PRENATAL DIAGNOSIS, VOL.

12, 19-29 ( 1992)

PRENATAL DIAGNOSIS AND INVESTIGATION OF A FETUS WITH CHONDRODYSPLASIA PUNCTATA, ICHTHYOSIS, AND KALLMANN SYNDROME DUE TO AN Xp DELETION PRICES,

DAVID P. BICK*, DANIEL F. SCHORDERET~,PAUL A. LESLIE CAMPBELL§, ROBERT w. HUFFJJ,LARRY J. S H A P I R O ~AND CHARLEEN M. MOORE**

*Geneticsand IVF Institute, Fairfax, Virginia, U.S.A.;?Department of Genetics, University of Washington, Seattle, Washington, U.S.A.;$Department ofBiology, University of California. San Diego, California. U.S.A.;qHoward Hughes Medical Instituie. Department of Pediatrics and Biological Chemistry. University of California. Los Angeles, California, U.S.A.;and the Departments of Pediatrics§, Obstetrics and Gynecologd, and Cellular and Structural Biology*'. University of Texas Health Science, Center at San Antonio, Texas, U.S.A.

SUM MARY We report the prenatal diagnosis of a male fetus with X-linked recessive chondrodysplasia punctata (CDPX), steroid sulphatase (STS) deficiency, X-linked Kallmann syndrome (KAL), and a chromosome deletion at Xp22.31. Biochemical analysis of bone from this case indicates that CDPX is not a defect of vitamin K metabolism. Immunocytochemical study of the brain suggests that KAL is a defect in neuronal migration. KEY WORDS

Chondrodysplasiapunctata Steroid sulphatase deficiency Kallmann syndrome Neuronal migration Vitamin K

INTRODUCTION The 'contiguous gene syndromes' are disorders characterized by a complex disease phenotype that is the result of the deletion or duplication of physically contiguous genes on a chromosome (Schmickel, 1986).More than 20 such syndromes have been identified throughout the genome (Harper et al., 1989; Ballabio et al., 1989). One of these contiguous gene syndromes is found at Xp22.3 (Harper et al., 1989). Deletions and translocations of this region can result in one or more of the following disorders, depending on the extent of the deletion: (1) X-linked Kallmann syndrome (KAL), a neurologic disorder, primarily characterized by hypogonadism due to hypothalamic gonadotropin-releasing hormone deficiency and anosmia secondary to an absence of olfactory bulbs and tracts, which is often associated with unilateral renal hypoplasia (Hermanussen and Sippell, 1985); (2) X-linked ichthyosis due to steroid sulphatase (STS) deficiency, a dermatologic disorder distinguished by the presence of large, dry, yellow-brown scales and corneal opacities (Williams and Elias, 1987) caused by a deficiency of the microsomal enzyme steroid sulphatase (Shapiro, 1989); (3) X-linked mental retardation (MRX), one of perhaps six nonspecific mental retardation loci on the X chromosome (Ballabio et al., 1989); Addressee for correspondence: David P. Bick, MD, Genetics and IVF Institute, 3020 Javier Rd., Fairfax, VA 22031, U.S.A.

0 197-385 1/92/010019-1 1$05.50 0 1992 by John Wiley & Sons, Ltd.

Received 20 November I990 Accepted 1 June I991

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Figure 1. (a) G-banded X chromosomes from two representative cells in the mother. Arrows indicate the breakpoint at Xp22.31. (b) G-banded X and Y chromosomes prepared from two amniocytes, showing deleted X

(4) X-linked recessive chondrodysplasia punctata (CDPX), a skeletal disorder characterized by punctate calcification or stippling of cartilage, distal phalangeal hypoplasia, and nasal hypoplasia (Curry et al., 1984); and (5) short stature (Ballabio et al., 1989). Prenatal diagnosis of a male fetus affected by a contiguous gene syndrome at Xp22.3 has been accomplished using cytogenetic, molecular genetic, and biochemical techniques. He had KAL, STS deficiency, CDPX, and an Xp chromosome deletion. Further investigation of the fetus yielded clues to the pathogenesis of KAL (Schwanzel-Fukuda et al., 1989) and CDPX.

