Case report: A 30-year-old woman G5, P4 presented for a routine ultrasound scan. Her obstetric history was significant for a postnatal fetal loss at 5 months of age due to unknown metabolic illness of the fetus. These are serial ultrasound scans that have been performed at 23, 32 and 34 weeks of gestation:
Scan at 23 weeks of gestation:
Profile view of the face: A flat mid-face is seen.
2-D and 3-D scans of the femur: Punctate epiphyeal calcifications as marked are seen.
Images of the fetal spine: Punctations are seen.
3-D and 2-D views of the face at 32 weeks of gestation:
View of the right eye at 32 weeks: A cataract can be seen.
View of the femur at 34 weeks of gestation:
Fetal biometric chart of the long bones:
As a chromosomal abnormality could not be excluded, an amniocentesis was performed (46 XY and 4p deletion: Wolf-Hirschhorn syndrome was eliminated). The parents decided to continue this pregnancy and at 37 weeks of gestation, the baby was delivered by a ceaserean section.
Postnatal photographs of the baby: Note the flattened appearance of the face and facial dysmorphism.
Photographs of the legs show arthrogryposis:
The baby was a male rhizomelic dwarf weighing 2510 g. Radiographs confirmed the anomalies along with epiphyseal punctations that were noted in the femorae and spine. Radiographs showed rhizomelic limb shortening. The humeri and the femorae were short, dumb-bell shaped and flared at the metaphyses. Stippled
epiphyseal calcifications were marked in the shoulders and hips and were also noted in the thoracic spine. The baby died on day 50. The parents refused an autopsy. A diagnosis of rhizomelic chondrodysplasia punctata was made.
History: Chondrodysplasia punctata was first described in 1914 by Conradi 1. Hunermann (1931) designated the disorder chondrodystrophia calcificans congenita. Although the condition has since been given a variety of other names, the most widely accepted nomenclature is chondrodysplasia punctata. In 1985 rhizomelic chondrodysplasia punctata was discovered to be a peroxisomal, metabolic disorder (Heymans et al, 1985) 1.
Etio-pathogenesis: Rhizomelic chondrodysplasia punctata is a metabolic disorder, a peroxisomal disorder. Biochemically, there is a severe deficiency of the activities of the following peroxisomal enzymes:
• Acyl-CoA : dihydroxyacetone phosphate acyl transferase (DHAP-AT) activity and
• Alkyl-dihydroxyacetone phosphate synthetase activity.
• There is defective phytanic acid oxidation and peroxisomal 3-oxoacyl-Co-A thiolase. Levels of plasma phytanic acid are elevated and tissue phytanic acid oxidation is impaired 3.
All the other peroxisomal functions are normal apart from the presence of a functional but structurally altered 3-ketoacyl-Co-A thiolase 3. Thus, a prenatal biochemical diagnosis of rhizomelic chondrodysplasia punctata can be made in either the first or second trimester of gestation by demonstrating deficient peroxisomal enzyme activity in either cultured chorionic villous or amniotic fluid cells.
In rhizomelic chondrodysplasia punctata, three genotypes have been described 7:
Type 1: is associated with a defect in the PEX7 gene, which codes for the receptor of peroxisome targeting sequence. The main biochemical abnormalities are a profound deficiency of plasmalogens due to impaired activity of dihydroxyacetonephosphate (DHAP) acyltransferase and alkyl-DHAP synthetase. Increased levels of plasma phytanic acid are seen due to deficiency of phytanoyl-CoA hydroxylase, an enzyme which contains the peroxisome targeting sequence. There is also impaired processing of peroxisomal 3-ketothiolase.
Type 2: There is an isolated deficiency of DHAP acyltransferase (DHAPAT).
Type 3: There is a defect of alkyl-DHAP synthetase. Plasmalogens levels are reduced in type 2 and 3 patients while phytanic acid levels and the processing of 3-ketothiolase are normal.
Prevalence: The frequency of chondrodysplasia punctata is 1 per 4000 births 6. The incidence of chondrodysplasia punctata is approximately 0.09 per 10.000 births (Stolle). Parental consanguinity is noted in 8-10 % of cases 6.
There are two forms: the nonrhizomelic (Conradi-Hunermann type) 1 and rhizomelic (Duff) 4. The nonrhizomelic or Conradi-Hunermann type is the milder form and appears to be inherited in a heterogeneous manner. Autosomal dominant, autosomal recessive and sex-linked recessive transmission has been described .4 Limb shortening is typically minimal. There is only mild disruption of the normal structures of the epiphyses and metaphyses. Stippling of the bones is mild and is usually limited to the tarsal and the carpal bones. 4 Other complications may include failure to thrive, cataracts, retinal detachments, scoliosis, ichtyosiform skin changes and recurrent infection.
The rhizomelic type of chondrodysplasia punctata is a rare dysplasia with an incidence of approximate 0.1 per 10000 births. It is known to be an autosomal recessive disorder. It is characterized by severe shortening of the long bones (humeri and femorae). There is also prominent stippling of the epiphyses of bones in the extremity and the pelvis. These areas of calcification are distinct from the normal ossification centers. 4 Abnormalities of the vertebral bodies are also common and typically take the form of coronal clefts. Additional anomalies include microcephaly, flat face, upwards slanting of the palpebral fissures, lymphedema of the cheeks, cataracts, optic nerve atrophy, ichtyosiform skin changes, alopecia, joint contractures and ascites 4.
