Clinical Profile:

A 30 year old woman, gravida 2 para 1 had come for a routine anomaly scan at 23 weeks of gestation. She had a third degree consanguineous marriage and had a daughter aged 5 years who was developmentally normal. There was no family history of any genetic disorders or any significant past medical history. There was no history of drug intake or any illness during the current pregnancy.

Figure 1

Verticalized nasal bone with increased nasofrontal angle and relative prognathism (Binder facies)

Radiological findings:

Ultrasound shows a flattened bridge of the nose with underdevelopment of the maxillary bone causing the mandible to appear to protrude forwards causing a relative prognathism. This characteristic appearance is termed as Binder facies. There is increase in the nasofrontal angle to 137 ° (Normal- 119 ° -133°). Stippling of the femoral epiphysis is seen along with ossification of all the sacral vertebrae, coccyx and cuboid bones which is not a normal finding at 23 weeks of gestation.

3D- ultrasound better delineates the facial and spinal features.

A QF- PCR test was done which was negative ruling out trisomy 21, 18 and 13. The parents were counselled regarding the prognosis of the baby and subsequently they decided to undergo a medical termination of pregnancy.

Frontal and lateral radiographs of the abortus were taken.

Skeletal survey of the abortus showed stippling (calcification) of the vertebrae, ends of the femur, humerus and premature ossification of the bones of the tarsal bones, sacral vertebrae and coccyx, prominent forehead, midfacial hypoplasia and depressed nasal bridge with relative prognathism (Binder facies).

As QF- PCR was negative, trisomy 21, 18 and 13 were ruled out. The patient did not have a history of warfarin/ phenytoin intake or vitamin K deficiency. So, the most likely cause was chondrodysplasia punctata due to inborn error of metabolism caused by abnormal peroxisomal function or abnormality in cholesterol biosynthesis. Further, the parents were counselled regarding gene sequencing of the foetus in order to determine the involved gene and thereby the actual subtype. However, they did not follow up for genetic testing.

Figure 2 A,B,C

3D ultrasound shows typical Binder facies in frontal (2A) and lateral (2B, 2C) views

Figure 3

Stippling of the femoral epiphysis seen on grey scale ultrasound.

Figure 4

The foot of the foetus shows ossified talus, calcaneum and cuboid at 23 weeks of gestation. They are normally ossified at the 6th, 7th and 9th month of gestation.

Figure 5

Ossification of all the sacral vertebrae is noted in the foetus. Normally only the S1 and S2 sacral vertebrae are expected to be ossified at 23 weeks of gestation.

Figure 6

Ossified coccyx is noted. The coccyx normally does not ossify till term.

Figure 7

3D ultrasound shows the prematurely ossified sacral vertebrae.

Figure 8 A, B

Post mortem examination- Frontal (8A) and lateral (8B) views of the abortus (phenotypic male) confirming Binder facies.

Discussion:

Chondrodysplasia punctata is not a disease entity but a radiological diagnosis comprising of a group of skeletal dysplasias of different etiological factors or chromosomal abnormalities. It is characterized by calcific stippling of the cartilage and the peri articular soft tissues. These calcifications arise due to premature calcium deposition in the epiphysis during enchondral bone formation.

They are characterized by short limb dwarfism, facial dysmorphism-maxillonasal hypoplasia (Binder syndrome), spinal abnormalities, skin lesions and cardiac malformations.

Binder in 1962 described a condition called as maxillofacial dysostosis characterized by a short nose, flat nasal bridge with a short columella, acute nasolabial angle, convex upper lip, high arched palate and dental malocclusions hence the term ‘Binder facies’.

Binder syndrome can be isolated or associated with multiple etiologies, some of them are as follows:

1. Isolated Binder type nasomaxillary dysplasia - AD or AR inherited

2. Chondrodysplasia punctata

3. Phenytoin / Warfarin exposure

4. Vitamin K deficiency

5. Systemic lupus erythematosus

Frontonasal angle is determined by the intersection of a line drawn from the upper point of the forehead to the nasal bone and a line drawn along the nasal bone to the nasal tip. Frontonasal angles measured by ultrasound were increased with verticalized nasal bones, ranging from 135–162° (normal value mean 126°±7° from 14 weeks to 39 weeks of gestational age).

Normal sacrococcygeal ossification:

Normal foot bone ossification

Types of chondrodysplasia punctata classified according to clinical and radiological profile.

References:

1. Indrajit IK, Narayan S. CHONDRODYSPLASIA PUNCTATA. Med J Armed Forces India. 1999;55(4):345-347. doi:10.1016/S0377-1237(17)30369

2. Irving, M. D., Chitty, L. S., Mansour, S., & Hall, C. M. (2008). Chondrodysplasia punctata: a clinical diagnostic and radiological review. Clinical Dysmorphology, 17(4), 229–241.

3. Andrea Sanfilippo, Stefano Bartoletti, Brachytelephalangic chondrodysplasia punctata: A difficult diagnosis, Radiology Case Reports,Volume 5, Issue 1, 2010, 308, ISSN 1930-0433,

4. Jain U, Thakur G, Kallury A. Binder's syndrome. BMJ Case Rep. 2011 Oct 11;2011:bcr0820114665. doi: 10.1136/bcr.08.2011.4665. PMID: 22675013; PMCID: PMC3207769.

5. Oztürk H, Ipek A, Tan S, Yener Öztürk S, Keskin S, Kurt A, Arslan H. Evaluation of fetal nasofrontal angle in the second trimester in normal pregnancies. J Clin Ultrasound. 2011 Jan;39(1):18-20. doi: 10.1002/jcu.20735. Epub 2010 Sep 24. PMID: 20872874.

6. Blask AR, Rubio EI, Chapman KA, Lawrence AK, Bulas DI. Severe nasomaxillary hypoplasia (Binder phenotype) on prenatal US/MRI: an important marker for the prenatal diagnosis of chondrodysplasia punctata. Pediatr Radiol. 2018 Jul;48(7):979-991. doi: 10.1007/s00247-018-4098-8. Epub 2018 Mar 23. PMID: 29572747; PMCID: PMC6365632.