American Journal of M e d i c a l Genetics 44:795-799 (1992)
Brief Clinical Report ~
Chondrodysplasia Punctata: Another Possible X-Linked Recessive Case C.P. Bennett, A. Caroline Berry, D.J. Maxwell, and Mary J. Seller Division of Medical and Molecular Genetics and South East Thames Regional Genetics Centre (C.P.B., A.C.B., M.J.S.) and Division of Obstetrics and Gynaecology (D.J.M.),Guy’s Hospital, London, UK
A 22-week fetus who had died in utero had a markedly hypoplastic nose a n d other facial abnormalities, short fingers, hypoplastic nails, and small phallus. Radiologically there was symmetrical cartilaginous stippling of the vertebral column, femoral heads, calcanei and elbows typical of chondrodysplasia punctata (CP), and metacarpal shortness and tiny pyramidal phalanges. The several causally different forms of C P are tabulated. Differential diagnosis suggests that the present case, which does not have limb shortness, could be a case of X-linked recessive brachytelephalangic chondrodysplasia punc-
tata.
0 1992 Wiley-Lies, Inc.
KEY WORDS: chondrodysplasia punctata, X-linked recessive, calcific stippling INTRODUCTION Chondrodysplasia punctata (CP) is a term used to describe a skeletal dysplasia characterised by distinctive, fine, localised stippling, particularly in the spine and epiphyses, which is observed prenatally and in infancy but which disappears in later childhood. This specific radiologically apparent defect, sometimes graphically described as “paint-spattered cartilaginous calcification, is found in a heterogeneous group of conditions and can be associated with a variety of other manifestations. There are multiple causes, including specific environmental and genetic causes (Spranger et al., 1971;Sheffieldet al., 1976;Happle, 1979;Ballabio et al., 1988;Bick et al., 1989).Although a number of classifications of the disorders exists, apparently there is no com-
Received for publication January 28, 1992; revision received June 12,1992. Address reprint requests to Dr. M.J. Seller, Division of Medical and Molecular Genetics, 7th Floor, Guy’s Tower, Guy’s Hospital, London SE1 9RT, UK.
0 1992 Wiley-Liss, Inc.
prehensive description to aid the diagnosis when a fetus such as we describe is encountered. CLINICAL REPORT This was the first pregnancy of a 21-year-old Irish Caucasian woman and a 23-year-old Moroccan man, during which no medication or alcohol was taken. At 19 weeks, an ultrasound scan showed that intrauterine fetal death had occurred and so labour was induced. The male fetus (Fig. 11, which was 22 weeks in size and somewhat macerated, had a markedly hypoplastic nose with anteverted nostrils and deep groove between each nasal ala and the tip; a depressed and short nasal bridge; protruding, convex upper lip; a bossed forehead; ocular hypertelorism; an upward slant of the palpebral fissures; posteriorly angulated ears with rolled over helices; and a short neck. The fingers were short and stubby, the thumbs bulbous, and the nails hypoplastic. The phallus was small. There was no shortness of the limbs. At autopsy, internal organs were grossly normal. Radiologically, there was cartilaginous stippling of the entire vertebral column (Fig. 21, which was particularly concentrated in the sacrum and coccyx, and also of both femoral heads, calcanei, and elbows. This stippling was symmetrical. All long bones appeared otherwise normal. In the hands (Fig. 3), the metacarpal and phalangeal bones were shorter than normal, the distal phalanges being markedly reduced: they were tiny and pyramidal in shape with the apex pointing proximally. On the left, the second, third, and fourth metacarpals were rather shorter than the other metacarpals, especially the fourth, which was affected both distally and proximally, whereas the second and third were only proximally short. There was no significant family history, but on the maternal side 3 of her sibs had been lost, 2 through first trimester miscarriage, one stillborn, and a female first cousin was also stillborn: there were no details. Another maternal cousin had Down syndrome, born when her mother was 40 years old. The skin biopsy from the fetus failed to grow in culture. The chromosomes ofboth parents were normal, the X chromosomes being especially scrutinized for a deletion. Regrettably, no material was available for bio-
796
Bennett et al.
Fig. 1. Fetus at 22 wks gestation.
chemical and DNA studies, since the parents required burial of the fetus for religious reasons.