Sonographic findings: Until 1990, antenatal diagnosis was only possible by means of fetoscopy. But now antenatal diagnosis is possible also by peroxisomal studies in chorionic villus biopsy or cultured amniocytes. Analysis of chorion villus samples has resulted in successful diagnosis of at risk pregnancies as early 10 weeks (Gendall) 2. The sonographic criteria for diagnosis are:
Profound humeral shortening
Less-marked femoral shortening, without shortening of other long bones and
Expanded epiphyses containing multiple hyperechoic foci.
Differential diagnosis: The premature ossification and disordered stippling of the epiphysis in rhizomelic chondrodysplasia punctata are characteristic features of this condition. But such findings are not unique to the disorder. Abnormal epiphyseal ossifications can also be found in other forms of chondrodysplasia punctata such as:
1. Non-rhizomelic chondrodysplasia punctata also termed Conradi-Hunermann syndrome and the tibia-metacarpal type of chondrodysplasia punctata.
2. Chromosomal aneuploidies (Trisomy 18 and 21).
3. Zellweger syndrome.
4. Vitamin K reductase deficiency
5. Drug and teratogen exposures: warfarin, warfarin sodium (Coumadin), phenytoin, acenocoumarol, fetal alcohol syndrome and phenacetin intoxication 5.
Associated ultrasonographic features can help to distinguish between these differential diagnoses. Rhizomelic chondrodysplasia punctata is distinctive for the profound rhizomelic shortening of long bones and the flaring of metaphyses that are not seen with the other causes of epiphyseal stippling. In contrast, proximal limb shortening is mild, asymmetric or absent in the nonrhizomelic form of chondrodysplasia punctata. A fetus with this nonrhizomelic form may also have a depressed nasal bridge, frontal bossing and additional skeletal anomalies such as scoliosis and shortening and bowing of the distal segments of the long bones (radius, ulna, tibia and femur). Fetus with the tibia-metacarpal form of chondrodysplasia punctata can have flattened midface and nasal bridge as well but will have characteristic shortening and bowing of the tibiae and radii and shortening of the second and third metacarpals. The teratogenic effects of warfarin and coumadin often produce severe shortening of the distal phalanges.
Rhizomelic chondrodysplasia punctata demonstrates stippling of the bones of the extremities and pelvis and abnormalities of the vertebral bodies. Short limbs may be present in the others forms of dwarfism, but only a few conditions are likely to present with the characteristic stippled appearance on sonographic examination.
A fetus exposed to warfarin derivatives may have such skeletal abnormalities. Stippling may also be observed in infants with Zellweger (cerebro-hepato-renal) syndrome, although such infants also typically have cystic changes in the liver and kidneys.
Prognosis: The rhizomelic chondrodysplasia punctata is a lethal autosomal recessive disorder of unknown cause. It is characterized by marked shortening and bowing of the proximal limbs, vertebral column abnormalities, eye and skin defects, severe mental retardation and recurrent infection. The rhizomelic form of chondrodysplasia punctata carries extremely poor prognosis 4. Most affected infants die in the first few weeks of life from recurrent infections. Those who survive beyond the first year are severely retarded and debilitated 4. While many patients do not survive beyond the first years, some have survived to five years and a few patients with the classical phenotype are alive in their second and third decade. Therapy and treatment is not available and the prognosis is poor. The patients are severely mentally retarded and most of them die before the age of two years. Some, however, survive and the oldest patient known to Oorthuys (1987)1 is 16 years of age.
Recurrence risk: The mode of inheritance is autosomal recessive.
Management: In our case, we acknowledge that we did not observe the abnormalities until 23 weeks of gestation, which was when the patient first presented for prenatal care. The diagnosis was confirmed after amniocentesis. We also acknowledge that we were alert to this diagnosis because of abnormalities noted in the previous gestation. If the diagnosis is equivocal, it may be appropriate to obtain a radiograph of the fetus to confirm the sonographic findings. In view of the grave prognosis associated with this form of rhizomelic chondrodysplasia punctata, a definitive diagnosis should be established as early in pregnancy as possible. When informed of the diagnosis, some patients may wish to terminate the pregnancy. Those who elect to continue the pregnancy can plan the care of a severely handicapped child.
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2 Gendall P.W., Baird C.E., Becroft D.M.O.- Rhizomelic chondrodysplasia punctata : Early recognition with antenatal ultrasonography. J Clin Ultrasound 1994 ; 22 : 271-4.
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4 Duff P., Harlas F.E., Milligan D.A.- Prenatal diagnosis of chondrodysplasia punctata by sonograpy. Obstet Gynecol 1990 ; 76 : 497-9.
5 Hertzberg B.S., Kliewer M.A., Decker M., Miller C.R., Bowie J.D.- Antenal ultrasonograic diagnosis of rhizomelic chondrodyplasia punctata. J Ultrasound Med 1999 ; 18 : 715-8.
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7 Brookhyser K.M., Lipson M.H., Moser A.B., Moser H.W., lachman R.S., Rimoin D.L.- Prenatal diagnosis of rhizomelic chondrodysplasia punctata due to isolated alkyldihydroacetonephosphate Acyltransferase synthetase deficiency. Prenatal diagn 1999; 19: 383-5.
8 Whittock N.V., Izatt L., Simpson-dent S.L., Becker K., Wakelin S.H.- Molecular prenatal diagnosis in a case of an X-linked dominant chondrodysplasia punctata. Prenatal diagn 2003 ; 23 : 701-4.