PEDIATRICS Vol. 120 No. 2 August 2007, pp. e436-e441 (doi:10.1542/peds.2006-2997)
EXPERIENCE & REASON |
Chondrodysplasia Punctata and Maternal Autoimmune Disease: A New Case and Review of the Literature
a Center for Craniofacial Disorders
b Division of Allergy and Immunology, Children's Hospital at Montefiore, Albert Einstein College of Medicine, Bronx, New York
ABSTRACT
Classic rhizomelic chondrodysplasia punctata is a rare, autosomal, recessively inherited disorder that is characterized by proximal shortening of the limbs, punctuate calcifications of the epiphyses, cataracts, developmental delay, and early lethality. A distinctive biochemical profile is characteristic for each of the several defects of peroxisomal metabolism. Recently, cases have been described that were not associated with peroxisomal dysfunction. These cases were found to be secondary to teratogen exposure or maternal conditions. Since 1993, there have been 9 reported cases of neonates with rhizomelic chondrodysplasia punctata who were born to mothers with connective tissue disease. We followed a newborn boy with features suggestive of rhizomelic chondrodysplasia punctata whose biochemical studies failed to demonstrate a defect in either plasmalogen or cholesterol biosynthesis. His mother developed systemic lupus erythematosus 8 months after delivery. This case is compared with the previously reported 9 cases from the literature and is instructive in demonstrating a lesser known effect of maternal autoantibodies on the fetus.
Key Words: chondrodysplasia punctata • autoimmune disease • systemic lupus erythematosus
Abbreviations: CDP, chondrodysplasia punctata • RCDP, rhizomelic chondrodysplasia punctata • VLCFA, very-long-chain fatty acid • SLE, systemic lupus erythematosus • DMA, dimethyl acetal • PTS, peroxisomal target signal • NLE, neonatal lupus erythematosus
The classic form of rhizomelic chondrodysplasia punctata (RCDP) is a rare, autosomal, recessively inherited disorder that is characterized by proximal shortening of the limbs, punctate calcifications of the epiphyses, and cataracts. Other common features include a distinct facial appearance, ichthyosis, growth failure, and psychomotor retardation. Although classic RCDP is commonly considered lethal, with death occurring by age 1 or 2 years, recent reports have documented an increased number of children who are surviving many years beyond the expected age. Approximately 60% survive the first year, 39% survive the second year, and a few survive beyond 10 years.1 As a disorder of peroxisomal function, there is usually a distinctive biochemical profile characterized by plasmalogen deficiency in red blood cells, increased plasma concentration of phytanic acid, a deficiency in the enzyme dihydroxy acetone phosphate acyltransferase, and normal concentrations of very-long-chain fatty acids (VLCFAs). In recent years, a few patients with features of RCDP who have not demonstrated abnormal peroxisomal function have been reported. Usually, such cases are secondary to teratogen exposure or maternal conditions (Table 1). Here we describe a newborn boy with features suggestive of RCDP whose biochemical studies failed to demonstrate a defect in either plasmalogen or cholesterol biosynthesis and whose mother developed systemic lupus erythematosus (SLE) 8 months after delivery.
