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2012-07-01-11 Binder syndrome ©Fabrice Cuillier www.TheFetus.net


 
Binder syndrome: 3 cases

Case 1:

Binder syndrome, with an unusual etiology.

Fabrice Cuillier, MD,* Mardamootoo D.*,  Alessandri J.L., MD

*
 Praticien Hospitalier, Department of Gynecology, Hôpital Félix Guyon, 97400 Saint-Denis, Ile de la Réunion, France.  

**Praticien Hospitalier, Department of Neonatology, Hôpital Félix Guyon, 97400 Saint-Denis, Ile de la Réunion, France.  

A 30-year-old P1G0 was referred to us for a routine screening at 22 weeks without relevant past obstetric of family, Warfarin exposure, alcohol abuse or vitamin K deficiency. The patient, however, presented a Systemic Lupus Erythematosus (SLE) which was treated by Plaquenyl (1/day).

Nuchal translucency measurement was 1.5 mm (62 mm CRL). Maternal risk for trisomy 21 was 1:2500. 

Binder syndrome was diagnosed at 18 weeks with nasal hypoplasia, reduced naso-frontal angle. There were no micro-retrognathia and no other sign of chondrodysplasia or abnormal stippling. 
An amniocentesis was normal (46 XX) without 4p deletion. A normal maternal vitamin dosage (vitamin A, D, E, Zinc, K) excluded malabsorption. Discussions of geneticists and neonatologists concluded that isolated Binder syndrome was the most likely diagnosis, however, possible underlying etiology could be Systemic Lupus Erythematosus. The parents decided to continue pregnancy.  

The congenital abnormalities found were always confirmed at 27 weeks with facial dysmorphism and flat mid-face.

The patient gave birth at 39 weeks (3300 g, with a length of 48 cm). Post-natal adaptation was normal. She had a flat nasal bridge and hypoplasia of the distal phalanges, an intact arched palate without choanal atresia.

At day 3, post-natal radiography confirmed marked hypoplasia of the distal phalanges. There were other bones anomalies: abnormal calcifications behind the upper extremity of the left femur and on the tarsus. The final diagnosis was brachyphalangic punctate chondrodysplasia with Binder phenotype caused by maternal Lupus. 

Discussion :  

Binder Phenotype is now considered to be a heterogeneous phenotype (associated with different etiology), rather than a single nosologic entity. 

Binder Phenotype is characterized by midface hypoplasia, with absence of the nasal spine leading to a flat profile and depressed nasal bridge. Short nose, short columella, flat naso-labial angle and perialar flattening are characteristic of Binder Phenotype. 

Isolated  Binder Phenotype  transmission would be autosomal dominant, according to different authors, but doubted by others authors as Levaillant.   
 

Binder Phenotype can also be an important sign of chondrodysplasia punctata (CDDP), a heterogeneous condition characterized by punctate calcifications secondary to abnormal calcium deposits during endochondrogenesis. Classification of chondrodysplasia punctata is classically divides in three groups of etiology: 

1.  Chromosomal abnormalities: As Trisomy 21.   

2.  Metabolic congenital abnormalities: As Zellweger syndrome.  

3.  Disruption of vitamin K metabolism: caused by inherited or extrinsic factors   

3.1  Inherited etiology: X-linked recessive brachytelephalangic type of chondrodysplasia punctata = CDPX1 caused by mutations of ARSE, localized in Xp22.3. ARSE codes Aryl Sulfatase Enzyme, a system Golgi enzyme. His activity is inhibited in vitro by Warfarin.    

3.2  Extrinsic factors:

-    Prenatal exposure to Phenytoin and Alcohol     

-    Prenatal exposure to Coumarin derivatives: especially between 6th and 9th weeks.

              -    Maternal chronic disease: with important vitamin K  deficiency during first trimester. So, untreated coeliac disease, secondary short bowel syndrome or another type of digestive malabsorption and intractable vomiting of early pregnancy can be responsible for important vitamin K deficiency, and so, Binder Phenotype. 

