American Journal of Medical Genetics 41:184-187 (1991)
Deletion of the Distal Short Arm of the X Chromosome (Xp) in a Patient With Short Stature, Chondrodysplasia Punctata, and X-Linked Ichthyosis Due to Steroid Sulfatase Deficiency A. Ballabio, M. Zollo, R. Carrozzo, A. Caiulo, 0. Zuffardi, C. F. Cascioli, D. Viggiano, and P. Strisciuglio Dipartimento di Pediatria, Uniuersita di Reggw Calabria (A.B.), Istituto Znternazwnale di Genetica e Biofisica, Napoli (M.Z.), Dipartimento di Pediatria, Uniuersita di Napoli (R.C., C.F.C., D.V., P.S.), Zstituto di Biologia e Genetica Medica, Uniuersita di Pauia (A.C., O.Z.), Italy
We observed a boy with short stature, chondrodysplasia punctata, ichthyosis, and a terminal deletion of Xp. Steroid sulfatase deficiency was demonstrated in the patient’s fibroblasts. Molecular analysis showed a deletion of the entire steroid sulfatase gene. This case represents another example of a contiguous gene syndrome in which the co-deletion of adjacent genes on a chromosome is responsible for a complex phenotype. KEY
WORDS: short stature, chondrodysplasia punctata, Xlinked ichthyosis, steroid sulfatase, Xp deletion, contiguous gene syndromes
acterized by the presence of brown scaly skin [see Shapiro, 1989 for review]. The gene for XLUSTS deficiency has been assigned to the Xp22.3 by deletion mapping [Tiepolo et al., 19801. We and others have observed patients with complex phenotypes characterized by the association of XLI with Kallmann syndrome, CDPX, short stature, and mental retardation in variable combinations [Curry et al., 1984; Sunohara et al., 1986; Andria et al., 1984; Ballabio et al., 1986, 19881 in whom STS gene deletions were observed. In this report we describe a boy with a terminal deletion of Xp. A partial description of this case was included in a recent survey of 27 patients with deletion in the Xp22.3 region [Ballabio et al., 19891. Here we report a detailed clinical description of this patient and the results of chromosome and DNA analysis using the full length STS cDNA as a probe.
CLINICAL REPORT This male infant was born by caeserean section at the 41st week of gestation t o a 27-year-oldmother. His birth weight, length, and head circumference were 3,150g (25th-50th centile), 47 cm (10th centile), and 33.5 cm (25th-50th centile), respectively. At birth he had severe nasal hypoplasia (Figs. 1,2), ichthyosis, and splenomegaly. X-Ray analysis showed punctate calcification of the paravertebral epiphyses (Fig. 3A) and pelvis and distal phalangeal hypoplasia (Fig. 3B). Absence of the 12th ribs was also noted. On a second examination a t age 8 months his weight was 9 kg (50th centile), length 65 cm (belowthe 5th centile) and head circumference43 cm (10th centile). Ophthalmological examination of the patient did not show any sign of ocular albinism. Renal echography did not show abnormalities. The BruFteceived for publication October 23, 1989; revision received n6t-Lezine test performed a t 19 months of age showed an I.&. = 77 (v.n. > 80). Moreover the child apparently June 20, 1990. Address reprint requests to Pietro Strieciuglio, M.D., Diparti- has normal hearing and absence of anosmia and hypogonadism. We also evaluated the patient’s mother who mento di Pediatria Via S. Pansini, 5, 80131 Napoli, Italy. Present address of A. Ballabio: Institute for Molecular Genetics, had short stature (141 cm), short arms, and brachyBaylor College of Medicine, 1 Baylor Plaza, Houston, TX. dactyly.
