.
46. Freeman PJ, Hart RK, Gretton LJ, Brookes AJ, Dalgleish R. VariantValidator: accurate validation, mapping, and formatting of sequence variation descriptions. Hum Mutat. 2018;39(1):61-68. doi:10.1002/humu.23348. PMID: 28967166.
47. Rajkumar J, Okoye AG, Belani P, Haque S, Greenough A. X-linked ARSL chondrodysplasia punctata: expanding the spectrum with a severe multisystem phenotype. Case Rep Perinat Med. 2026;15(1):20250031. doi:10.1515/crpm-2025-0031. PMID: 42591988. PMC13462689.
48. Mathonnet A, Cunat S, Allias F, Caillot S, Thonnon C, Till M, et al. GGCX-related congenital combined vitamin K-dependent clotting factors deficiency-1: Description of a fetus with chondrodysplasia punctata. Am J Med Genet A. 2022;188(1):314-318. doi:10.1002/ajmg.a.62503. PMID: 34558179.
49. Online Mendelian Inheritance in Man, OMIM®. #277450 Vitamin K-dependent clotting factors, combined deficiency of, 1; VKCFD1 [Internet]. Baltimore (MD): Johns Hopkins University [cited 2026-10-29]. Available from: https://omim.org/entry/277450
50. Online Mendelian Inheritance in Man, OMIM®. 118650 Chondrodysplasia punctata, autosomal dominant [Internet]. Baltimore (MD): Johns Hopkins University [cited 2026-10-29]. Available from: https://omim.org/entry/118650
51. Alessandri JD, Ramful D, Cuillier F. Binder phenotype and brachytelephalangic chondrodysplasia punctata secondary to maternal vitamin K deficiency. Clin Dysmorphol. 2010;19(2):85-87. doi:10.1097/MCD.0b013e328335c14a. PMID: 20177377.
52. Levaillant JM, Moeglin D, Zouiten K, Bucourt M, Burglen L, Soupre V, et al. Binder phenotype: clinical and etiological heterogeneity of the so-called Binder maxillonasal dysplasia in prenatally diagnosed cases, and review of the literature. Prenat Diagn. 2009;29(2):140-50. doi:10.1002/pd.2167. PMID: 19156647.
53. McHugh A, O'Sullivan MJ, Lynch SA, Heffernan C. Binder phenotype with palatal epulis in a girl with chromosome 5 duplication. Clin Dysmorphol. 2026;35(3):149-151. doi:10.1097/MCD.0000000000000560. PMID: 41817710.
54. Chawla N, Rajput M, Shriyan R, Bachani S, Gupta A. Clinical Observation of a Rare Binder Phenotype With Fetal Overgrowth Due to a SPIN4 Mutation. Matern Fetal Med. 2025;7(4):258-259. doi:10.1097/FM9.0000000000000298. PMID: 41158422. PMC12558193.
55. Gross-Kieselstein E, Har-Even Y, Navon P, Branski D. Familial variant of maxillonasal dysplasia?. J Craniofac Genet Dev Biol. 1986;6(3):331-4. PMID: 3771740.
56. Demirel G, Oguz SS, Celik IH, Erdeve O, Uras N, Dilmen U. A case of Keutel syndrome diagnosed in the neonatal period: associated with Binder phenotype. Genet Couns. 2012;23(1):25-30. PMID: 22611639.
57. Carach B, Woods M, Scott P. Maxillonasal dysplasia (Binder syndrome): a lateral cephalometric assessment. Aust Orthod J. 2002;18(2):82-91. PMID: 12462685.
58. Eliasson LA, Holmström H. Midface prognathism in maxillonasal dysplasia (Binder's syndrome) determined by a theoretical midface ratio. Int J Adult Orthodon Orthognath Surg. 1994;9(4):291-301. PMID: 7751761.
59. Akeredolu PA, Gbotolorun OM, Da Costa OO, Ogunlewe MO. Binder's maxillo-nasal dysplasia: report of a case. Odontostomatol Trop. 2007;30(118):5-8. PMID: 17933355.
60. Bharti L, Shrivastav S, Kamble RH, Bhargava A. Progressive Strategy for Congenitally Missing Anteriors in Binder Syndrome: A Case Report. Cureus. 2024;16(1):e52426. doi:10.7759/cureus.52426. PMID: 38371000. PMC10870340.
61. Rahul M, Shrivastava N, Tewari N, Mathur V. Dentofacial manifestations of fetal warfarin syndrome in a paediatric patient. BMJ Case Rep. 2022;15(1). doi:10.1136/bcr-2021-243890. PMID: 35039338. PMC8768003.
62. Silveira DB, da Rosa EB, de Mattos VF, Goetze TB, Sleifer P, Santa Maria FD, et al. Importance of a multidisciplinary approach and monitoring in fetal warfarin syndrome. Am J Med Genet A. 2015;167(6):1294-9. doi:10.1002/ajmg.a.36655. PMID: 25899236.