CASE REPORT A 23-year-old Hispanic G,P, Xp chromosome deletion carrier had previously delivered a normal male and subsequently a male infant with CDPX, STS deficiency, KAL, and a terminal deletion at Xp22.31 (Bick et al., 1989a). During the third pregnancy, amniocentesis at 15 weeks revealed an amniotic fluid dehydroepiandrosterone sulphate (DHEAS) level of 300 pg/ml (normal range at this gestation 16-50pg/ml). The karyotype was 46,del(X)(p22.3 1),Y (Figure 1). Cultured amniocyte STS activity was assayed using estrone sulphate substrate and found to be less than 5 pmol/h per mg protein (normal 100-600 pmol/h per mg protein) (Schorderet et al., 1988). Prior to termination a t 19 weeks, an ultrasound study identified nasal hypoplasia (Figure 2). The abortus (Figures 3a and 3b) weighed 215 g and was 20cm in length. The crown-rump length was 14.8 cm. The eyelids were fused. The ears were dysplastic

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Figure 2. Ultrasound examination at 19 weeks showing nasal hypoplasia in a midsagittal view

and 1 cm in length. The nose was hypoplastic with a depressed nasal bridge, a short septum, and a deep groove between the tip of the nose and the alae nasi. There was diastasis recti and a three-vessel umbilical cord. The phallus was very small, measuring 0.8 cm, and the testes were undescended. The limbs appeared short. Arm span was 17.5 cm. There was camptodactyly of the distal interphalangeal joints of all digits. Hand length was 2 cm and middle finger length was 0.6 cm. Foot length was 2.5 cm. All digits appeared broad and short. There was bilateral fifth-finger clinodactyly. The calcanei were prominent. Radiologic examination (Figure 4) showed paravertebral and epiphyseal stippling of cartilage as well as distal phalangeal hypoplasia. At autopsy, the brain showed bilateral absence of olfactory bulbs and tracts. The thymus was hypoplastic. There was a horseshoe kidney (Figure 5). The testes appeared normal in size. DNA was prepared from fetal liver, digested with BglII, Southern blotted onto Nytran (Schleicher and Schuell), and hybridized with the probe dic56, a probe that detects a single copy sequence in Xp22.3 (Old, 1986; Southern, 1975; Feinberg and Vogelstein, 1983; Kidd et af., 1989). Figure 6 demonstrates that dic56 recognized a 6.8 kb fragment in a control male but failed to hybridize to the fetal DNA, indicating that the fetus had a deletion involving that locus. Prenatal testing in a subsequent pregnancy showed a 46,XY karyotype, normal STS amniocyte activity, and an intact STS gene by Southern blot analysis of amniocyte DNA followed by the birth o f a normal male child.

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h

e

m

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Figure 4. Radiograph of affected fetus showing chondrodysplasia punctata and distal phalangeal hypoplasia

INVESTIGATION OF CDPX PATHOGENESIS A study of bone from the affected fetus and age-matched controls for matrix Gla protein (MGP) content was undertaken. The bone was prepared and MGP content

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Figure 5. Horseshoe kidney noted at autopsy

Probe: dic56 1 2

6.8 Kb -

Figure 6 . Southern analysis of DNA from the affected fetus (lane 1) and a male control (lane 2). The probe dicS6 was labelled by random oligonucleotide priming and recognizes a 6.8 kb fragment in lane 2. There is no signal in lane 1 indicating a deletion at this locus

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Table 1. MGP content of bone from a fetus with CDPX

Sample Control ( N = 3) CDPX Control epiphysis CDPX epiphysis

Formic acid extracted (ng MGP/mg dry wt)

Guanidine extracted (ng MGP/mg dry wt)