INTRODUCTION The X-linked recessive type of chondrodysplasia punctata (CDPX) is characterized by short stature, unusual face due to nasal hypoplasia, focal calcification of cartilage, detectable as radiologic stippling of epiphyses, and distal phalangeal hypoplasia [see Maroteaux, 1989 for review]. In the last few years several groups have reported CDPX associated with a terminal deletion of Xp [Curry et al., 1984; Bick et al., 19891 or with an XIY translocation involving the distal Xp [Agematsu et al., 1988; Ballabio et al., 19881.Therefore the CDPX locus was assigned to the Xp22.3 region and we tentatively mapped it distally to STS [Ballabio et al., 19881. X-linked ichthyosis (XLI)due t o steroid sulfatase (STS) deficiency is an inborn error of metabolism char-
0 1991 Wiley-Liss, Inc.
Chondrodysplasia Punctata and X-Linked Ichthyosis
Fig. 1. Nasal hypoplasia and flat nasal bridge are present.
CYTOGENETIC STUDIES Chromosome preparations from cultured lymphocytes of the propositus were made using standard methods. High-resolution karyotypes were obtained after BrdU synchronization, thymidine release, and G-banding after Hoechst staining [Dutrillaux and Viegas-Pequignot, 19811. On prometaphase analysis a
185
Fig. 2. Front view of patient.
terminal deletion of Xp was seen (Fig. 4a). The same deletion was present in one X chromosome of the mother (Fig. 4b). The replication pattern of the mother’s X chromosomes was studied in lymphocytes by high resolution G-banding [Dutrillaux and Viegas-Pequignot, 19811. Among 36 informative metaphases, 28 showed the deleted X to be late replicating while in 8 metaphases it
Fig. 3. X-ray films show punctate calcification of the epiphyses (A)and distal phalangeal hypoplasia (B).
186
Ballabio et al.
Fig. 4. (a)From left to right: idiogram of a normal chromosome X (the arrow indicates the breakpoint of the propositus’ X chromosome), a normal chromosome X from a 46XY male, two deleted X chromosomes from the patient. The distal band on the X short arm appears thicker in the normal than in the patient’s X chromosomes. (b)The normal (left)and the deleted (right) X chromosomes from the propositus’mother. ( c ) Chromosomes 9 from the propositus’mother: that on the right shows a extra G positive band proximally on the short arm. The same variant is present in the propositus.
was the normal X to be late replicating. The propositus cognizable syndromes [Schmickel,19861.There are sevand his mother had a variant of one chromosome 9 eral examples of such entities characterized by the (Fig. 4c) with an additional dark G-band in the proximal association of disorders whose loci, being in contiguous portion of the short arm. This variant, first seen in the regions on a chromosome, may be co-deleted in some mother’s karyotype, was initially suspected to be an patients [see Emanuel 1988, for review]. insertion of the region deleted from the X but its presIn recent studies we described the association of difference in the propositus, who has a deletion syndrome, ent disorders, such as STS deficiency, CDPX, mental seems to exclude such an hypothesis. The appearance retardation, short stature, and Kallmann syndrome, in and the localization of this extra band are similar to the 27 patients with deletions in Xp22.3, demonstrating the rare variant of chromosome 9 described by Spedicato et presence of contiguous gene syndromes [Ballabio et al., al. [1985].In conclusion the karyotypes ofthe propositus 19891. In the case described in the present paper the and his mother were 46,Y,del(X)(p22.32+pter),9p+ hypothesis of a contiguous gene syndrome was made at and 46,X,del(X)(p22.32+pter),9p + . The STS assay, birth solely on the basis of the patient’s clinical maniperformed on the patient’s cultured skin fibroblasts festations. Subsequent karyotype and molecular analusing a previously described method [Ballabio et al., ysis documented the presence of a terminal deletion of the distal Xp. Clinical heterogeneity should always 19851, showed absence of enzyme activity. Patient’s DNA, obtained from a venous blood sample, alert the clinician to the possible involvement of differwas analyzed by standard Southern blot analysis using ent loci through a deletion. On the other hand, maniprobe 7A5B, a full length STS cDNA, which was derived festations of some disorders may be overlooked in some from a previously isolated STS cDNA clone [Ballabio et cases depending on the age at which the patient is examal., 19871. Deletion ofthe entire STS gene was confirmed ined. Radiological manifestations of CDPX are age-deby the absence of the expected hybridization bands pendent and tend to disappear during childhood [Ballabio et al., 1987; Silengo et al., 19801.For these reasons (Fig. 5). high-resolution karyotype analysis should be performed DISCUSSION in order to detect a chromosomal abnormality. However, In 1986 Schmickel indicated the importance of look- in some instances a deletion will only be detected at the ing at contiguous gene syndromes as components of re- molecular level.
