*           Department Of Gynecology, Félix Guyon’hospital, 97400 Saint-Denis, Ile De La Réunion, France.

**         Cyto-Genetician, Department Of Genetic, 97440 Saint-Denis, Ile De La Réunion.

***        Department Of Neonatology, Félix Guyon’hospital, 97400Saint-Denis, Ile De La Réunion.

Definition :

Binder phenotype (Binder phenotype), also known maxillo-nasal dysplasia or dysostosis (MND), is an uncommon developmental anomaly affecting the anterior part of the maxilla and nasal complex. Binder phenotype is characterized by midface hypoplasia with absence of anterior nasal spine leading to a characteristic facial dysmorphism^1-2, with: flat profile with convex upper lip, short nose with flat or depressed nasal bridge, obtuse or flat fronto-nasal angle, short columella, with normal philtrum, acute naso-labial angle with peri-alar flatness.

There are different etiologies or syndromes associated with Binder phenotype, some with benign prognosis and others with very poor prognosis. Binder phenotype with benign etiology has a tendency to be a class III malocclusion, revealing itself during adolescence with prognathism and sometimes hypoplasia of the frontal sinus ^2-3.

Synonym :

Binder phenotype (BP); maxillo-nasal dysplasia (MND); maxillo-nasal dysostosis (MND); binder syndrome (but this last one must be forgotten).

History:

The Binder phenotype oldest case was recently reported by an anthropologist, Mulhern (2002). He described a probable case of Binder phenotype in a female skeleton (16 or 17 years at age of death), from Quarai, New Mexico (AD 1375-1450)⁴.

Binder phenotype was secondly described by Noyes in 1939 and by Zuckerland in 1882, called at the time, “congenital flat nose syndrome”⁵.

In 1962, Binder reported a condition which he called maxillo-nasal dysplasia ³. The kids had a short nose, with a flat bridge, a short columella, an acute naso-labial angle, perialar nose, a convex upper lip. Later, Binder phenotype seen in those adolescents have a tendency to be classified as a class III malocclusion. In the three original cases described by Binder, Binder phenotype seemed isolated.

In 1968, “Fetal Warfarin syndrome” was initially described by Kerber.

In 1976, Sheffield described 23 cases of brachytelephalangic chondrodysplasia punctata associated with Binder phenotype. Some patients had facial similarities with mild forms of chondrodysplasia punctata. He concluded that patient with Binder phenotype had a heterogeneous condition caused by various genetic (intrinsic) and extrinsic factors with chondrodysplasia punctata underlying most of the case, rather than a distinct entity⁶.

Gorlin (1976) considers that maxillo-nasal dysplasia was neither a nosologic nor syndromic entity, but rather a surgical entity. According to this author, the likeliness with certain form of brachytelephalangic chondrodysplasia punctata was stricking, and as Sheffield⁶, Gorlin was certainly the first author who sugested that Binder phenotype should be a subsidiary “symptom” of chondrodysplasia punctata. At this time, about 200 cases have been described mainly by plastic and reconstructive surgeons⁷.

Hall (1980) described also Coumarinic foetopathy (with stippled epiphyses, consequence of vitamin K deficiency) in 24 cases of 418 pregnancy with anti-vitamin K treatment (began between 6 and 9 weeks). It was chondrodysplasia punctata with Binder phenotype. The authors estimated the foetopathy risk to be 6 %.

Holmström, in 1986, reported the first series of fifty cases of Binder phenotype¹.

Toriello (1987), considered Binder syndrome as a phenotype, and not a syndrome, possibly related in many cases to probably prenatal deficiency of vitamin K².

Quarrel (1990) used either the term Binder “phenotype”, or “association”, instead of the word “syndrome”⁸.

First prenatal diagnosis of Binder phenotype was published in 2000, by Cook⁹. TOP was practiced, as “a serious syndrome could not be totally excluded”. The authors wrote that the similarities of the Binder syndrome features with the facial markers of chondrodysplasia punctata, would suggest that there is an underlying relation between Binder syndrome and chondrodysplasia punctata.

Eash (2003) described certainly the first case of Binder phenotype with vertebral stippling, consequence of intractable vomiting with severe vitamin K deficiency¹⁰.

Our team described in 2005, the second antenatal case¹. Unfortunately, we did not know at this time, the relationship between hypovitaminosis K and brachytelephalangic chondrodysplasia punctata with Binder phenotype. Alessandri (2010) studied again this case, and finally, Binder phenotype etiology was established: the fetal consequence of hypovitaminosis K during the first trimester of the pregnancy by hyperemesis gravidarum.

