* 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.
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 1-4: 2D sagittal section of the fetal face at 18 weeks, demonstrating an abnormal profile with flattened nose and abnormally positioned maxilla (fronto-nasal angle = 155°).