Chondrodysplasia Punctata and X-Linked Ichthyosis
187
REFERENCES
C P Fig. 5. Southern blot analysis of EcoRI restricted DNA from the proband (P)and a control (C). The filter was hybridized to probe 7A5B, which is a full length STS cDNA clone. A normal pattern is observed in lane C whereas only a band correspondingto the STS pseudogene on the Y chromosome is visible in lane P, thus revealing a n entire STS gene deletion in the patient.
In conclusion, our findings confirm that small cytogenetic abnormalities in the distal Xp may cause the association of different mendelian disorders, such as X-linked ichthyosis due to STS deficiency and CDPX, demonstrating that a n accurate characterization of the molecular defect underlying the patient’s phenotype may have important implications for both genetic counseling and treatment.
ACKNOWLEDGMENTS A.C. is supported by Associazione Studio Malformazioni-Milano. This work was supported in part by Grant SCE-0140 from the Commission of the European Community.
Agematsu K, Koike K, Morosawa H, Nakahori Y, Nakagome Y, Akabane T (1988): Chondrodysplasia punctata with WY translocation. Hum Genet 80:105-107. Andria G, Ballabio A, Parenti G, Di Maio S, Piccirillo A (1984):Steroid sulphatase deficiency is present in patients with X-linked ichthyosis and male hypogonadism and with Rud syndrome. J Inher Metab Dis (Suppl 2) 7:158-160. Ballabio A, Parenti G, Napolitano E, Di Natale P, Andria G (1985): Genetic complementation of steroid sulphatase after somatic cell hybridization of X-linked ichthyosis and multiple sulphatase deficiency. Hum Genet 70:315-317. Ballabio A, Parenti G, Tippett P, Mondello C, Di Maio S, Tenore A, Andria G (1986): X-linked ichthyosis due to steroid sulphatase deficiency, associated with Kallmann syndrome (hypogonadotropic hypogonadism and anosmia): Linkage relationships with Xg and cloned DNA sequences from the distal short arm of the X chromosome. Hum Genet 72:237-240. Ballabio A, Parenti G, Carrozzo R, Sebastio G, Andria G, Buckle V, Fraser N, Boyd Y, Craig I, Rocchi M, Romeo G, Jobsis AC, Persico MG (1987): Isolation and characterization of a steroid sulphatase cDNA clone: Genomic deletions in patients with X-chromosomelinked ichthyosis. Proc Natl Acad Sci USA 844519-4523. Ballabio A, Parenti G, Carrozzo R, Coppa G, Felici L, Migliori V, Silengo M, Franceschini P, Andria G (1988): WY translocation in a family with X-linked ichthyosis, chondrodysplasia punctata and mental retardation: DNA analysis reveals deletion of the steroid sulphatase gene and translocation of its Y pseudogene. Clin Genet 34:31-37. Ballabio A, Bardoni B, Carrozzo R, Andria G, Bick D, Compbell L, Hamel B, Ferguson-Smith MA, Gimelli G, Fraccaro M, Maraschio P, Zuffardi 0, 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:lOOOl-10005. Bick D, Curry C, McGill JR, Schorderet DF, Bux RC, Moore CM (1989): Male infant with ichthyosis, Kallmann syndrome, chondrodysplasia punctata and a n Xp chromosome deletion. Am J Med Genet 33:lOO-107. Curry CJR, Magenis RE, Brown M, Lanman JT, O’Lague P, Goodfellow P, Mohandas T, Bergner EA, Shapiro U (1984): Inherited chondrodysplasia punctata due to a deletion of the terminal short arm of an X chromosome. N Engl J Med 311:lOlO-1014. Dutrillaux B, Viegas-PequignotE (1981): High resolution R and G-banding on the same preparation. Hum Genet 