Levaillant (2009) presented eight fetuses referred for Binder phenotype. This series demonstrates the heterogeneity etiology of prenatal diagnosed of Binder phenotype². Binder phenotype was observed in half the siblings born to a mother with auto-immune disease.

Prevalence :

The overall incidence of fetal nasal malformations is approximatively 1 / 1600. But the real incidence of this Binder phenotype is actually unknown, in either the prenatal or postnatal population^2-9.

Etiology :

Binder phenotype can be isolated or Binder phenotype can be a part of different syndromes:

Majority of cases of Binder phenotype are sporadic. Nevertheless, familial occurrence has been reported by different authors¹¹. In these cases, transmission would be autosomal dominant or would be with multifactorial inheritance. But, autosomal dominant transmission of isolated Binder phenotype reported in some cases, is doubtful for other authors².

Nevertheless, other syndromes with Binder phenotype need to be excluded:

• Chromosomal abnormalities: Binder phenotype can be associated with Trisomy 21 : so, karyotype is necessarily proposed. However, 4p deletion must be eliminated.
• Vitamin K deficit in early embryogenesis (specially between 5 and 9 weeks ): must be strictly eliminated¹². This  can be secondary to:
• Maternal diseases: disruption of vitamin K metabolism : Sheffield et al. (1976)⁶ showed that patients with Binder phenotype had facial similarities with mild forms of chondrodysplasia punctata. According with theses authors, Binder phenotype was a heterogeneous condition caused by various genetic and extrinsic factors as AVK^13-14-15.
• Exposures to teratogens: fetal alcohol syndrome is described with Binder phenotype and with stippled epiphyses. Pathogenesis remains obscure¹⁶.
• Inherited or extrinsic factors disrupting maternal vitamin k metabolism are known to result in brachytelephalangic Chondrodysplasia punctata with Binder phenotype¹⁴. Chondrodysplasia punctata, X-linked recessive, brachytelephangic type is the main of Binder phenotype. ARSE gene is also responsible^17-18.
• Systemic Lupus Erythematosus (SLE): Austin-Ward (1998), Elçioglu with hall (1998), and Kelly (1999) described Binder phenotype with stippled epiphyses, mimicking fetal Warfarin syndrome, in a woman affected by Systemic Lupus Erythematosus ^2-19. Vitamin K deficiency may be related to the presence of circulating anticoagulant or antiphospholipid antibodies according with different authors.
• Inborn errors of metabolism diseases: including :

-Peroxisomal disorders or lysosomal storage disorders.

-Abnormalities of cholesterol biosynthesis.

Pathogenesis :

Clinical similarities, biological and molecular data convey a majority of brachytelephalangic chondrodysplasa punctata with Binder phenotype to a disruption of the same metabolic pathway: the vitamin K cycle²¹. Indeed, hydroxy-vitamin K is essential for the maturation of Glutamic Acid proteins, including coagulation factors (II, VII, IX, X), coagulation inhibitors (protein C, S) as well as bone Glutamic Protein (Osteocalcin) and cartilage Matrix-Gla-Protein (MPG). Hydroxy-vitamin K is the coenzyme of a vitamin K-Dependant Carboxylase that transforms Glutamate residues of the Gla-Proteins into Carboxyglutamate (figure 1). Matrix-Gla-Protein, a vitamin K dependant protein, synthesized by the growth plate cartilage and present in all unmineralized cartilages, inhibits hydroxyapatite formation in vitro, an ability lost in decarboxylated Matrix-Gla-Protein ¹².

Figure 1:  The vitamin K cycle

Three mechanisms can lead to a deficiency of vitamin K dependent carboxylation and cause striking phenotypic similarities with CDPX1.

1.      First : maternal administration of Coumarinic derivatives between the 6th and 9th weeks, leads to vitamin K deficiency and causes Warfarin embryopathy^15-21.

2.      Second: maternal chronic diseases with vitamin K deficiency during first trimester of pregnancy have resulted in infants with phenocopy of Warfarin embryopathy or CDPX1. These multiple maternal conditions included:

• Untreated celiac disease¹³
• Short bowel syndrome secondary to surgical tumor resection, jejuno-ileal bypass for morbid obesity
• Ileocaecal resection and duodeno-jejunostomy for idiopathic chronic intestinal obstruction.
• Intestinal obstruction secondary to a small bowel carcinoma, pancreatitis²².