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CASE REPORT
The propositus, a male infant, was the second child of healthy unrelated parents. His mother was 25 years old, and his father was 59 years old; both were born in the Dominican Republic. There was a history of 3 spontaneous abortions at 4 months' gestation. The pregnancy was uncomplicated except for a maternal urinary tract infection. The infant was delivered at 36 weeks' gestation by spontaneous vaginal delivery. The newborn physical examination showed a birth weight of 2176 g (25th percentile), a length of 42 cm (<10th percentile), and a head circumference of 33 cm (50th percentile). He was a short disproportionate infant in no apparent distress. His anterior and posterior fontanelles were patent. There was an upward obliquity of the palpebral fissures and bilateral epicanthal folds. No cataracts were noted. There was midfacial hypoplasia with a depressed nasal bridge, hypoplastic nasal bone, and anteverted nares. The pinnae were normally shaped and positioned, and his mouth was unremarkable. He had a short neck with nuchal fullness, a barrel-shaped chest, and slight abdominal protuberance. There were no skin lesions. Examination of the extremities revealed rhizomelic shortening of the arms and legs. There was bilateral brachydactyly of the second and third fingers. A skeletal survey demonstrated multiple anomalies including rhizomelic shortening of the extremities and the trunk. Bony stippling was noted in all of the vertebral bodies, carpal bones, and phalanges, as well as the shoulders, elbows, all of the tarsal bones and phalanges, and the knees and hips (Fig 1). There was exceptional shortening of the tibias with respect to the fibulas. The tibias also exhibited unusual cartilaginous extensions from the growth plate into the upper tibias. The pelvis appeared normal, but the spine exhibited striking changes, including very minimal ossification of the vertebral bodies, which appeared small and exhibited vertical clefts. There was also a striking decrease in the size of the vertebral bodies descending from the lower dorsal to the upper lumbar region, similar to that seen in sirenomelia. A diagnosis of RCDP was made on the basis of the rhizomelic dwarfing and punctate mineralizations. The infant was discharged from the NICU at 10 days of age. Follow-up visits at 1, 2, and 11 months and 2 years of age revealed mild psychomotor delays. He walked independently at 17 months and produces only a few words by 2 years. Psychologic evaluation at 3 and 6 months of age with the Stanford Binet intelligence scales, Fifth Edition, revealed borderline cognitive functioning with a nonverbal IQ of 81, a verbal IQ of 71, and a full-scale IQ of 74. He had severe growth retardation with height and weight below the 3rd percentile and a head circumference at the 50th percentile (Fig 2). The degree of rhizomelia has been stable, but the disproportionate growth of the digits has become more striking with the passage of time (Fig 3). A repeat skeletal survey at 19 months showed small vertebral bodies with posterior scalloping; shortening of the metacarpals and some of the proximal phalanges; multiple scattered stippled epiphyses; and flat acetabular roofs.
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Laboratory investigation was undertaken to identify any biochemical abnormalities associated with RCDP. All analyses were performed at the Kennedy Krieger Institute (Baltimore, MD). Measurement of red blood cell plasmalogen content was performed as dimethyl acetals (DMAs) as previously described.2, 3 The mean levels of C16:0 DMA/C16:0 fatty acid (0.051 µg/mL [reference mean: 0.077 µg/mL; range: 0.051–0.090 µg/mL]) and C18:0 DMAC18:0 fatty acid (0.126 µg/mL [reference mean: 0.167 µg/mL; range: 0.137–0.255 µg/mL]) were both within the reference range. VLCFA levels were also within the reference range, with a mean C26:0 level of 0.298 µg/mL (reference mean: 0.22 µg/mL; range: 0.10–0.36 µg/mL) and mean C26:1 level of 0.228 µg/mL (reference mean: 0.12 µg/mL; range: 0.02–0.22 µg/mL). The mean phytanic acid level was 0.533 µg/mL (reference range: 0.40–1.20 µg/mL). Plasma total lipid VLCFA and branched-chain fatty acid levels were measured by using capillary gas chromatography as previously described.4 Sterol quantification by gas chromatography/mass spectrometry5 revealed a normal plasma 8(9)-cholestenol level of <0.01 µg/mL (reference mean: 0.01 µg/mL; range: 0–0.10 µg/mL) and lymphoblast 8(9)-cholestenol/cholesterol ratio percent of 0.63 (control value: 0.16%; range: 0.04%–0.63%) (Table 2).
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The patient's mother developed a pruritic erythematous rash on the dorsum of the hands, right axilla, and inguinal areas
8 months after the delivery, accompanied by joint pain of the hands and the feet. Routine maternal laboratory test results included a slightly elevated erythrocyte sedimentation rate (35 mm/hour) and normal urinalysis and serum urea nitrogen and creatinine levels. Results of a punch biopsy of the dorsum of her left hand were consistent with discoid lupus erythematosus. Maternal serology results were diagnostic of SLE (positive for antinuclear antibody with a 1:640 titer in a speckled pattern; negative for anti-DNA antibody at 3.7 IU/mL [reference: <70.1 IU/mL]; negative for anticardiolipin antibodies; positive for extractable nuclear antigen with an anti-SM level of 36.90 EU/mL [reference: <20.01 EU/mL] and anti-RNP level of 166.30 EU/mL [reference: <20.01 EU/mL]; positive for anti-SSA[Ro] at 133.4 EU/mL [reference: <25.1 EU/mL]; positive for anti-SSB[La] at 149.7 EU/mL [<25.1 EU/mL]; a C4 component level of 24 mg/dL [reference: 16–56 mg/dL]; and immune activation complement of >250 U/mL [reference: 120–250 U/mL]), and the mother was begun on Plaquenil.