57:93-95. Emanuel BS (1988): Molecular cytogenetics: Toward dissection of the contiguous gene syndromes. Am J Hum Genet 43:575-578. Maroteaux P (1989): Brachytelephalangic chondrodysplasia punctata: A possible X-linked recessive form. Hum Genet 82:167-170. Schmickel RD (1986): Contiguous gene syndromes: A component of recognizable syndromes. J Pediatr 109:231-241. Shapiro W (1989): Steroid sulphatase deficiency and X-linked ichthvosis. In Scriver CR. Beaudet AL. Slv WS. Valle D (eds): “The Mitabolic Basis of Inherited Diseases,” &h ed.’NewYork: McGrawHill: pp 1945-1964. Silengo M, Luzzatti L, Silverman F (1980): Clinical and genetic aspect of Conradi-Hunerman disease. Report of a case and review of the literature. J Pediatr 97:911-9 17. Spedicato FS, Di Comite A, Tohidast-Akrad M (1985): An unusual variant chromosome 9 with a n extra C-negative, G-dark segment in the short arm. Clin Genet 28:162-165. Sunohara N, Sakuragawa N, Satoioshi E, Tanae A, Shapiro U (1986): A new syndrome of anosmia, ichthyosis, hypogonadism and various neurological manifestations with deficiency of steroid sulphatase and arylsulphatase C. Ann Neurol 19174-181. Tiepolo L, Zuffardi 0, Fraccaro M, di Natale D, Gargantini L, Muller CR, Ropers HH (1980): Assignment by deletion mapping of the steroid sulphatase X-linked ichthyosis locus to Xp22.3. Hum Genet 54:205-206.
Deletion of the Distal Short Arm of the X Chromosome (Xp) in a Patient With Short Stature, Chondrodysplasia Punctata, and X-Linked Ichthyosis Due to Steroid Sulfatase Deficiency A. Ballabio, M. Zollo, R. Carrozzo, A. Caiulo, 0. Zuffardi, C. F. Cascioli, D. Viggiano, and P. Strisciuglio Dipartimento di Pediatria, Uniuersita di Reggw Calabria (A.B.), Istituto Znternazwnale di Genetica e Biofisica, Napoli (M.Z.), Dipartimento di Pediatria, Uniuersita di Napoli (R.C., C.F.C., D.V., P.S.), Zstituto di Biologia e Genetica Medica, Uniuersita di Pauia (A.C., O.Z.), Italy
We observed a boy with short stature, chondrodysplasia punctata, ichthyosis, and a terminal deletion of Xp. Steroid sulfatase deficiency was demonstrated in the patient’s fibroblasts. Molecular analysis showed a deletion of the entire steroid sulfatase gene. This case represents another example of a contiguous gene syndrome in which the co-deletion of adjacent genes on a chromosome is responsible for a complex phenotype. KEY
WORDS: short stature, chondrodysplasia punctata, Xlinked ichthyosis, steroid sulfatase, Xp deletion, contiguous gene syndromes
acterized by the presence of brown scaly skin [see Shapiro, 1989 for review]. The gene for XLUSTS deficiency has been assigned to the Xp22.3 by deletion mapping [Tiepolo et al., 19801. We and others have observed patients with complex phenotypes characterized by the association of XLI with Kallmann syndrome, CDPX, short stature, and mental retardation in variable combinations [Curry et al., 1984; Sunohara et al., 1986; Andria et al., 1984; Ballabio et al., 1986, 19881 in whom STS gene deletions were observed. In this report we describe a boy with a terminal deletion of Xp. A partial description of this case was included in a recent survey of 27 patients with deletion in the Xp22.3 region [Ballabio et al., 19891. Here we report a detailed clinical description of this patient and the results of chromosome and DNA analysis using the full length STS cDNA as a probe.