Intractable vomiting during early pregnancy (hyperemesis gravidarum)^2-22 : indeed, series of cases with significant signs of vomiting, secondary maternal weight loss, and undernutrition have documented vitamin K deficiency. Thus, Matrix-Gla-Protein, a vitamin K-dependent protein which presents in all unmineralized cartilages, is deficient. Hyperemesis gravidarum is also a risk of fetal intra-cranial non-obstructive hydrocephalus due to vitamin K deficiency^23-24.

It is important to note that mutations of Matrix-Gla-Protein results in Keutel syndrome (OMIM 245150), a rare chondrodysplasia with midface hypoplasia, short terminal phalanges and abnormal cartilage calcifications (as on larynx)²⁵. All these data suggest that Decarboxylated Matrix-Gla-Protein is most likely to be responsible for the ectopic cartilage calcifications in chondrodysplasia punctata secondary to vitamin K metabolism disruption.

3.      Third : congenital deficit of Vitamin K Epoxide Reductase, due to homozygous mutations in the gene encoding the subunit 1 of the Vitamin K Epoxide Reductase (VKORC1) is responsible for the so-called Pseudo-Warfarin embryopathy²¹. But, this disease is really exceptionnal.

Sonographic findings :

During antenatal period, ultrasound findings of Binder phenotype are flat profile, verticalized basal bones, with retraction of the maxilla^1-2. According to the facial criteria analysis of Talmand²⁶, we can easily observe prenatal ultrasound images of Binder phenotype, which are typically the same :

• Flat naso-frontal angle : measured between 150° and 160° (normal values = 135°).   Abnormal flatness of the premaxillar area in the maxilla : measured between 34° and 46° (normal values = 26°)².
• Nasal bones : are always of normal sizes.
• Philtrum length: is normal.
• Epiphyseal stippling: can be found.

Chondrodysplasia punctata is a etiologically heterogeneous condition characterized by punctate calcifications secondary to abnormal deposition of calcium during endochondral bone formation. Chondrodysplasia punctata is diagnosed due to a clinical appearance and radiology. On radiographs, punctuate calcifications are observed in the epiphyses of the long bones, vertebrae, or in cartilaginous regions usually not calcified such as the trachea, larynx or rib ends.

Implications for targeted examinations :

When discovering an antenatal Binder phenotype, the entire fetal skeleton must be closely examined. Articular punctuations must be searched to rule out brachytelephalangic chondrodysplasia punctata.

Associated anomalies :

Malformations of the cervical spine are described in 50% of the patients²⁷ : the most common are

• Defective anterior or posterior wall of the axis and atlas.
• Fused vertebrae.
• Persistence of chorda dorsalis.

Stippling epiphyses : are possible.

Recurence risk :

Reccurence risk depends on etiology.

Differential diagnosis:

The main differential diagnosis of isolated Binder phenotype are:

1. Dyschromosomia: karyotype analysis will retablish² the diagnosis.

2. Chondrodysplasia punctata (brachytelephalangic chondrodysplasia punctata): are heterogenic diseases, which is reported in primilarly inherited diseases (including peroxisomal disorders, abnormalities of cholesterol biosynthesis or lysosomal storage) and sometimes, in acquired conditions secondary to maternal diseases or exposures to teratogens.

Some authors have suggested a biochemical and molecular based classification of chondrodysplasia punctata in two main groups:

- Metabolic congenital abnormalities - Disruption of vitamin K metabolism: inherited or extrinsic factors disrupting maternal vitamin K metabolism (as hyperemesis gravidarum ) are known to result in brachy-telephalangic with Binder syndrome²⁸.

• Coumarinic secondary effect:
• Vitamin K Epoxyde Reductase Defect
• Vitamin K deficit: by malabsortion or hyperemesis gravidarum .

3.   The brachytelephalangic chondrodysplasia punctata, X-linked recessive (or CDPX1), MIM 302950: is the main differential diagnosis of Binder phenotype. Congenital CDPX1 is caused by a deficiency the golgi enzyme, by mutations of ARSE localized in Xp22.³. Arse encodes Arylsulfatase E, a golgi enzyme whose activity is inhibited in vitro by Warfarin^17-23. This syndrome is characterized by hypoplasia of distal phalanges, stippled epiphyses and vertebrae and Binder phenotype¹⁸. This disorder is frequently benign in most affected males, but some have significant medical problems such as respiratory difficulty and cervical spine compression.

4.   The brachytelephalangic chondrodysplasia punctata, X-linked dominant

5.  Keutel syndrome, MIMS 245150: is a heterogeneous condition characterized by punctated calcifications secondary to abnormal deposition of calcium during endochondral bone formation²⁵. On radiographs, punctate calcifications are observed in the epiphyses of the long bones, vertebrae, or in cartilaginous regions which are usually not calcified such as the trachea, larynx or rib ends.