DISCUSSION
Chondrodysplasia punctata (CDP) describes a diverse group of disorders, all of which share in common punctate calcification of cartilage (Table 1). These include peroxisome biogenesis disorders (Zellweger syndrome, neonatal adrenoleukodystrophy, infantile Refsum disease, and RCDP1), maternal conditions, and teratogen exposure. Our patient presented with many of the characteristic features of RCDP. He differs clinically from the majority of patients with RCDP in that he has only mild developmental delays and lacks cataracts, and biochemical analysis failed to demonstrate a marked deficiency of red blood cell plasmalogens or any other commonly reported abnormality. Peroxisomal target signals (PTS1 and PTS2) serve to select and tag imported peroxisomal proteins. Peroxisomal receptors bind specific signals. The receptor, PEX7, binds only PTS2-containing proteins. The PEX7 receptor has been found to be absent in classical RCDP. Variant forms of RCDP have been categorized as nonclassical RCDP. Patients with classical RCDP have defective plasmalogen synthesis, phytanic acid oxidation, and proteolytic processing of peroxisomal thiolase. Patients with nonclassic RCDP manifest low plasmalogen levels as their sole biochemical abnormality. Nonclassical RCDP results from single rather than multiple peroxisomal enzyme defects and often present with milder phenotypes. CDPX1 and CDPX2 are X-linked forms secondary to a defect in arylsulfatase E and sterol 
8-isomerase, respectively. Our patient presented with normal plasmalogen and cholesterol levels.
Known teratogens include rubella, warfarin, and dilantin. Maternal factors include autoimmune disease and maternal phenylketonuria. Our patient is only the tenth reported patient born to a mother with SLE since the first report by Costa et al6 in 1993 (Table 3). His is not the first case in which the mother developed SLE postnatally.7, 8 Seven of the 10 have survived the newborn period. The longest reported survivor was growth retarded and had near-normal cognitive development at 35 months. Only 3 have had the characteristic skin lesions of neonatal lupus erythematosus (NLE), and none have had congenital heart block.
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The proposed mechanism for the bony defects and stippling in CDP-associated maternal lupus is immune-mediated by maternal autoantibodies crossing the placenta in early to midgestation and may involve the inhibition of a high-affinity calcium-binding protein, calreticulin, which is a multifunctional protein of the endoplasmic reticulum. Ro/SSA is an autoantigen complex that may include calreticulin. Autoantibodies to calreticulin and Ro/SSA are involved in the pathogenesis of congenital heart block and the cutaneous lesions of NLE and may also be responsible for the skeletal changes as a result of the inhibition of calcium binding. Recent study of an animal model demonstrated that immunization of mice with Ro resulted in the production of anti-Ro, anti-La, and anti-calreticulin antibodies and supported the role for immunity against the Ro particle and calreticulin in the development of conduction defects.9 Our patient's mother was positive for Ro/SSA. Alternatively, it was suggested that maternal autoantibodies affect the infant's vitamin K metabolism10 and result in bleeding into the epiphyseal cartilage, which produces the stippled appearance. However, the punctate calcifications are more probably caused by disharmonious ossification of the epiphyses, because blood is not generally this radiodense. This stippling disappears at
6 to 9 months, whereas the shortening of the limbs is permanent. Studying the antibody profiles in the maternal circulation of affected offspring is a first step in elucidating the causative mechanism, because there is no naturally occurring animal model for CDP.11 Autoantibodies may be the largest single risk factor for the development of CDP in the neonate, and not the maternal disease status, but the presence of autoantibodies cannot be the only determining factor to predict the occurrence of CDP, because the incidence of CDP in infants of mothers with SLE is very low.
CONCLUSIONS
Newborns born to mothers with SLE should be evaluated initially for clinical features of CDP, and mothers of infants with CDP should be followed for signs of autoimmune disease.
FOOTNOTES
Accepted Jan 29, 2007.
Address correspondence to Alan L. Shanske, MD, Center for Craniofacial Disorders, Children's Hospital at Montefiore, 3415 Bainbridge Ave, Bronx, NY 10467. E-mail: ashanske{at}montefiore.org
The authors have indicated they have no financial relationships relevant to this article to disclose.
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PEDIATRICS (ISSN 1098-4275). ©2007 by the American Academy of Pediatrics
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