CLINICAL REPORT This male infant was born by caeserean section at the 41st week of gestation t o a 27-year-oldmother. His birth weight, length, and head circumference were 3,150g (25th-50th centile), 47 cm (10th centile), and 33.5 cm (25th-50th centile), respectively. At birth he had severe nasal hypoplasia (Figs. 1,2), ichthyosis, and splenomegaly. X-Ray analysis showed punctate calcification of the paravertebral epiphyses (Fig. 3A) and pelvis and distal phalangeal hypoplasia (Fig. 3B). Absence of the 12th ribs was also noted. On a second examination a t age 8 months his weight was 9 kg (50th centile), length 65 cm (belowthe 5th centile) and head circumference43 cm (10th centile). Ophthalmological examination of the patient did not show any sign of ocular albinism. Renal echography did not show abnormalities. The BruFteceived for publication October 23, 1989; revision received n6t-Lezine test performed a t 19 months of age showed an I.&. = 77 (v.n. > 80). Moreover the child apparently June 20, 1990. Address reprint requests to Pietro Strieciuglio, M.D., Diparti- has normal hearing and absence of anosmia and hypogonadism. We also evaluated the patient’s mother who mento di Pediatria Via S. Pansini, 5, 80131 Napoli, Italy. Present address of A. Ballabio: Institute for Molecular Genetics, had short stature (141 cm), short arms, and brachyBaylor College of Medicine, 1 Baylor Plaza, Houston, TX. dactyly.
INTRODUCTION The X-linked recessive type of chondrodysplasia punctata (CDPX) is characterized by short stature, unusual face due to nasal hypoplasia, focal calcification of cartilage, detectable as radiologic stippling of epiphyses, and distal phalangeal hypoplasia [see Maroteaux, 1989 for review]. In the last few years several groups have reported CDPX associated with a terminal deletion of Xp [Curry et al., 1984; Bick et al., 19891 or with an XIY translocation involving the distal Xp [Agematsu et al., 1988; Ballabio et al., 19881.Therefore the CDPX locus was assigned to the Xp22.3 region and we tentatively mapped it distally to STS [Ballabio et al., 19881. X-linked ichthyosis (XLI)due t o steroid sulfatase (STS) deficiency is an inborn error of metabolism char-
0 1991 Wiley-Liss, Inc.
Chondrodysplasia Punctata and X-Linked Ichthyosis
Fig. 1. Nasal hypoplasia and flat nasal bridge are present.
CYTOGENETIC STUDIES Chromosome preparations from cultured lymphocytes of the propositus were made using standard methods. High-resolution karyotypes were obtained after BrdU synchronization, thymidine release, and G-banding after Hoechst staining [Dutrillaux and Viegas-Pequignot, 19811. On prometaphase analysis a
185
Fig. 2. Front view of patient.
terminal deletion of Xp was seen (Fig. 4a). The same deletion was present in one X chromosome of the mother (Fig. 4b). The replication pattern of the mother’s X chromosomes was studied in lymphocytes by high resolution G-banding [Dutrillaux and Viegas-Pequignot, 19811. Among 36 informative metaphases, 28 showed the deleted X to be late replicating while in 8 metaphases it
Fig. 3. X-ray films show punctate calcification of the epiphyses (A)and distal phalangeal hypoplasia (B).
186
Ballabio et al.