6.    Robinow syndrome: flat face; short forearms; clinodactyly with macrocephaly; autosomal dominant.

7.    Marschall syndrome: is characterized by saddle nose, deafness cataract and myopia.

8.  Aarskog–Scott syndrome  or facio-digito-genital syndrome: is X-linked recessive. Brachydactyly and shawl scrotum are the main features.           9.    Crouzon and Apert Syndrome: associated craniosynostosis and hand block (autosomal dominant).         10.    Rudiger syndrome and Stickler syndrome: will be eliminated too, because the fetal profile is more severe and there is other associated dysmorphology.

Prognosis :

The prognosis of a fetus affected by an isolated Binder phenotype is excellent. Later, during adolescent period, the faces will can be surgically corrected and improved by orthodontics or plastics surgeons. Nevertheless, some kids grow toward adulthood, the facial features can have a natural correction. Intelligence is always normal.

Nevertheless, according to Herman²⁵, the cervical spine is abnormal in 50% of the cases. The atlas and the axis are frequently involved. Different anomalies include short posterior arch, block vertebral, separate odontoid process, spina bifida occulta and persistence of chorda dorsalis²².

The prognosis of Binder Phenotype, associated with other syndrome is dependent of the type of the associated syndrome¹¹.

Management :

The patient reported here, had clinical features of isolated brachytelephalangic chondrodysplasia punctata with Binder syndrome. We described on the thefetus.net, six years ago, the second antenatal Binder phenotype diagnosis, but, later, we discovered that Vitamin K deficiency (during first trimester, important hyperemesis gravidarum  with low Prothombin time) was in fact, responsible for it . We will conclude:

Firstly, during second trimester, normal profile on ultrasound is fundamentally exclude facial abnormalities. However, in France, according to the latest recommendations, fetal profile analysis is not part of the sonogram, we believe that the sonogram is nevertheless essential in an ultrasound screening.

Secondly, our observation confirms that intractable hyperemesis gravidarum in early pregnancy is a risk for embryologic consequences due to maternal Vitamin K deficiency. According to other authors^2-22-24, early maternal vitamin K supplementation in pregnant women with undernutrition, including hyperemesis gravidarum, seem absolutely necessary.

Prenatal examination steps for Binder phenotype should include fetal karyotype to exclude dyskaryotype and helicoidal scan to exclude stippling.

References :

1-      Cuillier F., Cartault F., Lemaire P., Alessandri J.L. Maxillo-Nasal Dysplasia (Binder Syndrome): Antenatal discovery and implications. Fetal Diagn Ther 2005 ; 20: 301-305.

2-      Levaillant J.M., Moeglin D., Zouiten K., Bucourt M., Burglen L., Soupre V., Baumann C., Jaquemont M.L., Touraine R., Picard A., Vuillard E., Belarbi N., Oury J.F., Verloes A., Vazquez M.P., Labrune P., Delezoide A.L., Gerard-Blanluet M. Binder Phenotype: clinical and etiological heterogeneity of the so-called binder maxillonasal dysplasia in prenatally diagnosed cases, and review of the literature. Prenat Diag 2009 ; 29: 140-150.

3-      Binder K.H. Dysostosis Macillo-Nasalis, Ein Arhinencephaler Missbildungskomplex. Deutsch Zahnaertzl 1962-17-438.

4-      Mulhern D.M. Probable case of Binder syndrome in a skeleton from quarai, New Mexico- Am J Phys Anthropol 2002 ; 118 : 371-7.

5-      Noyes F.B.- Case Report. Angle Orthop 1939-9-160-5.

6-      Sheffield Lj, Halliday Jl, Jensen F. Maxillonasal Dysplasia (Binder’s Syndrome) And Chondrodysplasia Punctata. J Med Genet 1992 ; 28: 503-504.

7-      Gorlin R.J., Cohen M., Levin L.- Syndromes Of The Head And The Neck. Oxford : Oxforf University Press 1990.

8-      Quarrell O.W.J., Koch M., Hughes H.E. Maxillonasal Dysplasia (Binder’s Syndrome). J Med Genet 1990 ; 27: 384-387.

9-      Cook K., Prefumo F., Presti F., Homfray T., Campbelle S.- The Prenatal Diagnosis Of Binder syndrome Before 24 Weeks : Case Report. Ultrasound Obstet Gynecol 2000-16-57-81.

