Chondrodysplasia punctata is a skeletal abnormality characterized by premature foci of calcification within the cartilage, referred to as stippling. It is most commonly found in the epiphysis of the long bones, vertebral column and other cartilaginous regions that do not normally calcify, such as the trachea and the distal ribs. Fetal ultrasound and X-rays can visualize these foci of calcifications radiologically during the antenatal, newborn and infancy periods. As the cartilage starts to calcify, these foci are no longer visible, and the diagnosis may be missed.
Chondrodysplasia punctata has variable degrees of severity and outcomes, and variable genetic inheritance including X-linked recessive, X-linked dominant and autosomal recessive. It occurs with an incidence of approximately 1 in 100,000 live births. There are six main subtypes of chondrodysplasia punctata:
• Rhizomelic form is autosomal recessive and characterized by rhizomelic shortening of the long bones (humeri and femora) and punctate calcifications of the cartilaginous portions of skeleton, particularly the proximal humeri and femora. Rhizomelic chondrodysplasia punctata can be subclassified into types 1, 2, and 3 according to the affected gene (PEX7, DHAPAT and ADAPS) and is generally lethal.
• Non-rhizomelic types are characterized by asymmetric, dysplastic skeletal changes, punctate calcifications of the epiphyses, variably asymmetric limb lengths or normal limb lengths, nasal hypoplasia, variable upper airway compromise, skin changes, cataracts, and a generally favorable prognosis. Genetically, there is more heterogeneity and three types are distinguished: autosomal dominant type, X-linked recessive brachytelephalangic type (CDXP1), and X-linked dominant Conradi-Hünermann syndrome (CDPX2) which is usually lethal early in pregnancy in hemizygous males.
In all forms, there is evidence of cartilaginous stippling usually in the proximal humeri and femora, the distal portions of the femora, and the calcaneus. Under normal conditions, the distal femoral epiphyseal ossification center is seen at 33 to 34 weeks, although in some cases, it can be seen after 29 weeks. Visualization of the proximal and distal femoral epiphyseal ossification centers at 22 to 23 weeks gestational age is abnormal. In many cases, this stippling leads to significant shortening of the rhizomelic portions of the bones. Other findings that have been seen in chondrodysplasia punctata include coronal clefts of the vertebrae, scoliosis, micrognathia, microcephaly, cataracts, ocular coloboma, cleft palate, flat nasal bridge, frontal bossing, foot deformities, and polydactyly.
Ultrasound findings can help identify the subtype of chondrodysplasia punctata based on the location of the stippling and the associated malformations. For example in the dominant form, fine punctata are usually confined to the spine. In the tibia-metacarpal type, there is more discrete calcific stippling, particularly in the hands and vertebrae, short tibiae, and shortened second and third or third and fourth metacarpals. In the x-linked recessive, brachytelephalangic type (CDPX1) (OMIM # 302950), there are stippled epiphyses and vertebrae, shortening of the distal phalanges, and Binder phenotype. This congenital disorder of bone and cartilage development is caused by arylsulfatase E (ARSE) deficiency, located on Xp22.3, and affects only males. Although the disorder is benign in most affected fetuses, some have significant medical comorbidities including respiratory compromise, cervical spine compression and hearing loss. Warfarin inhibits ARSE activity, so there is a pathophysiological link between fetal warfarin syndrome and chondrodysplasia punctata.
Binder phenotype, also known as maxilla-nasal dysplasia or maxillo-nasal dysostosis, combines midface hypoplasia with absence of spina nasalis, leading to characteristic facial dysmorphism. Prenatally, ultrasonographic hallmarks of Binder phenotype are a flat nose with flattened nasal bridge, verticalized nasal bones, and an overall flattened midface known as an arhinoid face. This facial appearance was initially considered a syndrome, though the term Binder phenotype has been deemed more appropriate. Binder phenotype is considered a heterogeneous phenotype rather than a single nosologic entity. The majority of cases are sporadic, but some authors have reported a familial occurrence. Binder phenotype can be associated with:
• chromosomal abnormalities (trisomies 18 and 21)
• monogenic conditions (such as chondrodysplasia punctate and Keutel syndrome)
• vitamin K deficit in early embryogenesis secondary to the presence of circulating anticoagulant (warfarin) or antiphospholipid antibodies (systemic lupus erythematosus)
• inborn errors of metabolism diseases (peroxisomal disorders, lysosomal storage disorders, and cholesterol biosynthesis anomalies)
• exposure to teratogens (fetal alcohol syndrome)
Keutel syndrome is an autosomal recessive vitamin-K-related disorder characterized by diffuse calcification and/or ossification of the cartilage, characteristic dysmorphism reminiscent of Binder phenotype (midface hypoplasia, depressed nasal bridge and small alae nasi), brachytelephalangism, multiple peripheral pulmonary stenosis, sensory hearing loss, and borderline to mild mental retardation.
