Clinical Diagnosis

X-linked chondrodysplasia punctata 1 (CDPX1), a congenital disorder of bone and cartilage development, is caused by a deficiency of the enzyme arylsulfatase E (ARSE).

CDPX1 is suspected in a male with the following clinical findings:

• Chondrodysplasia punctata (CDP) (stippled epiphyses) (see Radiographic Findings)

• Brachytelephalangy (shortening of the distal phalanges)

• Nasomaxillary hypoplasia in which hypoplasia of the anterior nasal spine results in a characteristic flattened nasal base, reduced nasal tip protrusion with short columella, and in some cases vertical grooves within the alae nasi. The nostrils are crescent-shaped. It may appear as if the child’s nose is pressed flat against a window.

Note: Coagulopathy should be explicitly ruled out by measurement of clotting function (PT and PTT) and clotting factors II, VII, IX, and X (see Differential Diagnosis).

The diagnosis is confirmed by molecular genetic testing.

Testing

Arylsulfatase E enzyme activity. A reliable biochemical assay to measure ARSE enzyme activity is not yet available.

Cytogenetic analysis. Routine karyotype analysis reveals Xp deletions or rearrangements that include ARSE in approximately 25% of individuals with features of CDPX1. To identify these individuals, karyotype analysis or array genomic hybridization (array GH) should be performed. Smaller interstitial deletions are evaluated by array GH [Hou 2005].

Molecular Genetic Testing

Gene. Mutations in ARSE are the only known genetic cause of CDPX1.

Table 1. Summary of Molecular Genetic Testing Used in Chondrodysplasia Punctata 1, X-Linked Recessive

View in own window

Gene Symbol	Test Method	Mutations Detected	Mutation Detection Frequency by Test Method 1		Test Availability
			Affected Males	Carrier Females
ARSE	Sequence analysis	Sequence variants 2	60%-75% 3, 4, 5, 6	>50%-65% 7	Clinical
		Exonic, multiexonic, and whole-gene deletions		0% 7
	Deletion / duplication analysis 8	Exonic, multiexonic, and whole-gene deletions	10% 9	Unknown

Test Availability refers to availability in the GeneTests™ Laboratory Directory. GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.

1. The ability of the test method used to detect a mutation that is present in the indicated gene

2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.

3. Non-genetic phenocopies contribute to some cases in which ARSE sequence analysis does not identify a mutation [Brunetti-Pierri et al 2003, Eash et al 2003, Nino et al 2008].

4. [Franco et al 1995, Parenti et al 1997, Sheffield et al 1998, Brunetti-Pierri et al 2003, Garnier et al 2007, Nino et al 2008].

5. Lack of amplification by PCRs prior to sequence analysis can suggest a putative deletion of one or more exons or the entire X-linked gene in a male; confirmation may require additional testing by deletion/duplication analysis.

6. Includes the mutation detection frequency using deletion/duplication analysis.

7. Sequence analysis of genomic DNA cannot detect exonic, multiexonic, or whole-gene deletions on the X chromosome in carrier females.

8. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; a variety of methods including quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), or targeted chromosomal microarray analysis (gene/segment-specific) may be used. A full chromosomal microarray analysis that detects deletions/duplications across the genome may also include this gene/segment. See array GH.

9. Males initially suspected on sequence analysis of having a deletion in whom the deletion is subsequently confirmed by deletion/duplication analysis

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

Testing Strategy

To confirm/establish the diagnosis in a male proband

• CDP, brachytelephalangy, and nasomaxillary hypoplasia should be present on clinical examination.

• Perform molecular genetic testing for mutations in ARSE, including sequence analysis followed by deletion/duplication analysis.

• If no mutation is identified, array GH is indicated to detect possible duplications missed on sequence analysis.

If an Xp deletion syndrome is suspected (see Genetically Related Disorders), perform karyotype analysis or array GH before molecular genetic testing.

Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family.

Note: (1) Carriers are heterozygous females who are not known to be at risk of manifesting clinical findings of CDPX1. (2) Identification of female carriers requires either (a) prior identification of the disease-causing mutation in the family or, (b) if an affected male is not available for testing, molecular genetic testing first by sequence analysis, and then, if no mutation is identified, by methods to detect gross structural abnormalities.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.