DISCUSSION The punctate calcification of the skeleton suggested possible diagnoses in this fetus (Table 1). However, not all of these conditions are also associated with the very striking facial changes. The maternal history
Fig. 2. Radiological appearance of the skeleton with symmetrical cartilaginous stippling of the vertebral column concentrated in the sacrum and COCCYX, femoral heads, calcanei, and elbows. There is no shortness of the long bones.
Fig. 3. Radiological appearance of the hands, with metacarpal and phalangeal shortness, the distal phalanges being especially tiny and pyramidal in shape with the apex pointing proximally. On the left, metacarpals 2, 3, and 4 are more affected than the others, with the second being short both distally and proximally.
Chondrodysplasia Punctata excluded environmental causes (infection or teratogens). There is a marked phenotypic similarity of this case with warfarin teratogenesis. Unfortunately, the failure of the tissue culture meant that neither chromosome analysis nor biochemical studies could be performed. However, the clinical findings, particularly the unusual facial changes, the distribution of the punctate calcification, the tiny distal phalanges of the fingers
797
without gross limb shortness, closely resembled brachytelephalangic chondrodysplasia punctata described by Maroteaux [19891, which is probably an X-linked recessive disorder. One of Maroteaux’s [19891 4 cases also had bilateral specific shortness of some of the metacarpal bones, which was seen unilaterally in our fetus. However, this was also observed in the X-linked dominant case of Happle [19791: nonetheless, our case was
TABLE I. Classification of Conditions With Punctate Calcification in Infancv Reference
I. Environmental Causes A . Infective 1. Bacteraemia-induced calcifying arthritis and chondritis B . Teratogens 1. Warfarin
2. Diphenylhydantoin 3. Alcohol
11. Genetic Causes A . Chromosomal 1. Trisomy 18
2. Trisomy 21 3. 7:16 translocation 4. B:D translocation B. Single gene mutation 1 . Autosomal dominant i. Conradi-Hunermann CP ii. CP tibia-metacarpal type iii. Multiple epiphyseal dysplasia 2. Autosomal recessive i. Generalised GM1-gangllasldoslp ii. I-cell disease iii. Hurler syndrome iv. Zellweger syndrome (peroxisomal disorder) v. Rhizomelic CP (some cases have peroxisomal
disorders) 3. X-linked dominant i. X-linked dominant CP
Caffey, 1978 Shaul et al., 1975 Pettifor and Benson, 1975 Sheffield et al., 1989 Sheffield et al., 1976 Paditz et al., 1985 Rosenfeld et al., 1962 Spranger et al., 1971 Hunter et al., 1985 Valdmanis et al., 1967 Spranger et al., 1971; some cases overlap with other types of CP Holmes et al., 1987; 1 case, peroxisomal disorder Rittler et al., 1960; probable but not proven AD Caffey, 1978 Landing et al., 1964 Whelan et al., 1983 Caffey, 1978 Opitz et al., 1986 Schutgens et al., 1986 Spranger et al., 1971 Schutgens et al., 1986 Poulos et al., 1988 Sheffield et al., 1989 Happle et al., 1979 Manzke et al., 1980
4 . X-1i nked recessive
i. Brachytelephalangic CP May also include:ii. CP with terminal deletion of Xp iii. XIY translocation with loss of Xp
Maroteaux et al., 1989; normal chromosomes Curry et al., 1984 Bick et al., 1989 Ballabio et al., 1988 Agematsu et al., 1988 van Maldergem et al., 1991
5. Genetics not known
Sheffield et al., 1976; may overlap with other types of CP Sheffield et al., 1989 6. Miscellaneous distinct syndromes with skeletal abnormalities and punctate calcification (usually present with other major features) i. Smith-Lemli-Opitz Gibson, 1965 ii. Hypothyroidism (juvenile) Caffey, 1978 Vijoen and Beighton, 1991 iii. Acrodysostosis Pauli et al., 1987 iv. Vitamin K epoxide reductase deficiency Cormode et al., 1986 v. Keutel syndrome (possibly autosomal recessive) vi. CHILD syndrome Jones, 1988 i. CP mild type
798
Bennett et al.
