J. lnher. Metab. Dis. 15 (1992) 931-932 ~ SSIEM and KluwerAcademicPublishers. Printedin the Netherlands
CASE REPORT Rhizomelic chondrodysplasia punctata - A new clinical variant
R. G. F. Gray 1, A. Green 1, S. Chapman 2, C. McKeown 3, R. B. H. Schutgens 4 and R. J. A. Wanders 4
Rhizomelic chondrodysplasia punctata (RCDP) (McKusick 21510) is a peroxisomal disorder characterized classically by rhizomelic limb shortening, short stature, cataracts, mental retardation and epiphyseal and extra-epiphyseal punctate calcification. Biochemically there are deficiencies of plasmalogens and dihydroxyacetonephosphate acyl-CoA transferase (DHAP-AT) (EC 2.3.1.42). Plasma phytanic acid is grossly increased and the peroxisomal fl-ketoacyl-CoA thiolase is functional but present in a 44-kDa form instead of the 42-kDa form. Recently a patient has been described (Poll-The et al 1991) with the characteristic biochemical and clinical features of this disease but without rhizomelic limb shortening. We present a case with rhizomelic limb shortening but without substantial punctate calcification. The patient was female and the first child of first-cousin Caucasian parents. At 27 weeks gestation intrauterine growth retardation was detected and the baby was delivered at 38 weeks gestation because of fetal distress. Birth weight was 2.06 kg and it was noted at birth that she had rhizomelic shortening of the arms, fixed flexion of the elbows and abnormal feet. A skeletal survey at this time revealed no punctate calcification but there was coronal clefting of the vertebrae. At 18 weeks of age she was noted to be developmentally delayed and her weight and height were below the 3rd centile. She had a large fontanelle, a flat nasal bridge, hypertelorism, anteverted nares and a long philtrum. The hands exhibited campylodactyly with abnormal palmar creases, and there was limited movement of the knees and hips with prominent tall. The chest was long and narrow. The eyes showed evidence of early cataract formation. At 8 months of age a further skeletal survey revealed traces of punctate calcification of the epiphyses and spine. Echocardiography revealed pulmonary stenosis and an atrial septal defect. The electroretinogram was grossly abnormal. Erythrocyte plasmalogens and ptatelet and cultured fibroblast DHAP-AT were grossly deficient. Plasma phytanic acid was grossly elevated. The peroxisomal flketothiolase was present in its 44-kDa form. Plasma and cultured fibroblast very long-chain fatty acid profiles were normal (Wanders et al 1991). At 12 months of age she weighed only 3 kg. She was started on a reduced phytanic acid diet (< 5 mg phytanic acid per day). The diet substantially reduced plasma phytanic acid concentrations from a pretreatment level of 300#g/ml to a level of !Clinical Chemistry, Children's Hospital, Birmingham, UK; 2Department of Radiology, ChiIdren's Hospital, Birmingham, UK; 3Clinical Genetics, East Birmingham Hospital, Birmingham, UK; 4University Hospital of Amsterdam, Amsterdam, The Netherlands 931
932
Case Reports
17 #g/ml 7 months after treatment. There appeared to be some clinical improvement, but this was not sustained. At 15 months of age she developed minor seizures associated with an abnormal E E G and exhibited severe bilateral cataracts. She died aged 20 months having gained very little weight since birth. The initial observation of the absence of punctate calcification did not support the diagnosis of RCDP, although the similarity of other clinical features led to investigations for this disorder. The discovery of the typical biochemical abnormalities of R C D P extends the phenotype so that not only must the disorder be considered in patients without rhizomelic limb shortening but also in patients without puncatate calcification. The degree of punctate calcification at 8 months of age was still very slight and its detection required careful scrutiny by an experienced radiologist. The age at which punctate calcification occurs in this disorder has not been studied, although it is generally reported to be present in the neonatal period. However, examination of an abortus of 20 weeks gestation affected with the disorder failed to reveal punctate calcification (Gray et al 1990). Our patient clearly showed many of the other key features of this disorder at birth and the intrauterine growth failure suggests that clinical symptoms were present at 27 weeks gestation. This variability in expression may be a reflection of mutations in different genes or alleles or may be due to environmental influences. We thank Dr S. Brown, Consultant Paediatrician, and Mr J. Clegg, Consultant Orthopaedic Surgeon, of the Coventry and Warwickshire Hospital, Coventry UK. We also thank Mr R. A. Westhead of the Midland Centre for Neurology and Neurosurgery, Smethwick, UK.
REFERENCES
Gray RGF, Green A, Schutgens RBH, Wanders RJA, Farndon P, Kennedy CR (1990) Antenatal diagnosis of rhizomelic chondrodysplasia punctata in the second trimester. 3 Inher Metab Dis 13: 380-382. Poll-The BT, Maroteaux P, Narcy C et al (1991) A new type of chondrodysplasia punctata associated with peroxisomal dysfunction. J Inher Metab Dis 14: 361-363. Wanders RJA, Schutgens RBH, Van Den Bosch H, Tager JM, Kleijer WJ (199t) Prenatal diagnosis of inborn errors in perixisomal metabolism. Prenat Diagn 11: 253-261.
