1991-02-13-15 Chondrodysplasia punctata © Furness www.thefetus.net/
Chondrodysplasia punctata, mild symmetric type with echogenic coccyx in a 15 week fetus
Margaret E. Furness*, FRACR, DDU, Eric A. Haan, FRACP, B MedSc, P. Brian Hopkins, FRACR, Helen M. Chambers, FRCPA
Synonyms: Conradi‑Hünermann syndrome, Chondrodystrophia calcificans congenita.
Prevalence: Over 100 reported cases, many in Australia.
Definition: Depressed nasal bridge, mild stippling of the epiphysis (premature calcifications in ultrasound) that affects the vertebrae, tarsal and carpal bones.
Etiology: Autosomal dominant.
Pathogenesis: Disruption of the physis with abnormal calcification.
Associated Anomalies: Postaxial polydactyly (occasional).
Differential Diagnosis of abnormal coccygeal and talar calcifications: warfarin embryopathy, aneuploidy (trisomies 18, 21, triploidy), anencephaly, alcohol and phenytoin exposure, peroxisomal disorders, Smith‑Lemli‑Opitz syndrome, GM1 gangliosidosis.
Related anomalies: Chondrodysplasia punctata (X‑linked dominant type), Dysplasia epiphysealis punctata, Rhizomelic chondrodysplasia punctata.
Prognosis: Bone changes improve in the mild form; the lifespan and intelligence are normal. The only marker in adults is the nasal anomaly.
Risk of recurrence: Mendelian inheritance.
Management: Standard prenatal care.
MESH Chondrodysplasia‑Punctata ‑pathology; ‑diagnosis; ‑genetics; Femur‑abnormalities; Humerus‑abnormalities BDE 0153 MIM 11865 POS 3065 ICD9 756.59 CDC 756.575
* Address correspondence to Margaret E. Furness, FRACR, DDU, The Queen Victoria Hospital, 160 Fullarton Road, Rose Park, South Australia 5067, Phone 61‑8‑333 9105 Fax 61‑8‑333 9184
Chondrodysplasia punctata refers to a heterogeneous group of conditions which share calcific stippling of cartilage and periarticular soft tissues and, in particular, punctate calcification in the heel, in infancy. These disorders differ in clinical features, severity, inheritance pattern and radiological features, and an agreed upon classification has yet to be established.
The rhizomelic type1 (an autosomal recessive disorder of peroxisomal function) is usually lethal in infancy and consists of proximal limb shortening, short stature, flat facies, cataracts, mental retardation and ichthyosiform skin rash.
The X‑linked dominant type2, thought to be lethal in males, is characterized by asymmetrical skeletal abnormalities with short stature, shortening of the long bones, dysplasia and contracture of joints, and scoliosis together with flat nasal bridge, congenital ichthyosiform erythroderma, cicatricial alopecia of the scalp, abnormal hair and cataracts.
An X‑linked recessive form has been described3 in association with a deletion of the terminal short arm of an X chromosome, in brothers with epiphyseal stippling, nasal hypoplasia, ichthyosis and mental retardation.
The term Conradi‑Hünermann syndrome has been applied to an apparently heterogeneous group of conditions whose features include asymmetrical short stature, scoliosis, cataracts, ichthyotic skin and flat facies with nasal hypoplasia4. The patients included some with X‑linked dominant, autosomal dominant5 and sporadic forms6, and can be quite mildly affected. Patients with the mildest clinical features have been diagnosed in mid‑childhood to have Binder syndrome (maxillo‑nasal dysplasia)7.
Other causes of calcific epiphyseal stippling include warfarin8, alcohol, and phenytoin exposure in pregnancy, several peroxisomal disorders including Zellweger1 syndrome, Smith‑Lemli‑Opitz9 syndrome, trisomies 18 and 2110, GM1 gangliosidosis11 and anencephaly.
Chondrodysplasia punctata has been diagnosed by third‑trimester ultrasound in an at‑risk fetus12, and an association with fetal ascites and polyhydramnios has been reported13.
Radiographically visible ossification begins in the calcaneum and talus between 22 and 24 weeks of menstrual age10. Ossification in the first coccygeal segment usually begins after term, but may occasionally be seen in mid‑third trimester.