Inherited or extrinsic factors disrupting maternal vitamin K metabolism are known to result in brachytelephalangic chondrodysplasia punctata with maxillonasal dysplasia (Binder dysplasia). Vitamin K deficiency can occur in pregnant women with warfarin exposure, maternal systemic lupus erythematosus, intractable vomiting in early pregnancy, and in women with severe malabsorption due to celiac disease, or short bowel syndrome due to surgical resection or jejuno-ileal bypass. Biliary lithiasis associated with angiocholitis may lead to Binder phenotype through a maternal vitamin K deficiency in early pregnancy. In some cases of fetal alcohol syndrome, stippled epiphyses have been described in the lower limbs. Pathogeny remains obscure, but hypovitaminosis K is possible.
Differential diagnosis of fetal stippling with Binder phenotype include isolated Binder phenotype, CDPX1 brachytelephalangic chondrodysplasia punctate or acrodysostosis, CDPX2 Conradi-Hunermann, AR rhizomelic chondrodysplasia punctata (RCDP1, RCPD2, RCPD3), Keutel syndrome, infantile sialic acid storage disorder, fetal warfarin syndrome and maternal disseminate erythematous lupus. The features of Keutel syndrome overlaps those of CDPX1, but calcifications are more extensive, and brachytelephalangy spares the 5th finger. The presence of premature foci of calcifications within the cartilage (stippling) allows the diagnosis of one of the multiple variants of chondrodysplasia punctata. Since the long bones are not excessively short, we can exclude the rhizomelic forms. Of the three non-rhizomelic types, the finding of brachytelephalangia and a Binder phenotype in a male fetus orients the case as a non-rhizomelic chondrodysplasia punctata linked to a CDPX1 gene mutation (OMIM # 302950). The X-linked dominant form (Conradi-Hünermann syndrome) can be excluded, as it is usually lethal early in gestation.
Suggested readings
1. Alessandri JL, Ramful D, Cuillier F. Binder phenotype and brachytelephalangic chondrodysplasia punctata secondary to maternal vitamin K deficiency. Clin Dysmorphol. 2010;19(2):85–87. doi:10.1097/MCD.0b013e328335c14a
2. Benaicha A, Dommergues M, Jouannic JM, et al. Prenatal diagnosis of brachytelephalangic chondrodysplasia punctata: case report. Ultrasound Obstet Gynecol. 2009;34(6):724–726. doi:10.1002/uog.7452
3. Blask AR, Rubio EI, Chapman KA, et al. Severe nasomaxillary hypoplasia (Binder phenotype) on prenatal US/MRI: an important marker for the prenatal diagnosis of chondrodysplasia punctata. Pediatr Radiol. 2018;48(7):979–991. doi:10.1007/s00247-018-4098-8
4. Boulet S, Dieterich K, Althuser M, et al. Brachytelephalangic chondrodysplasia punctata: prenatal diagnosis and postnatal outcome. Fetal Diagn Ther. 2010;28(3):186–190. doi:10.1159/000297289
5. Krakow D. Chondrodysplasia Punctata. In: Copel JA, ed. Obstetric Imaging. Fetal diagnosis and care, 2nd ed. Elsevier, Philadelphia, PA, 2018; pg 259-261.e1
6. Lefebvre M, Dufernez F, Bruel AL, et al. Severe X-linked chondrodysplasia punctata in nine new female fetuses. Prenat Diagn. 2015;35(7):675–684. doi:10.1002/pd.4591
7. Levaillant JM, Moeglin D, Zouiten K, et al. Binder phenotype: clinical and etiological heterogeneity of the so-called Binder maxillonasal dysplasia in prenatally diagnosed cases, and review of the literature. Prenat Diagn. 2009;29(2):140–150. doi:10.1002/pd.2167
8. Mazzone E, Cos Sanchez T, Persico N, et al. Binder syndrome: a phenotype rather than a definitive diagnosis? Ultrasound Obstet Gynecol. 2019;53(1):131–132. doi:10.1002/uog.19198
9. Pradhan GM, Chaubal NG, Chaubal JN, et al. Second-trimester sonographic diagnosis of nonrhizomelic chondrodysplasia punctata. J Ultrasound Med. 2002;21(3):345–349. doi:10.7863/jum.2002.21.3.345
10. Pryde PG, Bawle E, Brandt F, et al. Prenatal diagnosis of nonrhizomelic chondrodysplasia punctata (Conradi-Hünermann syndrome). Am J Med Genet. 1993;47(3):426–431. doi:10.1002/ajmg.1320470327
Chondrodysplasia punctata has variable degrees of severity and outcomes, and variable genetic inheritance including X-linked recessive, X-linked dominant and autosomal recessive. It occurs with an incidence of approximately 1 in 100,000 live births. There are six main subtypes of chondrodysplasia punctata:
• Rhizomelic form is autosomal recessive and characterized by rhizomelic shortening of the long bones (humeri and femora) and punctate calcifications of the cartilaginous portions of skeleton, particularly the proximal humeri and femora. Rhizomelic chondrodysplasia punctata can be subclassified into types 1, 2, and 3 according to the affected gene (PEX7, DHAPAT and ADAPS) and is generally lethal.