Recently, according to Levaillant’s article and others authors, Binder Phenotype was observed in half the siblings born to a mother with auto-immune disease. Conversely, Auto-Immune diseases have been observed in mother of infants with chondrodysplasia punctata with Binder Phenotype. Nevertheless, the relation between chondrodysplasia punctata with Binder Phenotype and disturbance of maternal vitamin K metabolism is still unclear. But according to different authors, Systemic Lupus Erythematosus during pregnancy can cause fetal pathology, as nasal hypoplasia and stippled epiphyses, mimicking fetal Warfarin syndrome.  

About our case, we think that modification of the vitamin K metabolism is certainly the responsible of Binder Phenotype with brachyphalangic chondrodysplasia punctata. As in our case with maternal Systemic Lupus Erythematosus, antiphospholipid antibodies may probably interact with vitamin K metabolism.   

Figure 1-42D sagittal section of the fetal face at 18 weeks, demonstrating an abnormal profile with flattened nose and abnormally positioned maxilla (fronto-nasal angle = 155°). 




Figure 5, 6: 2D  view of the left and right femur. No stipplings are noted.  



Figure 7, 8: 2D sagittal section of the fetal face at 27 weeks (same abnormal profile). Nasal bones are normal (9 mm). 


Figure 9-12: 3D sagittal and coronal section of the fetal face at 27 weeks and 32 weeks showing the abnormal fronto-nasal angle and semi lunar nostrils. 




Figure 13, 14: Post-natal sagittal and coronal section of the fetus. 



Figure 15, 16: 
Postnatal radiography of the face of the baby: Note flat nose.  
 


Figure 17, 18:
Postnatal radiography of the hand and the foot. Note hypoplasia of the distal phalanges, but without stippled calcifications.   


Figure 19Postnatal radiography of the left inferior member. Note abnormal tarsal stippled calcifications.   

 





Case 2:
  Binder phenotype with brachytelephalangic chrondrodysplasia

Fabrice Cuillier, MD.*, Dr Rio**, Alessandri J.L.***,MD.  


* Department of Gynecology, Félix Guyon’Hospital, 97400 Saint-Denis, Ile de la Réunion, France.  

** Gynecologist, Commerce’Street, 97460 Saint-Paul, Ile de la Réunion, France.  

*** Department of Neonatology, Félix Guyon’Hospital, 97400 Saint-Denis, Ile de la Réunion, France. 

 

A 29-year-old woman (G2P1) was referred to our antenatal unit at 24 weeks for a second opinion. There was no history of Warfarin exposure, alcohol abuse or vitamin K deficiency or other remarkable personal and familial history. 

Gestational age was previously confirmed during the first trimester by CRL measurement at 13 weeks. Nuchal translucency was normal (1 mm). Maternal risk for trisomy 21 was 1:1000. Vomiting was absent during the first trimester.  

At 24 weeks, ultrasound scanning showed fetal biometry within normal range, flat profile with reduced naso-frontal angle and nasal hypoplasia. There was no cleft lip or palate. Sagittal and coronal section of the fetal face at 25 weeks and 29 weeks confirmed an abnormal profile with flattened nose, abnormal position of the maxilla and thick convexed lips. Ears morphology was normal. The facial findings were confirmed by 3D ultrasound. No other structural abnormalities were noted. 

Chromosomal analysis was normal (46 XY). A 4p deletion (Wolf-Hirschhorn syndrome) was not identified by Fluorescence in situ hybridization (FISH). Discussion of the geneticists, neonatologists and orthopedic surgeons concluded that Binder syndrome was the most likely diagnosis. 

At 25 weeks, the cervix was short, and opened at 29 weeks. The patient gave birth at 33 weeks (2000gr). Post-term findings were flat nasal bridge and hypoplasia of the distal phalanges. Three months later, radiograph of hands confirmed hypoplasia distal phalanges with few stippled carpal calcifications. 

The final diagnosis was brachytelephalangic chondrodysplasia with Binder Phenotype. The diagnosis was confirmed by ARSE gene study.  

Figure 20-23: Flat profile with reduced naso-frontal angle and nasal hypoplasia.



Figure 24, 25:
3D view



Figure 26, 27: The cervix was short, and opened at 29 weeks.





 
Case 3: Binder phenotype with brachytelephalangy secondary to maternal vitamin K deficiency.

Fabrice Cuillier, MD.*, Mardamootoo D.*, Cartault F.**, Alessandri J.L.***.  

*     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, 97400 Saint-Denis, Ile De La Réunion. 