J. Inher. Metab. Dis. 15 (1992)
CASE REPORT Rhizomelic chondrodysplasia punctata - A new clinical variant
R. G. F. Gray 1, A. Green 1, S. Chapman 2, C. McKeown 3, R. B. H. Schutgens 4 and R. J. A. Wanders 4
Rhizomelic chondrodysplasia punctata (RCDP) (McKusick 21510) is a peroxisomal disorder characterized classically by rhizomelic limb shortening, short stature, cataracts, mental retardation and epiphyseal and extra-epiphyseal punctate calcification. Biochemically there are deficiencies of plasmalogens and dihydroxyacetonephosphate acyl-CoA transferase (DHAP-AT) (EC 2.3.1.42). Plasma phytanic acid is grossly increased and the peroxisomal fl-ketoacyl-CoA thiolase is functional but present in a 44-kDa form instead of the 42-kDa form. Recently a patient has been described (Poll-The et al 1991) with the characteristic biochemical and clinical features of this disease but without rhizomelic limb shortening. We present a case with rhizomelic limb shortening but without substantial punctate calcification. The patient was female and the first child of first-cousin Caucasian parents. At 27 weeks gestation intrauterine growth retardation was detected and the baby was delivered at 38 weeks gestation because of fetal distress. Birth weight was 2.06 kg and it was noted at birth that she had rhizomelic shortening of the arms, fixed flexion of the elbows and abnormal feet. A skeletal survey at this time revealed no punctate calcification but there was coronal clefting of the vertebrae. At 18 weeks of age she was noted to be developmentally delayed and her weight and height were below the 3rd centile. She had a large fontanelle, a flat nasal bridge, hypertelorism, anteverted nares and a long philtrum. The hands exhibited campylodactyly with abnormal palmar creases, and there was limited movement of the knees and hips with prominent tall. The chest was long and narrow. The eyes showed evidence of early cataract formation. At 8 months of age a further skeletal survey revealed traces of punctate calcification of the epiphyses and spine. Echocardiography revealed pulmonary stenosis and an atrial septal defect. The electroretinogram was grossly abnormal. Erythrocyte plasmalogens and ptatelet and cultured fibroblast DHAP-AT were grossly deficient. Plasma phytanic acid was grossly elevated. The peroxisomal flketothiolase was present in its 44-kDa form. Plasma and cultured fibroblast very long-chain fatty acid profiles were normal (Wanders et al 1991). At 12 months of age she weighed only 3 kg. She was started on a reduced phytanic acid diet (< 5 mg phytanic acid per day). The diet substantially reduced plasma phytanic acid concentrations from a pretreatment level of 300#g/ml to a level of !Clinical Chemistry, Children's Hospital, Birmingham, UK; 2Department of Radiology, ChiIdren's Hospital, Birmingham, UK; 3Clinical Genetics, East Birmingham Hospital, Birmingham, UK; 4University Hospital of Amsterdam, Amsterdam, The Netherlands 931
932
Case Reports
17 #g/ml 7 months after treatment. There appeared to be some clinical improvement, but this was not sustained. At 15 months of age she developed minor seizures associated with an abnormal E E G and exhibited severe bilateral cataracts. She died aged 20 months having gained very little weight since birth. The initial observation of the absence of punctate calcification did not support the diagnosis of RCDP, although the similarity of other clinical features led to investigations for this disorder. The discovery of the typical biochemical abnormalities of R C D P extends the phenotype so that not only must the disorder be considered in patients without rhizomelic limb shortening but also in patients without puncatate calcification. The degree of punctate calcification at 8 months of age was still very slight and its detection required careful scrutiny by an experienced radiologist. The age at which punctate calcification occurs in this disorder has not been studied, although it is generally reported to be present in the neonatal period. However, examination of an abortus of 20 weeks gestation affected with the disorder failed to reveal punctate calcification (Gray et al 1990). Our patient clearly showed many of the other key features of this disorder at birth and the intrauterine growth failure suggests that clinical symptoms were present at 27 weeks gestation. This variability in expression may be a reflection of mutations in different genes or alleles or may be due to environmental influences. We thank Dr S. Brown, Consultant Paediatrician, and Mr J. Clegg, Consultant Orthopaedic Surgeon, of the Coventry and Warwickshire Hospital, Coventry UK. We also thank Mr R. A. Westhead of the Midland Centre for Neurology and Neurosurgery, Smethwick, UK.
REFERENCES
Gray RGF, Green A, Schutgens RBH, Wanders RJA, Farndon P, Kennedy CR (1990) Antenatal diagnosis of rhizomelic chondrodysplasia punctata in the second trimester. 3 Inher Metab Dis 13: 380-382. Poll-The BT, Maroteaux P, Narcy C et al (1991) A new type of chondrodysplasia punctata associated with peroxisomal dysfunction. J Inher Metab Dis 14: 361-363. Wanders RJA, Schutgens RBH, Van Den Bosch H, Tager JM, Kleijer WJ (199t) Prenatal diagnosis of inborn errors in perixisomal metabolism. Prenat Diagn 11: 253-261.
J. Inher. Metab. Dis. 15 (1992)