Fig. 4. (a)From left to right: idiogram of a normal chromosome X (the arrow indicates the breakpoint of the propositus’ X chromosome), a normal chromosome X from a 46XY male, two deleted X chromosomes from the patient. The distal band on the X short arm appears thicker in the normal than in the patient’s X chromosomes. (b)The normal (left)and the deleted (right) X chromosomes from the propositus’mother. ( c ) Chromosomes 9 from the propositus’mother: that on the right shows a extra G positive band proximally on the short arm. The same variant is present in the propositus.
was the normal X to be late replicating. The propositus cognizable syndromes [Schmickel,19861.There are sevand his mother had a variant of one chromosome 9 eral examples of such entities characterized by the (Fig. 4c) with an additional dark G-band in the proximal association of disorders whose loci, being in contiguous portion of the short arm. This variant, first seen in the regions on a chromosome, may be co-deleted in some mother’s karyotype, was initially suspected to be an patients [see Emanuel 1988, for review]. insertion of the region deleted from the X but its presIn recent studies we described the association of difference in the propositus, who has a deletion syndrome, ent disorders, such as STS deficiency, CDPX, mental seems to exclude such an hypothesis. The appearance retardation, short stature, and Kallmann syndrome, in and the localization of this extra band are similar to the 27 patients with deletions in Xp22.3, demonstrating the rare variant of chromosome 9 described by Spedicato et presence of contiguous gene syndromes [Ballabio et al., al. [1985].In conclusion the karyotypes ofthe propositus 19891. In the case described in the present paper the and his mother were 46,Y,del(X)(p22.32+pter),9p+ hypothesis of a contiguous gene syndrome was made at and 46,X,del(X)(p22.32+pter),9p + . The STS assay, birth solely on the basis of the patient’s clinical maniperformed on the patient’s cultured skin fibroblasts festations. Subsequent karyotype and molecular analusing a previously described method [Ballabio et al., ysis documented the presence of a terminal deletion of the distal Xp. Clinical heterogeneity should always 19851, showed absence of enzyme activity. Patient’s DNA, obtained from a venous blood sample, alert the clinician to the possible involvement of differwas analyzed by standard Southern blot analysis using ent loci through a deletion. On the other hand, maniprobe 7A5B, a full length STS cDNA, which was derived festations of some disorders may be overlooked in some from a previously isolated STS cDNA clone [Ballabio et cases depending on the age at which the patient is examal., 19871. Deletion ofthe entire STS gene was confirmed ined. Radiological manifestations of CDPX are age-deby the absence of the expected hybridization bands pendent and tend to disappear during childhood [Ballabio et al., 1987; Silengo et al., 19801.For these reasons (Fig. 5). high-resolution karyotype analysis should be performed DISCUSSION in order to detect a chromosomal abnormality. However, In 1986 Schmickel indicated the importance of look- in some instances a deletion will only be detected at the ing at contiguous gene syndromes as components of re- molecular level.
Chondrodysplasia Punctata and X-Linked Ichthyosis
187
REFERENCES
C P Fig. 5. Southern blot analysis of EcoRI restricted DNA from the proband (P)and a control (C). The filter was hybridized to probe 7A5B, which is a full length STS cDNA clone. A normal pattern is observed in lane C whereas only a band correspondingto the STS pseudogene on the Y chromosome is visible in lane P, thus revealing a n entire STS gene deletion in the patient.
In conclusion, our findings confirm that small cytogenetic abnormalities in the distal Xp may cause the association of different mendelian disorders, such as X-linked ichthyosis due to STS deficiency and CDPX, demonstrating that a n accurate characterization of the molecular defect underlying the patient’s phenotype may have important implications for both genetic counseling and treatment.
ACKNOWLEDGMENTS A.C. is supported by Associazione Studio Malformazioni-Milano. This work was supported in part by Grant SCE-0140 from the Commission of the European Community.