• Non-rhizomelic types are characterized by asymmetric, dysplastic skeletal changes, punctate calcifications of the epiphyses, variably asymmetric limb lengths or normal limb lengths, nasal hypoplasia, variable upper airway compromise, skin changes, cataracts, and a generally favorable prognosis. Genetically, there is more heterogeneity and three types are distinguished: autosomal dominant type, X-linked recessive brachytelephalangic type (CDXP1), and X-linked dominant Conradi-Hünermann syndrome (CDPX2) which is usually lethal early in pregnancy in hemizygous males.
In all forms, there is evidence of cartilaginous stippling usually in the proximal humeri and femora, the distal portions of the femora, and the calcaneus. Under normal conditions, the distal femoral epiphyseal ossification center is seen at 33 to 34 weeks, although in some cases, it can be seen after 29 weeks. Visualization of the proximal and distal femoral epiphyseal ossification centers at 22 to 23 weeks gestational age is abnormal. In many cases, this stippling leads to significant shortening of the rhizomelic portions of the bones. Other findings that have been seen in chondrodysplasia punctata include coronal clefts of the vertebrae, scoliosis, micrognathia, microcephaly, cataracts, ocular coloboma, cleft palate, flat nasal bridge, frontal bossing, foot deformities, and polydactyly.
Ultrasound findings can help identify the subtype of chondrodysplasia punctata based on the location of the stippling and the associated malformations. For example in the dominant form, fine punctata are usually confined to the spine. In the tibia-metacarpal type, there is more discrete calcific stippling, particularly in the hands and vertebrae, short tibiae, and shortened second and third or third and fourth metacarpals. In the x-linked recessive, brachytelephalangic type (CDPX1) (OMIM # 302950), there are stippled epiphyses and vertebrae, shortening of the distal phalanges, and Binder phenotype. This congenital disorder of bone and cartilage development is caused by arylsulfatase E (ARSE) deficiency, located on Xp22.3, and affects only males. Although the disorder is benign in most affected fetuses, some have significant medical comorbidities including respiratory compromise, cervical spine compression and hearing loss. Warfarin inhibits ARSE activity, so there is a pathophysiological link between fetal warfarin syndrome and chondrodysplasia punctata.
Binder phenotype, also known as maxilla-nasal dysplasia or maxillo-nasal dysostosis, combines midface hypoplasia with absence of spina nasalis, leading to characteristic facial dysmorphism. Prenatally, ultrasonographic hallmarks of Binder phenotype are a flat nose with flattened nasal bridge, verticalized nasal bones, and an overall flattened midface known as an arhinoid face. This facial appearance was initially considered a syndrome, though the term Binder phenotype has been deemed more appropriate. Binder phenotype is considered a heterogeneous phenotype rather than a single nosologic entity. The majority of cases are sporadic, but some authors have reported a familial occurrence. Binder phenotype can be associated with:
• chromosomal abnormalities (trisomies 18 and 21)
• monogenic conditions (such as chondrodysplasia punctate and Keutel syndrome)
• vitamin K deficit in early embryogenesis secondary to the presence of circulating anticoagulant (warfarin) or antiphospholipid antibodies (systemic lupus erythematosus)
• inborn errors of metabolism diseases (peroxisomal disorders, lysosomal storage disorders, and cholesterol biosynthesis anomalies)
• exposure to teratogens (fetal alcohol syndrome)
Keutel syndrome is an autosomal recessive vitamin-K-related disorder characterized by diffuse calcification and/or ossification of the cartilage, characteristic dysmorphism reminiscent of Binder phenotype (midface hypoplasia, depressed nasal bridge and small alae nasi), brachytelephalangism, multiple peripheral pulmonary stenosis, sensory hearing loss, and borderline to mild mental retardation.