not considered to be of this type because there was no asymmetric limb shortness [Happle, 19791. Similarly, rhizomelic C P was excluded because there was no severe reduction of the femora and humeri [Spranger et al., 1971;Poulos et al., 19881, and the tibia-metacarpal type of CP was excluded because the tibiae too were normal [Rittler et al., 19901. Maroteaux [1989] points to the similarity of his X-linked recessive cases with those of Curry et al. [19841, Bick et al. [19891, Ballabio et al. 119881, and Agematsu et al. [19881, all of which were associated with loss of terminal Xp chromosome material, due to a terminal deletion in the first 2 instances and an XIY translocation in the others. However, in addition, these cases have ichthyosis, consistent with the loss of more than one contiguous gene. Maroteaux’s [19891 4 cases have normal chromosomes and are males, as is our fetus, and he suggests that brachytelephalangic CP involves a mutation of a gene localised at the tip of Xp. No other form of CP seems t o be associated with terminal phalangeal hypoplasia, without severe limb shortness, and the tiny phalanges can be diagnostic of brachytelephalangic CP in older children when the skeletal stippling has disappeared. The occurrence of terminal phalangeal hypoplasia and metacarpal shortness in both the X-linked dominant and X-linked recessive forms of CP may indicate that they are allelic and caused by different mutations. However, on the basis of mousehuman homology, McKusick 119901 suggests the dominant form is located on Xq or in the middle of Xp. It is unfortunate that we were unable to obtain a fetal karyotype or to perform DNA studies. The parental chromosomes were normal, but that does not exclude a de novo deletion or translocation involving Xp. The fetal skin appeared normal, but this does not mean that the fetus did not have ichthyosis. It could be significant that the fetus had a small phallus, for the Xp deletion case of Bick et al. [1989], where the breakpoint was Xp22.31, had Kallmann syndrome, characterised by hypogonadotropic hypogonadism, as well as ichthyosis and CP. Only ichthyosis was present as well as CP when the breakpoint wasXp22.32 [Curry et al., 19841.For genetic counselling purposes, we also cannot exclude a new point mutation in the fetus. The classification of conditions with CP given in Table I is almost certainly incomplete. Also, there is probably overlap between some of the types listed because in many cases, as in our fetus, comprehensive studies, including biochemical and chromosomal, as well as radiological examinations, were not performed. The table is given to indicate the wide range of possible diagnoses when a subject presents with punctate calcification of the skeleton. It is important to remember also that, according to Caffey [ 19781,irregular spotted epiphyseal ossification is a normal variant at certain ages in childhood. A fully comprehensive survey of disorders, with their related clinical and other features, in which CP is found is sorely needed.
ACKNOWLEDGMENTS We thank Miss E. Joyce for the X-rays.
REFERENCES Agematsu K, Koike K, Morosawa H, Nakahori Y, Nakagome Y, Akabane T (1988):Chondrodysplasia punctata with X;Y translocation. Hum Genet 80:105-107. Ballabio A, Parenti G, C a r r o m R, Coppa G, Felici L, Migliori V, Silengo M, Franceschini P, Andria G (1988): XIY 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. Bick D, Curry CJR, McGill 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. Caffey J (1978): “Paediatric X-ray Diagnosis,” 7th ed. Chicago: Yearbook Medical Publishers. Cormode EJ, Dawson M, Lowry RB (1986): Keutel syndrome: Clinical report and literature review. Am J Med Genet 24:289-294 Curry CJR, Magenis RE, Brown M, Lanman JT, Tsai J, O’Lague P, Goodfellow P, Mohandas T, Bergner EA, Shapiro LJ (1984):Inher. ited chondrodysplasia punctata due to a deletion of the terminal short arm of a n X chromosome. N Engl J Med 311:lOlO-1015. Gibson R (1965):A case ofthe Smith-Lemli-Optiz syndrome of multiple congenital anomalies in association with dysplasia