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 embryopathy15-21.
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 deficiency23-24.
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 maxilla1-2. 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.
Persistence of chorda dorsalis.
Stippling epiphyses : are possible.
Recurence risk :
Reccurence risk depends on etiology.
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 Warfarin17-23. 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.
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.
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 authors2-22-24, 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.
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