Agematsu K, Koike K, Morosawa H, Nakahori Y, Nakagome Y, Akabane T (1988): Chondrodysplasia punctata with WY translocation. Hum Genet 80:105-107. Andria G, Ballabio A, Parenti G, Di Maio S, Piccirillo A (1984):Steroid sulphatase deficiency is present in patients with X-linked ichthyosis and male hypogonadism and with Rud syndrome. J Inher Metab Dis (Suppl 2) 7:158-160. Ballabio A, Parenti G, Napolitano E, Di Natale P, Andria G (1985): Genetic complementation of steroid sulphatase after somatic cell hybridization of X-linked ichthyosis and multiple sulphatase deficiency. Hum Genet 70:315-317. Ballabio A, Parenti G, Tippett P, Mondello C, Di Maio S, Tenore A, Andria G (1986): X-linked ichthyosis due to steroid sulphatase deficiency, associated with Kallmann syndrome (hypogonadotropic hypogonadism and anosmia): Linkage relationships with Xg and cloned DNA sequences from the distal short arm of the X chromosome. Hum Genet 72:237-240. Ballabio A, Parenti G, Carrozzo R, Sebastio G, Andria G, Buckle V, Fraser N, Boyd Y, Craig I, Rocchi M, Romeo G, Jobsis AC, Persico MG (1987): Isolation and characterization of a steroid sulphatase cDNA clone: Genomic deletions in patients with X-chromosomelinked ichthyosis. Proc Natl Acad Sci USA 844519-4523. Ballabio A, Parenti G, Carrozzo R, Coppa G, Felici L, Migliori V, Silengo M, Franceschini P, Andria G (1988): WY translocation in a family with X-linked ichthyosis, chondrodysplasia punctata and mental retardation: DNA analysis reveals deletion of the steroid sulphatase gene and translocation of its Y pseudogene. Clin Genet 34:31-37. Ballabio A, Bardoni B, Carrozzo R, Andria G, Bick D, Compbell L, Hamel B, Ferguson-Smith MA, Gimelli G, Fraccaro M, Maraschio P, Zuffardi 0, 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:lOOOl-10005. Bick D, Curry C, McGill JR, Schorderet DF, Bux RC, Moore CM (1989): Male infant with ichthyosis, Kallmann syndrome, chondrodysplasia punctata and a n Xp chromosome deletion. Am J Med Genet 33:lOO-107. Curry CJR, Magenis RE, Brown M, Lanman JT, O’Lague P, Goodfellow P, Mohandas T, Bergner EA, Shapiro U (1984): Inherited chondrodysplasia punctata due to a deletion of the terminal short arm of an X chromosome. N Engl J Med 311:lOlO-1014. Dutrillaux B, Viegas-PequignotE (1981): High resolution R and G-banding on the same preparation. Hum Genet 57:93-95. Emanuel BS (1988): Molecular cytogenetics: Toward dissection of the contiguous gene syndromes. Am J Hum Genet 43:575-578. Maroteaux P (1989): Brachytelephalangic chondrodysplasia punctata: A possible X-linked recessive form. Hum Genet 82:167-170. Schmickel RD (1986): Contiguous gene syndromes: A component of recognizable syndromes. J Pediatr 109:231-241. Shapiro W (1989): Steroid sulphatase deficiency and X-linked ichthvosis. In Scriver CR. Beaudet AL. Slv WS. Valle D (eds): “The Mitabolic Basis of Inherited Diseases,” &h ed.’NewYork: McGrawHill: pp 1945-1964. Silengo M, Luzzatti L, Silverman F (1980): Clinical and genetic aspect of Conradi-Hunerman disease. Report of a case and review of the literature. J Pediatr 97:911-9 17. Spedicato FS, Di Comite A, Tohidast-Akrad M (1985): An unusual variant chromosome 9 with a n extra C-negative, G-dark segment in the short arm. Clin Genet 28:162-165. Sunohara N, Sakuragawa N, Satoioshi E, Tanae A, Shapiro U (1986): A new syndrome of anosmia, ichthyosis, hypogonadism and various neurological manifestations with deficiency of steroid sulphatase and arylsulphatase C. Ann Neurol 19174-181. Tiepolo L, Zuffardi 0, Fraccaro M, di Natale D, Gargantini L, Muller CR, Ropers HH (1980): Assignment by deletion mapping of the steroid sulphatase X-linked ichthyosis locus to Xp22.3. Hum Genet 54:205-206.