epiphysealis punctata. Canad Med Assoc J 92574-575. Happle R (1979): X-linked dominant chondrodysplasia punctata. Hum Genet 5355-73. Holmes RD. Wilson GN. Haira AK (1987): . , Peroxisomal enzvme deticiency in the Conradi-Hinermann form of chondrodyspl&ia punctata. N Engl J Med 3161608. Hunter AGW, Rimoin DL, Koch UM, MacDonal GJ, Cox DM, Lachman RS, Adomian G (1985): Chondrodysplasia punctata in a n infant with duplication 16p due to a 7:16 translocation. Am J Med Genet 21:581-589. Jones KL (1988): “Smith’s %cognizable Patterns of Human Malformation,” 4th ed. Philadelphia: Saunders. Kalter DC, Atherton DJ, Clayton F T (1989): X-linked dominant Conradi-Hunermann syndrome presenting as congenital erythroderma. J Am Acad Derm 21248-256. Landing BH, Silverman FN, Craig MM, Jacoby MD, Lahey ME, Chadwic DL (1964): Familial neurovisceral lipidosis. Amer J Dis Child 108:503-522. McKusick VA (1990): “Mendelian Inheritance in Man,” 9th ed. Baltimore: Johns Hopkins University Press. Manzke H, Christophers E, Wiedemann H-R (1980): Dominant sexlinked inherited chondrodysplasia punctata: A distinct type of chondrodysplasia punctata. Clin Genet 17:97-107. Maroteaux P (1989): Brachytelephalangic chondrodysplasia punctata: A possible X-linked recessive form. Hum Genet 82:167-170. Opitz JM, Zurrhein GM, Vitale L, Shahidi NT, Howe J J , Chou SM, Shanklin DR, Sybers HD, Dood AR, Gerritsen T (1969): The Zellweger syndrome (corebro-hepato-renal syndrome). Birth Defects Original Art Series V(2):144-160. Paditz E, Rupprecht E (1985): Alkoholembryopathie mit symp. tomatischer chondroplasia punctata. Vierter publizierter Fall. Helv Paediatr Acta 4061-68. Pauli RM, Lian JB, Mosher DF, Suttie JW (1987): Association of congenital deficiency of multiple vitamin K-dependent coagulation factors and the phenotype of the warfarin embryopathy: Clues to the mechanism of teratogenicity of coumarin derivatives. Am J Hum Genet 41566-583. Pettifor JM, Benson R (1975): Congenital malformations associated with the administration of oral anticoagulants during pregnancy. J Pediatr 86459-462. Poulos A, Shefield L, Sharp P, Sherwood G , Johnson D, Beckman K, Fellenberg AJ, Wraith J E , Chow CW, Usher S, Singh H (1988): Rhizomelic chondrodysplasia punctata: clinical, pathologic and biochemical findings in two patients. J Pediatr 113:685-690. Rittler M, Menger H, Spranger J (1990): Chondrodysplasia punctata, tibia-metacarpal (MT) type. Am J Med Genet 37:ZOO-208. Rosenfield RL, Breibart S, Isaacs H, Klevit HD, Mellman WT (1962): lkisomy of chromosomes 13-15 and 17-18 Its association with infantile arteriosclerosis. Amer J Med Sci 244:763-779.
Chondrodysplasia Punctata Schutgens RBH, Heymans HSA, Wanders WA, van den Bosch H, Tager J M (1986): Peroxisomal disorders: A newly recognised group of genetic disease. Eur J Pediatr 144:430-440. Shaul WL, Emery H, Hall J G (1975): Chondrodysplasia punctata and maternal warfarin use in pregnancy. Am J Dis Child 129:360-362. Sheftield LJ,Danks DM, Mayne V, Hutchinson LA (1976): Chondrodysplasia punctata-23 cases of a mild and relatively common variety. J Pediatr 89:916-923. Sheffield LJ,Halliday JL, Danks DM, Rogers JG, Poulos A, Morrison N (1989):Clinical, radiological and biochemical classification of chondrodysplasia punctata. Amer J Hum Genet 45 (Supplement):A64. Spranger JW, Opitz JM, Bidder V (1971): Heterogeneity of chondrodysplasia punctata. Humangenetik 11:190-212.
799
Valdmanis A, Wilson JR, Mann JD, Pearson G, Shaw MW (1967): Subglottic pseudotumor, laryngeal dysplasia and chondrodysplasia calcifans congenita with a t(D;B) chromosomal translocation. Ann Genet 10:55-59. van Maldergem L, Espeel M, Roels F, Petit C, Dacremont G, Wanders RJA, Verloes A, Gillerot Y (1991): X-linked recessive chondrodysplasia punctata with XY translocation in a stillborn fetus. Hum Genet 87561-664. Viljoen D, Beighton P (1991): Epiphyseal stippling in acrodysostosis. Am J Med Genet 3843-45. Whelan DT, Chang PL, Cockshott PW (1983): Mucolipidosis 11. The clinical, radiological and biochemical features in three cases. Clini Genet 2490-96.