63. Bosselut H, Panuel M, Sigaudy S, Gorincour G, Chaumoitre K, Bretelle F. The complementary role of imaging modalities in Binder phenotype. Can prognostic factors of neonatal respiratory distress be found?. Prenat Diagn. 2019;39(7):549-562. doi:10.1002/pd.5469. PMID: 31046133.
64. Blumenfeld YJ, Davis AS, Hintz SR, Milan K, Messner AH, Barth RA, et al. Prenatally Diagnosed Cases of Binder Phenotype Complicated by Respiratory Distress in the Immediate Postnatal Period. J Ultrasound Med. 2016;35(6):1353-8. doi:10.7863/ultra.15.02050. PMID: 27162279.
65. Tessier P, Tulasne JF, Delaire J, Resche F. Therapeutic aspects of maxillonasal dysostosis (Binder syndrome). Head Neck Surg. 1981;3(3):207-15. doi:10.1002/hed.2890030308. PMID: 7461980.
66. Vogel TW, Menezes AH. Natural history and management of cervical spine disease in chondrodysplasia punctata and coumarin embryopathy. Childs Nerv Syst. 2012;28(4):609-19. doi:10.1007/s00381-012-1694-z. PMID: 22274407.
67. Basu S, Aggarwal P, Kakani N, Kumar A. Low-dose maternal warfarin intake resulting in fetal warfarin syndrome: In search for a safe anticoagulant regimen during pregnancy. Birth Defects Res A Clin Mol Teratol. 2016;106(2):142-7. doi:10.1002/bdra.23435. PMID: 26389802.
68. Van Mieghem T, Van Schoubroeck D, Depiere M, Debeer A, Hanssens M. Fetal cerebral hemorrhage caused by vitamin K deficiency after complicated bariatric surgery. Obstet Gynecol. 2008;112(2 Pt 2):434-6. doi:10.1097/AOG.0b013e3181649e7b. PMID: 18669754.
69. Onesimo R, Proli F, Leoni C, Contaldo I, Salerni A, Conti G, et al. Embryopathy Following Maternal Biliopancreatic Diversion: Is Bariatric Surgery Really Safe?. Obes Surg. 2021;31(1):445-450. doi:10.1007/s11695-020-04882-w. PMID: 32720264.
70. Hosenfeld D, Wiedemann HR. Chondrodysplasia punctata in an adult recognized as vitamin K antagonist embryopathy. Clin Genet. 1989;35(5):376-81. doi:10.1111/j.1399-0004.1989.tb02957.x. PMID: 2758688.
71. Cook K, Prefumo F, Presti F, Homfray T, Campbell S. The prenatal diagnosis of Binder syndrome before 24 weeks of gestation: case report. Ultrasound Obstet Gynecol. 2000;16(6):578-81. doi:10.1046/j.1469-0705.2000.00259.x. PMID: 11169356.
72. Cuillier F, Cartault F, Lemaire P, Alessandri JL. Maxillo-nasal dysplasia (binder syndrome): antenatal discovery and implications. Fetal Diagn Ther. 2005;20(4):301-5. doi:10.1159/000085090. PMID: 15980645.
73. INFARMED. Kanakion MM Pediátrico 2 mg/0,2 ml solução injetável (fitomenadiona): resumo das características do medicamento. Holder: CHEPLAPHARM Arzneimittel GmbH. Infomed, med_id 4765 [cited 2026-10-29]. Available from: https://extranet.infarmed.pt/INFOMED-fo/download-ficheiro.xhtml?med_id=4765&tipo_doc=rcm
74. Online Mendelian Inheritance in Man, OMIM®. #607473 Vitamin K-dependent clotting factors, combined deficiency of, 2; VKCFD2 [Internet]. Baltimore (MD): Johns Hopkins University [cited 2026-10-29]. Available from: https://omim.org/entry/607473
75. Jones KL, Jones MC, del Campo M. Smith's Recognizable Patterns of Human Malformation. 8th ed. Philadelphia: Elsevier; 2022. p. 626–627.
76. Online Mendelian Inheritance in Man, OMIM®. #101800 Acrodysostosis 1 with or without hormone resistance; ACRDYS1 [Internet]. Baltimore (MD): Johns Hopkins University [cited 2026-10-29]. Available from: https://omim.org/entry/101800
77. Online Mendelian Inheritance in Man, OMIM®. #614613 Acrodysostosis 2 with or without hormone resistance; ACRDYS2 [Internet]. Baltimore (MD): Johns Hopkins University [cited 2026-10-29]. Available from: https://omim.org/entry/614613
78. Online Mendelian Inheritance in Man, OMIM®. #302950 Chondrodysplasia punctata 1, X-linked recessive; CDPX1 [Internet]. Baltimore (MD): Johns Hopkins University [cited 2026-10-29]. Available from: https://omim.org/entry/302950
79. Online Mendelian Inheritance in Man, OMIM®. #245150 Keutel syndrome; KTLS [Internet]. Baltimore (MD): Johns Hopkins University [cited 2026-10-29]. Available from: https://omim.org/entry/245150
80. Olow-Nordenram M, Thilander B. The craniofacial morphology in persons with maxillonasal dysplasia (Binder syndrome). A longitudinal cephalometric study of orthodontically treated children. Am J Orthod Dentofacial Orthop. 1989;95(2):148-58. doi:10.1016/0889-5406(89)90393-4. PMID: 2916471.