76-106 50.6 Not done Not done

154-343 81

20-6 24.1

measured as described (Hale et al., 1988). While MGPcontent was somewhat lower in total bone from the affected fetus as compared with control samples, MGP content in epiphyses appeared identical (Table 1). DISCUSSION Prenatal assessment of a fetus with a contiguous gene syndrome affords an unusual opportunity to develop a diagnosis using multiple independent pieces of evidence. In our case, prenatal diagnosis and post-mortem confirmation were readily demonstrated through cytogenetic and molecular evidence of a deletion and through study of the individual gene loci involved in the deletion. Cytogenetic analysis represents one general method of establishing the aetiology of a contiguous gene syndrome (Gessler et al., 1989). In our case, we demonstrated, prenatally, a small terminal deletion at Xp22.3 1. Many contiguous gene syndromes, however, are due to cytogenetically invisible deletions (Ledbetter et al., 1989). In these cases, molecular genetic analysis can establish the diagnosis. In our case, DNA analysis of a brother with the same deletion had shown that a number of contiguous loci were deleted (Bick et al., 1989b). Post-mortem DNA analysis using a probe, dic56, that recognizes one of the loci, DXS143, within the deletion confirmed the diagnosis. STS deficiency was diagnosed prenatally by demonstrating an elevation of amniotic fluid DHEAS, a substrate for STS (Shapiro, 1989), and by demonstrating the absence of amniocyte STS activity. These results are consistent with the biochemical and molecular analysis of fibroblasts from the affected brother which showed no STS activity and a deletion of the STS locus (Bick et al., 1989a,b). Our data are consistent with previous work in prenatal and postnatal diagnosis of STS deficiency (Herrmann et al., 1989). Prenatal diagnosis of CDPX was accomplished by ultrasound examination of the nasal region. This was confirmed by the post-mortem examination and X-ray evaluation. Parent et al. (1 989) reported prenatal diagnosis of chondrodysplasia punctata by ultrasound examination. These investigators demonstrated profound nasal hypoplasia at 20 and 31 weeks in two pregnancies of two different families with previously affected sons. Examination and radiographic evaluation following termination of the 20-week pregnancy and birth of the other child revealed punctate calcification, distal phalangeal hypoplasia, and a facial appearance similar to our case. Curry et al. (1984) have also studied two fetuses with CDPX, one at 22 weeks

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and one at 14 weeks. While they found the same facial appearance and distal phalangeal hypoplasia as those seen in our case, they did not see unusual calcification or stippling. Analysis of DNA from our case and one of Curry et al.’s cases (case B) shows that they both have a chromosome deletion stretching from the locus DXS143 into the pseudoautosomal region of the X chromosome and therefore encompassing the entire CDPX locus (Bick et al., 1989b and unpublished observation) Thus, simple differencesin the nature of the mutation at the CDPX locus do not explain the difference in phenotypes. A comparison of the phenotypic features of warfarin embryopathy, vitamin K epoxide reductase deficiency (VKERD), and CDPX shows a remarkable similarity, suggesting that these disorders share a common pathogenesis (Bick et al., 1989a; Pauli, 1988). Current evidence indicates that warfarin exerts its effect on the developing fetus by inhibiting vitamin K-dependent post-translational carboxylation of certain bone proteins. During the process of vitamin K-dependent carboxylation, vitamin K is converted to vitamin K epoxide. The enzyme vitamin K epoxide reductase then converts the epoxide back to vitamin K. Warfarin exerts its effect by inhibiting this reductase, thereby depriving the vitamin K-dependent carboxylases of their cofactor. Given this evidence, it is not surprising that warfarin embryopathy and VKERD have a similar phenotype. While warfarin embryopathy and VKERD share a common pathogenesis through vitamin K epoxide reductase, it has been show that CDPX does not (Bick et at., 1989a). Hence an investigation of MGP and oesteocalcin, two bone proteins that undergo vitamin K-dependent carboxylation, was undertaken. Our data indicated that the MGP content of CDPX bone at the site of the abnormal calcification, the epiphysis, was normal, suggesting that matrix Gla protein deficiency is not the cause of CDPX. Analysis of the osteocalcin levels in one of the CDPX patients described by Curry et al. (1984) showed normal levels of osteocalcin with normal levels of carboxylation of the protein, suggesting that neither osteocalcin nor its bone carboxylase causes CDPX (unpublished observation). It is interesting to note that two of the other known causes of chondrodysplasia punctata are peroxisome defects: rhizomelic chondrodysplasia punctata, a defect in peroxisome distribution and structure (Lazarow and Moser, 1989); and X-linked dominant chondrodysplasia punctata, a defect in the peroxisomal enzyme dihydroxyacetone phosphate acetyl transferase (Wilson et al., 1988; Clayton et al., 1989). While we have previously eliminated a generalized deficiency of peroxisomes as the cause of CDPX (Bick et al., 1989a), further study of individual peroxisomal enzymes may disclose the cause of this disorder. Prenatal diagnosis of KAL in this case was accomplished by identifying an Xp deletion that included the KAL locus, found between STS and DXS143 (Ballabio et al., 1989). Because STS and DXS143 were both deleted in this case and because the fetus had the same deletion as a previously affected sibling known to have KAL, it was clear that this fetus would have KAL. Recent work by Meitinger et al. (1989) has shown that the highly polymorphic probe CRI-S232 is very closely linked to KAL and should permit prenatal diagnosis by linkage analysis in families without contiguous gene syndromes. Careful study of the brain and nasal region from this case showed that the luteinizing hormone-releasing hormone (LHRH) cells and the olfactory, terminalis,