Brief Clinical Report ~
Chondrodysplasia Punctata: Another Possible X-Linked Recessive Case C.P. Bennett, A. Caroline Berry, D.J. Maxwell, and Mary J. Seller Division of Medical and Molecular Genetics and South East Thames Regional Genetics Centre (C.P.B., A.C.B., M.J.S.) and Division of Obstetrics and Gynaecology (D.J.M.),Guy’s Hospital, London, UK
A 22-week fetus who had died in utero had a markedly hypoplastic nose a n d other facial abnormalities, short fingers, hypoplastic nails, and small phallus. Radiologically there was symmetrical cartilaginous stippling of the vertebral column, femoral heads, calcanei and elbows typical of chondrodysplasia punctata (CP), and metacarpal shortness and tiny pyramidal phalanges. The several causally different forms of C P are tabulated. Differential diagnosis suggests that the present case, which does not have limb shortness, could be a case of X-linked recessive brachytelephalangic chondrodysplasia punc-
tata.
0 1992 Wiley-Lies, Inc.
KEY WORDS: chondrodysplasia punctata, X-linked recessive, calcific stippling INTRODUCTION Chondrodysplasia punctata (CP) is a term used to describe a skeletal dysplasia characterised by distinctive, fine, localised stippling, particularly in the spine and epiphyses, which is observed prenatally and in infancy but which disappears in later childhood. This specific radiologically apparent defect, sometimes graphically described as “paint-spattered cartilaginous calcification, is found in a heterogeneous group of conditions and can be associated with a variety of other manifestations. There are multiple causes, including specific environmental and genetic causes (Spranger et al., 1971;Sheffieldet al., 1976;Happle, 1979;Ballabio et al., 1988;Bick et al., 1989).Although a number of classifications of the disorders exists, apparently there is no com-
Received for publication January 28, 1992; revision received June 12,1992. Address reprint requests to Dr. M.J. Seller, Division of Medical and Molecular Genetics, 7th Floor, Guy’s Tower, Guy’s Hospital, London SE1 9RT, UK.
0 1992 Wiley-Liss, Inc.
prehensive description to aid the diagnosis when a fetus such as we describe is encountered. CLINICAL REPORT This was the first pregnancy of a 21-year-old Irish Caucasian woman and a 23-year-old Moroccan man, during which no medication or alcohol was taken. At 19 weeks, an ultrasound scan showed that intrauterine fetal death had occurred and so labour was induced. The male fetus (Fig. 11, which was 22 weeks in size and somewhat macerated, had a markedly hypoplastic nose with anteverted nostrils and deep groove between each nasal ala and the tip; a depressed and short nasal bridge; protruding, convex upper lip; a bossed forehead; ocular hypertelorism; an upward slant of the palpebral fissures; posteriorly angulated ears with rolled over helices; and a short neck. The fingers were short and stubby, the thumbs bulbous, and the nails hypoplastic. The phallus was small. There was no shortness of the limbs. At autopsy, internal organs were grossly normal. Radiologically, there was cartilaginous stippling of the entire vertebral column (Fig. 21, which was particularly concentrated in the sacrum and coccyx, and also of both femoral heads, calcanei, and elbows. This stippling was symmetrical. All long bones appeared otherwise normal. In the hands (Fig. 3), the metacarpal and phalangeal bones were shorter than normal, the distal phalanges being markedly reduced: they were tiny and pyramidal in shape with the apex pointing proximally. On the left, the second, third, and fourth metacarpals were rather shorter than the other metacarpals, especially the fourth, which was affected both distally and proximally, whereas the second and third were only proximally short. There was no significant family history, but on the maternal side 3 of her sibs had been lost, 2 through first trimester miscarriage, one stillborn, and a female first cousin was also stillborn: there were no details. Another maternal cousin had Down syndrome, born when her mother was 40 years old. The skin biopsy from the fetus failed to grow in culture. The chromosomes ofboth parents were normal, the X chromosomes being especially scrutinized for a deletion. Regrettably, no material was available for bio-
796
Bennett et al.
Fig. 1. Fetus at 22 wks gestation.
chemical and DNA studies, since the parents required burial of the fetus for religious reasons.