Note: It is the policy of GeneReviews to include in GeneReviews™ chapters any clinical uses of testing available from laboratories listed in the GeneTests™ Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Genetically Related (Allelic) Disorders

Contiguous Xp gene deletions that include ARSE have additional phenotypic features that may include ichthyosis, hypogonadotropic hypogonadism, anosmia, cataracts, intellectual disability, and autism. Affected males have Xp terminal deletions, interstitial deletions, or translocations, most involving SHOX or ARSC (STS). (See also SHOX-Related Haploinsufficiency Disorders.) In one of the more well-characterized deletion syndromes, the presence of ichthyosis, cataracts, anosmia, and hypogonadotropic hypogonadism reflects associated deletions of ARSC (STS) and KAL1. (See also Kallman Syndrome.)

Natural History

Affected males. The most consistent clinical features of X-linked chondrodysplasia punctata 1 (CDPX1) in affected males are CDP, brachytelephalangy, and nasomaxillary hypoplasia. Of note, a child with brachytelephalangy, nasomaxillary hypoplasia, and tracheobronchial calcifications did not have CDP at age 14 months [Casarin et al 2009].

Most affected males have minimal morbidity, and skeletal findings improve by adulthood; however, some have significant medical problems including airway stenosis and cervical spine instability.

Growth measures tend to be normal at birth; short stature usually develops postnatally but only some affected adults have small stature. The shortening of the distal phalanges may become less apparent with age such that older individuals may show brachytelephalangy only in some digits.

Affected individuals have been thought to have a normal life span; however, recent descriptions have identified persons with more severe morbidity and mortality. These complications include the following:

• Respiratory compromise caused by severe nasal hypoplasia or extensive punctate calcifications along the tracheobronchial tree requiring choanal stents, tracheostomy, or tracheal reconstruction [Wolpoe et al 2004]

• Abnormal ossification of the cervical vertebrae that leads to cervical spine stenosis and instability and spinal cord compression [Garnier et al 2007]

These complications have led to early death in some cases [Brunetti-Pierri et al 2003, Garnier et al 2007, Nino et al 2008].

In a retrospective review of clinical features associated with CDPX1 and proven mutations in ARSE, the following were observed [Nino et al 2008]:

• Significant respiratory abnormalities (30%)

• Mixed conductive and sensorineural hearing loss (~25%)

• Significant cervical spine abnormalities (20%)

• Delayed cognitive development (16%)

Less frequently seen findings included the following:

• Ophthalmologic abnormalities (cataracts, optic disc atrophy, small optic nerves)

• Cardiac abnormalities (PDA, VSD, ASD)

• Gastroesophageal reflux

• Feeding difficulties

Heterozygotes. Affected carrier females have not been described, presumably because they have sufficient levels of ARSE enzyme activity expressed from both X chromosomes. Some carrier females may have smaller than expected stature [Sheffield et al 1998, Brunetti-Pierri et al 2003].

Genotype-Phenotype Correlations

The absence of common mutations precludes identifying correlations between genotype and phenotype.

The severity of the phenotype differed significantly between two brothers with the missense allele p.Ile40Ser, demonstrating variable intrafamilial disease expression [Nino et al 2008].

Thus far, affected individuals with intragenic deletions do not appear to be more severely affected than those with missense alleles.

Penetrance

Penetrance appears to be complete; however, in one report, the mutation p.Gly137Ala was identified in a proband and his maternal grandfather, the latter of whom was considered asymptomatic [Sheffield et al 1998]. This missense substitution involving a conserved amino acid was identified in a second unrelated, clinically affected proband [Nino et al 2008], implicating it as pathologic. In a second, similar case [Casarin et al 2009] a deletion of exons 7-10 was identified in a proband and his asymptomatic maternal grandfather. Considering that physical features of CDPX1 improve with age, it is uncertain if such cases represent non-penetrance.

Nomenclature

CDPX1 refers specifically to a deficiency of ARSE enzyme activity.

Brachytelephalangic chondrodysplasia punctata (BCDP) is a descriptive term associated with CDPX1 and its non-genetic phenocopies.

Prevalence

The prevalence of CDPX1 is unknown; in one study it was estimated to be 1:500,000 [Malou et al 2001], but it is likely more common.

CDPX1 is pan ethnic.

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with X-linked chondrodysplasia punctata 1 (CDPX1), the following evaluations are recommended:

• Full skeletal survey

• Flexion, neutral, and extension lateral views of the C-spine in every patient. If clinical evidence suggests cervical myelopathy or if significant instability is demonstrated radiographically, a cervical MRI should be performed. Special consideration should be given to performing this study in flexion and extension positions as spinal cord compression may only occur with these movements (i.e., a normal neutral cervical MRI does not rule out dynamic compression).