 
 A 28-year-old woman (G4P3) was referred to our antenatal unit at 28 weeks. The fetus was suspected of craniosynostosis. The parents were healthy of Caucasian origin and non-consanguineous. The family history was unremarkable. The mother reported no exposure to teratogens or alcohol during the pregnancy, no history of Warfarin exposure.  
 
Gestational age was confirmed during the first trimester by CRL measurement at 13 weeks. Nuchal translucency was normal (1 mm, 68 mm). Maternal risk for trisomy 21 was 1:1000. 
 
 At 18 weeks, the patient was hospitalized for persistent vomiting with severe weight loss (48 kg to 37 kg). Biological screening revealed normal blood bilirubine (< 20 μmol/l), hepatic cytolysis (ASAT = 600 UI/l and ALAT = 300 UI/l, normal range within 8-31 UI/l), elevated Gamma Glutaryl Transferase (80 UI/l, normal values within 5-36 UI/l), but with normal blood Amylase and Lipase. The prothrombin level was 22 % and factor V level was 126 % suggesting a vitamin K deficiency. Albumin level was 24 g/l. Serologic tests for CMV, Herpes, Hepatitis A, B And C were all negative. Abdominal ultrasound scan showed normal gallbladder and normal pancreas. The mother received parenteral nutrition during one week with intravenous vitamin K supplementation. Prothrombin level was normalized after few days of treatment. The patient was hospitalized during twelve days. 

The second ultrasound was done at 26 weeks. Craniosynostosis  was suspected.  

 At 28 weeks, ultrasound findings were: 

  • An abnormal cranium (figure 28, 29), with normal corpus callosus and peri-callosus artery.
  • Normal biometry, including the intra and external-orbital diameter. 
  • Fetal profile was flat with reduced naso-frontal angle, but without nasal hypoplasia.
  • Sagittal and coronal section of the fetal face confirmed an abnormal profile with flattened nose, abnormally positionned maxilla and thick convexed lips. The facial findings were confirmed by 3D ultrasound with thick lips at 35 weeks. 
  • Ears were normal. Slightly increased amniotic fluid was noted, with normal umbilical cord. No other structural abnormalities were noted. 
  • The hands seemed normal. Feet seemed also normal. There were no bones stippling and no other signs of chondrodysplasia.   

At 35 weeks, facial anomalies were confirmed, with an aspect of exorbitism and with thick lips. Chromosomal analysis on the amniotic fluid showed normal karyotype (46 XY). A 4p-deletion (Wolf-Hirschhorn syndrome) was not identified by a fluorescence in situ hybridization (FISH). At 32 weeks, fetal brain MRI showed normal brain. Spiral scan was done. Craniosynostosis was eliminated. 

Geneticists and neonatologists concluded that isolated Binder syndrome was the most likely diagnosis, and possible underlying etiology was Hypovitaminosis K during the end of first trimester. The parents decided to continue the pregnancy.  

The patient was uneventfully born at 38 weeks (2,52 kg; 45 cm; normal head circumference). Six month later follow-up examination revealed particular faces with a flat nasal bridge. Radiography of hands and the feet confirmed hypoplasia distal phalanges with absent stippled calcifications. 

The final diagnosis was brachytelephalangic chondrodysplasia with Binder phenotype due to hypo-vitaminosis K during first trimester. The diagnosis was confirmed by ARSE gene study.

Figure 28, 29: An abnormal cranium with normal brain.



Figure 30 : Reduced naso-frontal angle, but without nasal hypoplasia.



Figure 31, 32: 3D ultrasound with thick lips at 35 weeks.

 

Figure 33, 34, 35: Facial anomalies were confirmed, with an aspect of exorbitism and with thick lips



Video Clip: 


Figure 36 : Radiography of hands and the feet confirmed hypoplasia distal phalanges with absent stippled calcifications. 




Figure 37, 38, 39, 40: Craniosynostosis was excluded.
 

Figure 41, 42: Postnatal appearance

 


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, however, later, we discovered that Vitamin K deficiency (during first trimester, important hyperemesis gravidarum  with low Prothombin time) was, in fact, responsible for it.

 
For further discussion of Binder syndrome, please click here

 

 

 




 
 

 


 
 

 


 
 

 


 
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