DISCUSSION The punctate calcification of the skeleton suggested possible diagnoses in this fetus (Table 1). However, not all of these conditions are also associated with the very striking facial changes. The maternal history
Fig. 2. Radiological appearance of the skeleton with symmetrical cartilaginous stippling of the vertebral column concentrated in the sacrum and COCCYX, femoral heads, calcanei, and elbows. There is no shortness of the long bones.
Fig. 3. Radiological appearance of the hands, with metacarpal and phalangeal shortness, the distal phalanges being especially tiny and pyramidal in shape with the apex pointing proximally. On the left, metacarpals 2, 3, and 4 are more affected than the others, with the second being short both distally and proximally.
Chondrodysplasia Punctata excluded environmental causes (infection or teratogens). There is a marked phenotypic similarity of this case with warfarin teratogenesis. Unfortunately, the failure of the tissue culture meant that neither chromosome analysis nor biochemical studies could be performed. However, the clinical findings, particularly the unusual facial changes, the distribution of the punctate calcification, the tiny distal phalanges of the fingers
797
without gross limb shortness, closely resembled brachytelephalangic chondrodysplasia punctata described by Maroteaux [19891, which is probably an X-linked recessive disorder. One of Maroteaux’s [19891 4 cases also had bilateral specific shortness of some of the metacarpal bones, which was seen unilaterally in our fetus. However, this was also observed in the X-linked dominant case of Happle [19791: nonetheless, our case was
TABLE I. Classification of Conditions With Punctate Calcification in Infancv Reference
I. Environmental Causes A . Infective 1. Bacteraemia-induced calcifying arthritis and chondritis B . Teratogens 1. Warfarin
2. Diphenylhydantoin 3. Alcohol
11. Genetic Causes A . Chromosomal 1. Trisomy 18
2. Trisomy 21 3. 7:16 translocation 4. B:D translocation B. Single gene mutation 1 . Autosomal dominant i. Conradi-Hunermann CP ii. CP tibia-metacarpal type iii. Multiple epiphyseal dysplasia 2. Autosomal recessive i. Generalised GM1-gangllasldoslp ii. I-cell disease iii. Hurler syndrome iv. Zellweger syndrome (peroxisomal disorder) v. Rhizomelic CP (some cases have peroxisomal
disorders) 3. X-linked dominant i. X-linked dominant CP
Caffey, 1978 Shaul et al., 1975 Pettifor and Benson, 1975 Sheffield et al., 1989 Sheffield et al., 1976 Paditz et al., 1985 Rosenfeld et al., 1962 Spranger et al., 1971 Hunter et al., 1985 Valdmanis et al., 1967 Spranger et al., 1971; some cases overlap with other types of CP Holmes et al., 1987; 1 case, peroxisomal disorder Rittler et al., 1960; probable but not proven AD Caffey, 1978 Landing et al., 1964 Whelan et al., 1983 Caffey, 1978 Opitz et al., 1986 Schutgens et al., 1986 Spranger et al., 1971 Schutgens et al., 1986 Poulos et al., 1988 Sheffield et al., 1989 Happle et al., 1979 Manzke et al., 1980
4 . X-1i nked recessive
i. Brachytelephalangic CP May also include:ii. CP with terminal deletion of Xp iii. XIY translocation with loss of Xp
Maroteaux et al., 1989; normal chromosomes Curry et al., 1984 Bick et al., 1989 Ballabio et al., 1988 Agematsu et al., 1988 van Maldergem et al., 1991
5. Genetics not known
Sheffield et al., 1976; may overlap with other types of CP Sheffield et al., 1989 6. Miscellaneous distinct syndromes with skeletal abnormalities and punctate calcification (usually present with other major features) i. Smith-Lemli-Opitz Gibson, 1965 ii. Hypothyroidism (juvenile) Caffey, 1978 Vijoen and Beighton, 1991 iii. Acrodysostosis Pauli et al., 1987 iv. Vitamin K epoxide reductase deficiency Cormode et al., 1986 v. Keutel syndrome (possibly autosomal recessive) vi. CHILD syndrome Jones, 1988 i. CP mild type
798
Bennett et al.