Inherited or extrinsic factors disrupting maternal vitamin K metabolism are known to result in brachytelephalangic chondrodysplasia punctata with maxillonasal dysplasia (Binder dysplasia). Vitamin K deficiency can occur in pregnant women with warfarin exposure, maternal systemic lupus erythematosus, intractable vomiting in early pregnancy, and in women with severe malabsorption due to celiac disease, or short bowel syndrome due to surgical resection or jejuno-ileal bypass. Biliary lithiasis associated with angiocholitis may lead to Binder phenotype through a maternal vitamin K deficiency in early pregnancy. In some cases of fetal alcohol syndrome, stippled epiphyses have been described in the lower limbs. Pathogeny remains obscure, but hypovitaminosis K is possible.
Differential diagnosis of fetal stippling with Binder phenotype include isolated Binder phenotype, CDPX1 brachytelephalangic chondrodysplasia punctate or acrodysostosis, CDPX2 Conradi-Hunermann, AR rhizomelic chondrodysplasia punctata (RCDP1, RCPD2, RCPD3), Keutel syndrome, infantile sialic acid storage disorder, fetal warfarin syndrome and maternal disseminate erythematous lupus. The features of Keutel syndrome overlaps those of CDPX1, but calcifications are more extensive, and brachytelephalangy spares the 5th finger. The presence of premature foci of calcifications within the cartilage (stippling) allows the diagnosis of one of the multiple variants of chondrodysplasia punctata. Since the long bones are not excessively short, we can exclude the rhizomelic forms. Of the three non-rhizomelic types, the finding of brachytelephalangia and a Binder phenotype in a male fetus orients the case as a non-rhizomelic chondrodysplasia punctata linked to a CDPX1 gene mutation (OMIM # 302950). The X-linked dominant form (Conradi-Hünermann syndrome) can be excluded, as it is usually lethal early in gestation.
Suggested readings
1. Alessandri JL, Ramful D, Cuillier F. Binder phenotype and brachytelephalangic chondrodysplasia punctata secondary to maternal vitamin K deficiency. Clin Dysmorphol. 2010;19(2):85–87. doi:10.1097/MCD.0b013e328335c14a
2. Benaicha A, Dommergues M, Jouannic JM, et al. Prenatal diagnosis of brachytelephalangic chondrodysplasia punctata: case report. Ultrasound Obstet Gynecol. 2009;34(6):724–726. doi:10.1002/uog.7452
3. Blask AR, Rubio EI, Chapman KA, et al. Severe nasomaxillary hypoplasia (Binder phenotype) on prenatal US/MRI: an important marker for the prenatal diagnosis of chondrodysplasia punctata. Pediatr Radiol. 2018;48(7):979–991. doi:10.1007/s00247-018-4098-8
4. Boulet S, Dieterich K, Althuser M, et al. Brachytelephalangic chondrodysplasia punctata: prenatal diagnosis and postnatal outcome. Fetal Diagn Ther. 2010;28(3):186–190. doi:10.1159/000297289
5. Krakow D. Chondrodysplasia Punctata. In: Copel JA, ed. Obstetric Imaging. Fetal diagnosis and care, 2nd ed. Elsevier, Philadelphia, PA, 2018; pg 259-261.e1
6. Lefebvre M, Dufernez F, Bruel AL, et al. Severe X-linked chondrodysplasia punctata in nine new female fetuses. Prenat Diagn. 2015;35(7):675–684. doi:10.1002/pd.4591
7. Levaillant JM, Moeglin D, Zouiten K, et al. Binder phenotype: clinical and etiological heterogeneity of the so-called Binder maxillonasal dysplasia in prenatally diagnosed cases, and review of the literature. Prenat Diagn. 2009;29(2):140–150. doi:10.1002/pd.2167
8. Mazzone E, Cos Sanchez T, Persico N, et al. Binder syndrome: a phenotype rather than a definitive diagnosis? Ultrasound Obstet Gynecol. 2019;53(1):131–132. doi:10.1002/uog.19198
9. Pradhan GM, Chaubal NG, Chaubal JN, et al. Second-trimester sonographic diagnosis of nonrhizomelic chondrodysplasia punctata. J Ultrasound Med. 2002;21(3):345–349. doi:10.7863/jum.2002.21.3.345
10. Pryde PG, Bawle E, Brandt F, et al. Prenatal diagnosis of nonrhizomelic chondrodysplasia punctata (Conradi-Hünermann syndrome). Am J Med Genet. 1993;47(3):426–431. doi:10.1002/ajmg.1320470327