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and vomeronasal nerves developed normally from the olfactory placode, but failed to migrate properly, ending prematurely at the meninges. The absence of olfactory nerve connection to the forebrain can therefore explain the anosmia found in KAL, while the failure of LHRH cells to reach the hypothalamus would account for the LHRH deficiency seen in KAL (Schwanzel-Fukuda et al., 1989). Most disorders of neuronal migration in man are associated with extensive brain abnormalities that are profoundly debilitating or lethal (Barth, 1987; Dobyns, 1989).Thus, it is not surprising to find that some affected individuals in families with Kallmann syndrome have neurologic abnormalities beyond LHRH deficiency and anosmia including mental retardation, synkinesis, colour blindness, and spastic paraplegia (Kallmann et al., 1944; Wegenke et al., 1975; Turner et al., 1974), suggesting that the brain malformations in this disorder may be more extensive than previously suspected. The other brain abnormalities may be secondary to the absence of LHRH cells in the brain. It is known, for example, that LHRH cells project efferent fibres to many areas of the central nervous system (Witkin et al., 1982). Alternatively, the KAL gene product itself may be involved in areas of the developing brain beyond those described (Schwanzel-Fukuda et al., 1989). The presence of renal malformations in some * X-linked Kallmann patients (Hermanussen and Sippel, 1985; Wegenke et al., 1975) may also be explained by a gene with pleiotropic effects. It is interesting to note that the renal malformations in this case and in a previously affected sibling with the same deletion were different. The KAL gene may be one of a number of loci critical to this developmental field (Opitz, 1982). The deletion in this case appears to extend from DSX143 to the telomere, a distance of about 10 million base pairs (Petit et al., 1990). Clearly, there are more disease loci in this region beyond the three noted in this case, STS, CDPX, and KAL, and the two described by Ballabio, non-specific X-linked mental retardation and short stature (Ballabio et al., 1989).As more loci are identified, we may be able to use tissue samples from this case to learn more about the nature of those loci. Note added in proof

Recently, Franco et al. (199 1) have isolated a cDNA, KALIG- 1 in the region of the KAL locus. Using this probe, we have studied a number of patients with isolated Kallmann syndrome and found one with an intragenic deletion within the KALIG-I gene. This data strongly supports the hypothesis that the KALIG- 1 gene is the KAL gene (Bick et al., manuscript in preparation). Bick, D., Franco, B., Ballabio, A . KALIG-I is the X-linked Kallmann syndrome gene. Manuscript in preparation. Franco, B., Guioli, S., Pragliola, A., Incerti, B., Bardoni, B., Tonlorenzi, R., Carrozzo, R., Maestrini, E., Pieretti, M., Taillon-Miller, P., Brown, C. J., Huntington, W. F., Lawrence, C., Persico, M. G., Camerino, G., Ballabio, A. (1991). A gene deleted in Kallmann syndrome shares homology with neural cell adhesion and axonal pathfinding molecules. Nature, in press. ACKNOWLEDGEMENTS

We wish to thank Merry Passage for the STS assays, Pauline Yen for the STS genomic blots, and Regina Maschino for assistance in the preparation of the