The first pregnancy of a non‑consanguineous couple ended in unexplained fetal death of a male at 31 weeks" gestation. At the time of the second pregnancy, the mother was 28 years old and measured 1.53 m; she had been on no medication. The father was 31, and 1.70 m tall. Neither had the facies of chondrodysplasia punctata.
Ultrasound scan of the second pregnancy at 15 weeks" gestation showed striking echogenicity of the coccyx (fig. 1).
Fig. 1: Coronal scan of distal fetal trunk at 15 weeks, showing echogenic coccyx.
The long bone lengths were all near the 5th percentile for age10 on this and subsequent scans. There were no other abnormal findings. Fetal karyotype and amniotic fluid alpha‑fetoprotein level were normal.
Delivery and neonatal death, from birth asphyxia, of a male infant weighing 1.320 kg followed placental abruption at 29 weeks. He had a flat nasal bridge, typical of chondrodysplasia punctata. The diagnosis was based on radiographs showing punctate calcification in the heels (fig 2), coccyx (figs. 2,3), larynx and paravertebral regions.
Fig. 2: AP radiograph, showing calcification in coccyx and heel, 29 weeks.
Fig. 3: Lateral radiograph of distal spine.
Coronal clefting affected several cervical and thoracic vertebrae. The femoral length was 48 mm (below the 5th percentile). Review of the sibling"s postmortem radiographs revealed lesser but definite punctate calcification in the coccyx and heels.
Coccygeal and tarsal calcification study: material and methods
As a result of this diagnosis, we investigated the incidence of coccygeal and tarsal calcification in normal and abnormal second trimester fetuses, to assess the limitations of these findings.
We reviewed postmortem radiographs of a number of 2nd trimester abortuses known to have aneuploidy or neural tube defects, and of 200 second trimester fetuses either delivered spontaneously or aborted for reasons other than fetal abnormality, and considered normal by a perinatal pathologist. The heel and coccyx regions were inspected in the next 300 ultrasound scans at 16‑22 weeks of pregnancy. Gestational age estimates were based on good menstrual dates where available, on biparietal diameter, or on femoral length.
No normal second trimester fetus had coccygeal calcification on radiographs or ultrasound. Four normal fetuses out of 100 at 17‑18 weeks, and 9 out of 100 at 18‑19 weeks, showed an echogenic focus in the heel on ultrasound.
Postmortem radiographs showed heel calcification in 2 of 31 fetuses with spina bifida, and 3 of 24 with anencephaly (fig. 4).
Fig. 4: Number of fetuses with heel radiodensity among spina bifida, anencephaly, triploidy and trisomy 21 subgroups.
Four of 7 triploid fetuses had abnormal calcification, in the coccyx in one case. Cell cultures failed in a 15‑week female fetus which was considered likely to be aneuploid. She had cervical cystic hygromas with hydrops, a solitary kidney, and calcification in coccyx, hips and heels. Three of twelve fetuses with trisomy 21 had premature ossification in the heels, on postmortem X‑ray. They were aged 17,19 and 19 weeks by menstrual dates; we expect that the heels would have had echogenic foci on ultrasound earlier than this.
Of 7 second trimester fetuses or early third trimester infants with punctate coccygeal calcification, 4 had chondrodysplasia punctata, 2 were aneuploid or probably so, and one was anencephalic.
This case demonstrates that punctate calcifications can be visualized by ultrasound in the second‑trimester fetus. Ultrasound is unlikely to differentiate between calcification and ossification. Our preliminary study indicates several aspects which require assessment in larger series for confirmation:
· An echogenic focus in the heel after 17 weeks" gestation is normal.
· Before 17 weeks, it may provide additional information in short‑limbed fetuses or those suspected of aneuploidy, but as an isolated finding probably does not warrant karyotyping.
· Abnormal echogenicity in the heel or coccyx may be a useful marker for warfarin embryopathy in at‑risk cases, since sonographic assessment of other features (in particular, depression of the nasal bridge) may be difficult.
However, coccygeal calcification is not a constant finding in reported cases of chondrodysplasia punctata and related conditions, and its absence does not exclude them.
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