not considered to be of this type because there was no asymmetric limb shortness [Happle, 19791. Similarly, rhizomelic C P was excluded because there was no severe reduction of the femora and humeri [Spranger et al., 1971;Poulos et al., 19881, and the tibia-metacarpal type of CP was excluded because the tibiae too were normal [Rittler et al., 19901. Maroteaux [1989] points to the similarity of his X-linked recessive cases with those of Curry et al. [19841, Bick et al. [19891, Ballabio et al. 119881, and Agematsu et al. [19881, all of which were associated with loss of terminal Xp chromosome material, due to a terminal deletion in the first 2 instances and an XIY translocation in the others. However, in addition, these cases have ichthyosis, consistent with the loss of more than one contiguous gene. Maroteaux’s [19891 4 cases have normal chromosomes and are males, as is our fetus, and he suggests that brachytelephalangic CP involves a mutation of a gene localised at the tip of Xp. No other form of CP seems t o be associated with terminal phalangeal hypoplasia, without severe limb shortness, and the tiny phalanges can be diagnostic of brachytelephalangic CP in older children when the skeletal stippling has disappeared. The occurrence of terminal phalangeal hypoplasia and metacarpal shortness in both the X-linked dominant and X-linked recessive forms of CP may indicate that they are allelic and caused by different mutations. However, on the basis of mousehuman homology, McKusick 119901 suggests the dominant form is located on Xq or in the middle of Xp. It is unfortunate that we were unable to obtain a fetal karyotype or to perform DNA studies. The parental chromosomes were normal, but that does not exclude a de novo deletion or translocation involving Xp. The fetal skin appeared normal, but this does not mean that the fetus did not have ichthyosis. It could be significant that the fetus had a small phallus, for the Xp deletion case of Bick et al. [1989], where the breakpoint was Xp22.31, had Kallmann syndrome, characterised by hypogonadotropic hypogonadism, as well as ichthyosis and CP. Only ichthyosis was present as well as CP when the breakpoint wasXp22.32 [Curry et al., 19841.For genetic counselling purposes, we also cannot exclude a new point mutation in the fetus. The classification of conditions with CP given in Table I is almost certainly incomplete. Also, there is probably overlap between some of the types listed because in many cases, as in our fetus, comprehensive studies, including biochemical and chromosomal, as well as radiological examinations, were not performed. The table is given to indicate the wide range of possible diagnoses when a subject presents with punctate calcification of the skeleton. It is important to remember also that, according to Caffey [ 19781,irregular spotted epiphyseal ossification is a normal variant at certain ages in childhood. A fully comprehensive survey of disorders, with their related clinical and other features, in which CP is found is sorely needed.
ACKNOWLEDGMENTS We thank Miss E. Joyce for the X-rays.
REFERENCES Agematsu K, Koike K, Morosawa H, Nakahori Y, Nakagome Y, Akabane T (1988):Chondrodysplasia punctata with X;Y translocation. Hum Genet 80:105-107. Ballabio A, Parenti G, C a r r o m R, Coppa G, Felici L, Migliori V, Silengo M, Franceschini P, Andria G (1988): XIY 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. Bick D, Curry CJR, McGill 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. Caffey J (1978): “Paediatric X-ray Diagnosis,” 7th ed. Chicago: Yearbook Medical Publishers. Cormode EJ, Dawson M, Lowry RB (1986): Keutel syndrome: Clinical report and literature review. Am J Med Genet 24:289-294 Curry CJR, Magenis RE, Brown M, Lanman JT, Tsai J, O’Lague P, Goodfellow P, Mohandas T, Bergner EA, Shapiro LJ (1984):Inher. ited chondrodysplasia punctata due to a deletion of the terminal short arm of a n X chromosome. N Engl J Med 311:lOlO-1015. Gibson R (1965):A case ofthe Smith-Lemli-Optiz syndrome of multiple congenital anomalies in association with dysplasia