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manuscript. This work was supported by grants HD12178 from the National Institutes of Health and 1-639 from the March of Dimes (LJS) and 3.754-0.87 from the Swiss National Science Foundation (DFS). REFERENCES Ballabio, A., Bardoni, B., Carrozzo, R., Andria, G., Bick, D., Campbell, L., Hamel, B., Ferguson-Smith, M.A., Gimelli, G., Fraccaro, M., Maraschio, P., Zuffardi, O., Guioli, S., Camerino, G. (1989). Contiguous gene syndromes due to deletions in the distal short arm of the human X chromosome, Proc. Natl. Acad. Sci. USA, 86,10001-10005. Barth, P.G. (1987). Disorders of neuronal migration, Can. J. Neurol. Sci., 14, 1-16 Bick, D., Curry, C.J.R., McGill, J.R., Schorderet, D.F., Bux, R.C., Moore, C.M. (1989a). Male infant with ichthyosis, Kallmann syndrome chondrodysplasia punctata, and an Xp chromosome deletion, Am. J . Med. Genet., 33,100-107. Bick, D.P., Snead, M.L., Yen, P.H., McGill, J.R., Schorderet, D.F., Hejtmancik, F.J., Ballabio, A., Campbell, L., Moore, C.M., Curry, C.J., Lau, E.C., Shapiro, L.J. (1989b). Mapping chondrodysplasia punctata, ichthyosis, Kallmann syndrome and DNA markers in male patients with Xp chromosome deletions, Cytogenet. Cell Genet., 51,962-963. Clayton, P.T., Kalter, D.C., Atherton, D.J., Besley, G.T.N., Broadhead, D.M. (1989). Peroxisomai enzyme deficiency in X-linked dominant Conradi-Hunermann syndrome, J . Znher. Metab. Dis., 12 (Suppl. 2), 358-360. Curry, C.J.R., Magenis, R.E., Brown, M., Lanman, J.T., Tsai, J., O’Lague, P., Goodfellow, P., Mohandas, T., Bergner, E.A., Shapiro, L.J. (1984). Inherited chondrodysplasia punctata due to a deletion of the terminal short arm of an X chromosome, N . Engl. J . Med., 311,lOlO-1015. Dobyns, W.B. (1989). The neurogenetics of lissencephaly, Neurol. Clin., 7,89-105. Feinberg, A.P., Vogelstein, B. (1983). A technique for radiolabeling DNA restriction endonuclease fragments to high specific activity, Anal. Biochem., 132,613, Gessler, M., Thomas, G.H., Couillin, P., Junien, C., McGillivray, C., Hayden, M., Jaschek, G., Bruns, G.A.P. (1989). A deletion map of the WAGR region on chromosome 11, Am. J. Hum. Genet., 44,48&495. Hale, J.E., Fraser, J.D., Price, P.A. (1988). The identification of matrix Gla protein in cartilage, J. Biol. Chem., 263,5820-5824. Harper, P.S., Frezal, J., Ferguson-Smith, M.A., Schinzel, A. (1989). Report of the committee on clinical disorders and chromosomal deletion syndromes, Cytogenet. Cell Genet., 51, 563-61 1. Hermanussen, M., Sippell, W.G. (1985). Heterogeneity of Kallmann’s syndrome, Clin. Genet, 28,1061 1 1. Herrmann, F.H., Wirth, B., Wulff, K., Hadlich, J., Voss, M., Gillard, E.F., Kruse, T.A., Ferguson-Smith, M.A., Gal, A. (1989). Gene diagnosis in X-linked ichthyosis, Arch. Dermatol. Res., 280,457-461. Kallmann, F.J., Schoenfeld, W.A., Barrera, S.E. (1944). The genetic aspects of primary eunuchoidism, Am. J . Ment. Dejic., 48,203-236. Kidd, K.K., Bowcock, A.M., Schmidtke, J., Track, R.K., Ricciuti, F., Hutchings, G., Bale, A., Pearson, P., Willard, H.F., with help from Gelernter, J., Giuffra, L., Kubzdela, K. (1989). Report of the DNA committee and catalogs of cloned and mapped genes and DNA polymorphism, Cytogenet. Cell Genet, 51,622-947. Lazarow, P.B., Moser, H.W. (1989). Disorders of peroxisome biogenesis. In: Scriver, C.R., Beaudet, A.L., Sly, W.S., Valle, D. (Eds). The Metabolic Basis of Inherited Diseases, New York: McGraw-Hill, 1479-1 509. Ledbetter, D.H., Ledbetter, S.A., VanTuinen, P., Summers, K.M., Robinson, T.J., Nakamura, Y., Wolff, R., White, R., Barker, D.F., Wallace, M.R., Collins, F.S., Dobyns, W.B. (1989). Molecular dissection of a contiguous gene syndrome: frequent submicroscopic deletions, evolutionarily conserved sequences, and a hypomethylated ‘island’ in the Miller-Dieker chromosome region, Proc. Natl. Acad. Sci. USA, 86,5136-5140.