81. Holmström H. Surgical correction of the nose and midface in maxillonasal dysplasia (Binder's syndrome). Plast Reconstr Surg. 1986;78(5):568-80. PMID: 3763744.
82. Rune B, Aberg M. Bone grafts to the nose in Binder's syndrome (maxillonasal dysplasia): a follow-up of eleven patients with the use of profile roentgenograms. Plast Reconstr Surg. 1998;101(2):297-304; discussion 305-6. doi:10.1097/00006534-199802000-00005. PMID: 9462760.
83. Draf W, Bockmühl U, Hoffmann B. Nasal correction in maxillonasal dysplasia (Binder's syndrome): a long term follow-up study. Br J Plast Surg. 2003;56(3):199-204. doi:10.1016/s0007-1226(03)00099-7. PMID: 12859914.
84. Tian L, You J, Wang H, Zhang B, Xu Y, Lu X, et al. Comparison of Two Different Grafts in Nasal Framework Reconstruction of Binder Syndrome: Cartilage and Silicone. J Craniofac Surg. 2017;28(6):1413-1417. doi:10.1097/SCS.0000000000003660. PMID: 28796097.
85. Afifi T, Saleh D, Shaker A. Our Strategy in Management of Maxillonasal Dysplasia in Pediatric Patients. J Craniofac Surg. 2021;32(3):1037-1041. doi:10.1097/SCS.0000000000007188. PMID: 34779597.
86. Arroyo HH, Olivetti IP, Santos VGW, Weber R, Jurado JRP. Nasal reconstruction in Binder syndrome. Braz J Otorhinolaryngol. 2017;83(4):488-489. doi:10.1016/j.bjorl.2015.08.017. PMID: 26541235. PMC9442711.
87. Hao J, Al-Watary MQ, He Y, Wei Y, Zhao Q, Li J. Stepwise surgical management of binder syndrome with skeletal class III malocclusion in adults. J Craniomaxillofac Surg. 2024;52(11):1211-1218. doi:10.1016/j.jcms.2024.03.029. PMID: 39181744.
88. Jawade S, Kantode VV, Wanjari MB, Meghe A, Sharma DR, Wankhede P, et al. A Periodic Case of Maxillo-Nasal Dysplasia or Binder Syndrome Successfully Operated With Bilateral Le Fort II Osteotomy With Distraction Osteogenesis. Cureus. 2022;14(9):e29706. doi:10.7759/cureus.29706. PMID: 36320970. PMC9616321.
89. INFARMED. Kanakion MM 10 mg/1 ml solução injetável (fitomenadiona): resumo das características do medicamento. Holder: CHEPLAPHARM Arzneimittel GmbH. Infomed, med_id 4764 [cited 2026-10-29]. Available from: https://extranet.infarmed.pt/INFOMED-fo/download-ficheiro.xhtml?med_id=4764&tipo_doc=rcm
90. Fresenius Kabi USA. Phytonadione injectable emulsion, USP 10 mg/mL: prescribing information (ANDA219212) [Internet]. Silver Spring (MD): U.S. Food and Drug Administration; 2025 Apr 17 [cited 2026-10-29]. Available from: https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=02a39690-38e6-42e9-9897-391c2df9e07e
91. Agência Nacional de Vigilância Sanitária (ANVISA). Dados abertos: medicamentos registados no Brasil (DADOS_ABERTOS_MEDICAMENTOS.csv) [Internet]. Brasília: ANVISA [cited 2026-10-29]. Available from: https://dados.anvisa.gov.br/dados/DADOS_ABERTOS_MEDICAMENTOS.csv
92. R Sousa A, Barreira R, Santos E. Low-dose warfarin maternal anticoagulation and fetal warfarin syndrome. BMJ Case Rep. 2018;2018. doi:10.1136/bcr-2017-223159. PMID: 29627779. PMC5893982.
93. Deng Q, Wang W, Wang M, Wu Y, Jin Y, Zhou X, et al. Fetal chondrodysplasia punctata: a clinical study of five cases. Am J Transl Res. 2026;18(4):3182-3189. doi:10.62347/XMJV3287. PMID: 42170480. PMC13186731.
94. Ferreira S, Costa R, Malveiro D, Vieira F, Tuna M. Warfarin embryopathy: Balancing maternal and fetal risks with anticoagulation therapy. Pediatr Neonatol. 2018;59(5):534-535. doi:10.1016/j.pedneo.2018.02.005. PMID: 29501347.
95. Headlines Craniofacial Support [Internet]. United Kingdom [cited 2026-10-29]. Available from: https://www.headlines.org.uk/