epiphysealis punctata. Canad Med Assoc J 92574-575. Happle R (1979): X-linked dominant chondrodysplasia punctata. Hum Genet 5355-73. Holmes RD. Wilson GN. Haira AK (1987): . , Peroxisomal enzvme deticiency in the Conradi-Hinermann form of chondrodyspl&ia punctata. N Engl J Med 3161608. Hunter AGW, Rimoin DL, Koch UM, MacDonal GJ, Cox DM, Lachman RS, Adomian G (1985): Chondrodysplasia punctata in a n infant with duplication 16p due to a 7:16 translocation. Am J Med Genet 21:581-589. Jones KL (1988): “Smith’s %cognizable Patterns of Human Malformation,” 4th ed. Philadelphia: Saunders. Kalter DC, Atherton DJ, Clayton F T (1989): X-linked dominant Conradi-Hunermann syndrome presenting as congenital erythroderma. J Am Acad Derm 21248-256. Landing BH, Silverman FN, Craig MM, Jacoby MD, Lahey ME, Chadwic DL (1964): Familial neurovisceral lipidosis. Amer J Dis Child 108:503-522. McKusick VA (1990): “Mendelian Inheritance in Man,” 9th ed. Baltimore: Johns Hopkins University Press. Manzke H, Christophers E, Wiedemann H-R (1980): Dominant sexlinked inherited chondrodysplasia punctata: A distinct type of chondrodysplasia punctata. Clin Genet 17:97-107. Maroteaux P (1989): Brachytelephalangic chondrodysplasia punctata: A possible X-linked recessive form. Hum Genet 82:167-170. Opitz JM, Zurrhein GM, Vitale L, Shahidi NT, Howe J J , Chou SM, Shanklin DR, Sybers HD, Dood AR, Gerritsen T (1969): The Zellweger syndrome (corebro-hepato-renal syndrome). Birth Defects Original Art Series V(2):144-160. Paditz E, Rupprecht E (1985): Alkoholembryopathie mit symp. tomatischer chondroplasia punctata. Vierter publizierter Fall. Helv Paediatr Acta 4061-68. Pauli RM, Lian JB, Mosher DF, Suttie JW (1987): Association of congenital deficiency of multiple vitamin K-dependent coagulation factors and the phenotype of the warfarin embryopathy: Clues to the mechanism of teratogenicity of coumarin derivatives. Am J Hum Genet 41566-583. Pettifor JM, Benson R (1975): Congenital malformations associated with the administration of oral anticoagulants during pregnancy. J Pediatr 86459-462. Poulos A, Shefield L, Sharp P, Sherwood G , Johnson D, Beckman K, Fellenberg AJ, Wraith J E , Chow CW, Usher S, Singh H (1988): Rhizomelic chondrodysplasia punctata: clinical, pathologic and biochemical findings in two patients. J Pediatr 113:685-690. Rittler M, Menger H, Spranger J (1990): Chondrodysplasia punctata, tibia-metacarpal (MT) type. Am J Med Genet 37:ZOO-208. Rosenfield RL, Breibart S, Isaacs H, Klevit HD, Mellman WT (1962): lkisomy of chromosomes 13-15 and 17-18 Its association with infantile arteriosclerosis. Amer J Med Sci 244:763-779.
Chondrodysplasia Punctata Schutgens RBH, Heymans HSA, Wanders WA, van den Bosch H, Tager J M (1986): Peroxisomal disorders: A newly recognised group of genetic disease. Eur J Pediatr 144:430-440. Shaul WL, Emery H, Hall J G (1975): Chondrodysplasia punctata and maternal warfarin use in pregnancy. Am J Dis Child 129:360-362. Sheftield LJ,Danks DM, Mayne V, Hutchinson LA (1976): Chondrodysplasia punctata-23 cases of a mild and relatively common variety. J Pediatr 89:916-923. Sheffield LJ,Halliday JL, Danks DM, Rogers JG, Poulos A, Morrison N (1989):Clinical, radiological and biochemical classification of chondrodysplasia punctata. Amer J Hum Genet 45 (Supplement):A64. Spranger JW, Opitz JM, Bidder V (1971): Heterogeneity of chondrodysplasia punctata. Humangenetik 11:190-212.
799
Valdmanis A, Wilson JR, Mann JD, Pearson G, Shaw MW (1967): Subglottic pseudotumor, laryngeal dysplasia and chondrodysplasia calcifans congenita with a t(D;B) chromosomal translocation. Ann Genet 10:55-59. van Maldergem L, Espeel M, Roels F, Petit C, Dacremont G, Wanders RJA, Verloes A, Gillerot Y (1991): X-linked recessive chondrodysplasia punctata with XY translocation in a stillborn fetus. Hum Genet 87561-664. Viljoen D, Beighton P (1991): Epiphyseal stippling in acrodysostosis. Am J Med Genet 3843-45. Whelan DT, Chang PL, Cockshott PW (1983): Mucolipidosis 11. The clinical, radiological and biochemical features in three cases. Clini Genet 2490-96.