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Meitinger, T., Heye, B., Dorner, C., Sippell, W., Murken, J.D., Petit, C., Levilliers, J., Weissenbach, J., Dalla Piccola, B., Andria, G., Ballabio, A. (1989). Localization of Xlinked Kallmann syndrome (hypogonadotropic hypogonadism and anosmia) to Xp22.3: close linkage to locus DXS278, Am. J . Hum. Genet., 45, A151. Old, J.M. (1986). Fetal DNA analysis. In: Davies, K.E. (Ed.). Human Genetic Disease, A Practical Approach, Oxford: IRL Press, 1-1 7. Opitz, J.M. (1982). The developmental field concept in clinical genetics, J . Pediatr., 101, 805-809. Parent, P.H., Le Gonidec, A,, Le Guern, H., Thomas, M., Toudic, L., Bellet, M., Castel, Y. (1989). La chondrodysplasie ponctuee: a propos de quatre observations en deux fratries, J . Genet. Hum., 36,475484. Pauli, R. M. (1988). Mechanism of bone and cartilage maldevelopment in the warfarin embryopathy, Pathol. Immunopathol. Res., 7 , 107-1 12. Petit, C., Leveilliers, J., Weissenbach, J. (1990). Long-range restriction map of the terminal part of the short arm of the human X chromosome, Proc. Natl. Acad. Sci. USA, 87, 3680-3684. Schmickel, R.D. (1 986). Contiguous gene syndromes: a component of recognizable syndromes, J. Pediatr., 109,231-241. Schorderet, D.F., Keitges, E.A., Dubois, P.M., Gartler, S.M. (1988). Inactivation and reactivation of sex-linked steroid sulfatase gene in murine cell culture, Somatic Cell Mol. Genet., 14, 113-121. Schwanzel-Fukuda, M., Bick, D., Pfaff, D.W. (1989). Luteinizing hormone-releasing hormone (LHRH)-expressing cells d o not migrate normally in an inherited hypogonadal (Kallmann) syndrome, Mol. Brain Res., 6,311-326. Shapiro, L.J. (1 989). Steroid sulfatase deficiency and X-linked ichthyosis. In: Scriver, C.R., Beaudet, A.L., Sly, W.S., Valle, D. (Eds). The Metabolic Basis ofInherited Disease, New York: McGraw-Hill, 1945-1964. Southern, E.M. (1975). Detection of specific sequences among DNA fragments separated by gel electrophoresis, J. Mol. Eiol., 98, 503-517 Turner, R.C., Bobrow, M., Bobrow, L.G., MacKinnon, P.C.B., Bonnar, J., Hockaday, T.D.R., Ellis, J.D. (1974). Cryptorchidism in a family with Kallmann’s syndrome, Proc. R. SOC.Med., 67,33-35. Wegenke, J.D., Uehling, D.T., Wear, J.B., Gordon, E.S., Bargman, J.G., Deacon, J.S.R., Herrmann, J.P.R., Optiz, J.M. (1975). Familial Kallmann syndrome with unilateral renal aplasia, Clin. Genet., 7,368-381. Williams, M.L., Elias, P.M. (1987). Genetically transmitted generalized disorders of cornification, the ichthyoses, Dermatol. Clin., 5, 155-178. Wilson, G.N., Holmes, R.D., Hajra, A.K. (1988). Chondrodysplasia punctatas and the peroxisomopathies: overlapping syndrome communities, Pathol. Immunopathol. Res, 7, 113-1 18. Witkin, J.W., Paden, C.M., Silverman, A.J. (1982). The luteinizing hormone-releasing hormone (LHRH) systems in the rat brain, Neuroendocrinology, 35,429438.

Prenatal diagnosis and investigation of a fetus with chondrodysplasia punctata, ichthyosis, and Kallmann syndrome due to an Xp deletion.

We report the prenatal diagnosis of a male fetus with X-linked recessive chondrodysplasia punctata (CDPX), steroid sulphatase (STS) deficiency, X-link...
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