10-    Eash Dd, Weaver Dd, Brunetti-Pierri N. Cervical Spine Stenosis And Possible Vitamin K Deficiency Embryopathy In An Unusual Case Of Chondrodysplasia Punctata And An Updated Classification System. Am J Med Genet 2003 ; 122a: 70-75.  11-    Roy-Doray B., Geraudel A., Alembik Y., Stoll C.- Binder Syndrome In A Mother And Her Son. Genetic Counseling 1997- 8- 227-33.

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13-    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: 129-134.

14-    Bony C., Zyka F., Tiran-Rajaofera I., Attali T., De Napoli S., Alessandri J.L. Warfarin Fetopathy. Arch Pediatr 2002 ; 9: 705-708.

15-    Hall J.G., Pauli Rm, Wilson Km. Maternal And Fetal Sequelae Of Anticoagulation During Pregnancy. Am J Med 1980 ; 68: 122-140.

16-    Irving Md, Chitty Ls, Mansour S, Hall Cm. Chondrodysplasia Punctata : A Clinical Diagnosis And Radiological Review. Clin Dysmorphol 2008 ; 17: 229-241.

17-    Franco B, Meroni G, Parenti G, Levilliers J, Bernard L, Gebbia M, Cox L, Maroreaux P, Sheffield L, Rappold Ga, Andria G, Petit C, Ballabio A. A Cluster Of Sulfatase Genes On Xp22.3: Mutations In Chondrodysplasia Punctata (Cdpx) And Implications For Warfarin Embryopathy. Cell 2005 ; 81: 15-25.

18-    Maroteaux P. Brachytelephalangic Chondrodysplasia Punctata: A Possible X-Linked Recessive Form. Hum Genet 1989 82: 167-170.

19-    Chitayat D., Keating S., Zand D.J., Costa T., Zackai E.H., Silverman E., Tiller G., Unger S., Miller S., Kingdom J., Toi A., Curry C.J.R. Brachytelephalangic chondrodysplasia punctata associated with maternal autoimmune diseases: expanding the spectrum from systemic lupus erythematosus to mixed connective tissue disease and scleroderma report of eight cases. Am J Med Genet 2008 ; 146a: 3038-3053.

20-    Nino M, Matos-Miranda C, Maeda M, Chen L, Allanson J, Armour C, Greene C, Kamaluddeen M, Rida D, Medne L, Zackai E, Mansour S, Superti-Furga A, Lewanda A, Bober M, Rosenbaum K, Braverman N. Clinical and molecular analysis of arylsulfatase e in patients with brachytelephalangic chondrodysplasia punctata. Am J Med Genet 2008 ; 146a: 997-1008.

21-    Pauli Rm, Lian Jb, Mosher Df, Suttie Jw. Association Of Congenital Deficiency Of Multiple Vitamin K-Dependent Coagulation Factors And The Phenotype Of The Warfarin Embryopathy: Clues To The Mechanism Of Teratogenicity Of Coumarin Derivatives. Am J Hum Genet 1987 ; 41: 566-583.

22-    Alessandri J.L., Ramful D., Cuillier F.- Clin Dysm 2010- 19- 85-87.

23-    Kawamura Y., Kawamata K., Shinya M., Higashi M., Niiro M., Douchi T. Vitamin k deficiency in hyperemesis gravidarum  as a potential cause of fetal intra-cranial hemorrhage and hydrocephalus. Pren Diag 2008-28-59-61.

24-    Brunetti-Pierri N., Hunter J.V., Boerkoel C.F. Gray matter heterotopias and brachytelephalangic chondrodysplasia punctata: a complication of hyperemesis gravidarum  induced vitamin k deficiency? Am J Med Genet 2007 ; 143a: 200-4.

25-    Munroe Pb, Olgunturk Ro, Fryns Jp, Van Maldergem L, Ziereisen F, Yuksel B, Gardiner Rm, Chung E. Mutations in the gene encoding the human matrix gla protein cause keutel s. Nat Genet 1999 ; 21: 142-144.

26-    Talmand C.- 608 Profils : « Vous Avez Dit Bizarre ! » Présenté Aux Jp Echo Paris Juin 2008. Http://Www.Cfef.Org/Basedocumentaire.Php

27-    Herman T.E., Lee B.C.P., Mcalister W.H. brachytelephalangic chondrodysplasia punctata with marked cervical stenosis and cord compression: report of two cases. Pediatr Radiol 2002 ; 32: 452-456.

28-    Jaillet J., Robert-Gransia 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 2006 ; 73: 188-193.