Binder syndrome: a phenotype rather than a definitive diagnosis?

Binder syndrome is a congenital malformation characterized by nasomaxillary hypoplasia. It can be isolated or associated with multiple etiologies, such as maternal intake of coumarin-based anticoagulants during pregnancy, systemic lupus erythematosus and some other monogenic conditions, such as Keutel syndrome or chondrodysplasia punctata (CDP)1. We report the case of a 24-year-old primigravida referred to our fetal medicine unit at 27 + 2 weeks' gestation, following the finding of significant fetal facial dysmorphism during a routine ultrasound examination at 23 weeks. Amniocentesis with a traditional cell culture of the amniotic fluid followed by array comparative genomic hybridization, 37 kb, revealed a normal karyotype, 46XY. The woman's medical history was unremarkable. Ultrasound examination and fetal magnetic resonance imaging (MRI) performed in our center confirmed facial malformation suggestive of Binder phenotype, characterized by a flat nose and abnormal convexity of the maxilla (Figure 1). Other findings included abnormal epiphyseal ossification centers, short limbs and brachytelephalangy. When Binder phenotype is diagnosed prenatally, a thorough search for associated abnormalities is mandatory in order to identify correctly the etiology, of which one of the most important is CDP. CDP is a heterogeneous group of congenital skeletal dysplasias. This condition may have a genetic cause with several different inheritance patterns and, as in our case, the clinical presentation of the X-linked recessive type (CDPX1, brachytelephalangic type) includes Binder phenotype, stippling calcifications and brachytelephalangy associated with hypoplastic nails2. CDPX1 is a rare condition affecting only males, due to the X-linked recessive inheritance pattern. The condition is associated with mutations either within the arylsulfatase E gene (ARSE) or chromosomal deletions in the region of the short arm of the X chromosome encompassing ARSE3. In the current case, the diagnosis of CDPX1 was proposed following a multidisciplinary meeting between perinatologists and geneticists. Given the variability of the clinical manifestations and no clear genotype–phenotype correlation, prenatal counseling was challenging. The couple decided to terminate the pregnancy at 28 weeks' gestation and the confirmed diagnosis of CDPX1 was available only after completion of full postmortem investigation. Pathological examination confirmed Binder phenotype and brachytelephalangy. Multiple and abnormal calcifications of the trachea and skeleton were also found (Figure 1). Targeted genetic studies performed on the amniotic fluid detected a hemizygous mutation (c.1743G > A, p.Trp581) in ARSE, confirming the diagnosis of CDPX1 (Online Mendelian Inheritance in Man (OMIM) number 302950). To date, there are only two published reports describing the prenatal diagnosis of CDPX1 based on brachytelephalangy and stippling calcifications of the femora and vertebrae4, 5. In our case, Binder phenotype, brachytelephalangy and abnormal epiphyseal ossifications in a male fetus were identified prenatally on ultrasound examination and confirmed on fetal MRI. In conclusion, tertiary-level conventional ultrasound can be accurate for the prenatal diagnosis of CDP due to the detection of Binder phenotype associated with abnormal epiphyseal ossification centers and hypoplasia of the distal phalanges of the hands. However, to identify the specific type of CDP, targeted genetic analysis is required.