• Growth measures

• Developmental assessment

• Hearing assessment

• Assessment of upper and lower airways if stridor is present

• Polysomnography if clinical findings suggest increased upper-airway resistance, disordered breathing in sleep, or apnea

• Ophthalmologic evaluation

• Cardiac ultrasound examination

• Brain imaging studies

• Genetics consultation

Treatment of Manifestations

Management is supportive.

Respiratory difficulty can require frequent monitoring, nasal stents, and oxygen.

Severe maxillary hypoplasia or maxillary retrognathia may require reconstructive surgery in older individuals [Carach et al 2002].

Instability of the cervical spine may require a cervical collar or spinal fusion.

Surveillance

Surveillance of the following is according to recommended pediatric practice, with closer follow-up recommended if abnormalities are identified:

• Hearing

• Growth

• Development

• Thoracic and lumbar spine (for scoliosis)

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to evaluation of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Registries

Contact information for voluntary patient registries is provided by GeneReviews staff.

International Skeletal Dysplasia Registry
Phone: 800-233-2771 (toll-free)
Fax: 310-423-0462
http://www.cedars-sinai.edu/Patients/Programs-and-Services/Skeletal-Dysplasia/

Other

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals.

Mode of Inheritance

X-linked chondrodysplasia punctata 1 (CDPX1) is inherited in an X-linked manner.

Risk to Family Members

Parents of the proband

• The father of an affected male will not have the disease nor will he be a carrier of the mutation. In a family with more than one affected individual, the mother of an affected male is an obligate carrier.

• If pedigree analysis reveals that the proband is the only affected family member, the mother may be a carrier or the affected male may have a de novo gene mutation, in which case the mother is not a carrier.

• If a woman has more than one affected son and the disease-causing mutation cannot be detected in her DNA, she has germline mosaicism.

• When an affected male is the only affected individual in the family, several possibilities regarding his mother's carrier status need to be considered:

• He has a de novo disease-causing mutation in the ARSE gene and his mother is not a carrier.

• His mother has a de novo disease-causing mutation in the ARSE gene, either (a) as a “germline mutation” (i.e., present at the time of her conception and therefore in every cell of her body); or (b) as “germline mosaicism” (i.e., present in some of her germ cells only).

• His mother has a disease-causing mutation that she inherited from a maternal female ancestor.

Sibs of the proband

• The risk to sibs depends on the carrier status of the mother.

• If the mother of the proband has a disease-causing mutation, the chance of transmitting it in each pregnancy is 50%. Male sibs who inherit the mutation will be affected; female sibs who inherit the mutation will be carriers and have thus far not been affected.

• If the disease-causing mutation cannot be detected in the DNA of the mother of the only affected male in the family, the risk to sibs is low but greater than that of the general population because of the possibility of germline mosaicism.

Offspring of a proband. Males with CDPX1 will pass the disease-causing mutation to all of their daughters and none of their sons.

Other family members. The proband's maternal aunts may be at risk of being carriers and the aunts’ offspring, depending on their gender, may be at risk of being carriers or of being affected.

Carrier Detection

Carrier testing of at-risk female relatives is possible if the disease-causing mutation has been identified in the family.

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.

• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. See for a list of laboratories offering DNA banking.

Prenatal Testing

If the ARSE mutation has been identified in a family member, prenatal testing is possible for pregnancies at increased risk. The usual procedure is to determine fetal sex by performing chromosome analysis on fetal cells obtained by chorionic villus sampling (CVS) at approximately ten to 12 weeks' gestation or by amniocentesis usually performed at approximately 15 to 18 weeks' gestation. If the karyotype is 46,XY, DNA from fetal cells can be analyzed for the known disease-causing mutation. For laboratories offering custom prenatal testing, see .

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutation has been identified. For laboratories offering PGD, see .

Note: It is the policy of GeneReviews to include in GeneReviews™ chapters any clinical uses of testing available from laboratories listed in the GeneTests™ Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Literature Cited

1. Alessandri JL, Ramful D, Cuillier F. Binder phenotype and brachytelephalangic chondrodysplasia punctata secondary to maternal vitamin K deficiency. Clin Dysmorphol. 2010;19:85–7. [PubMed: 20177377]
2. Aughton DJ, Kelley RI, Metzenberg A, Pureza V, Pauli RM. X-linked dominant chondrodysplasia punctata (CDPX2) caused by single gene mosaicism in a male. Am J Med Genet A. 2003;116A:255–60. [PubMed: 12503102]
3. Braverman N, Chen L, Lin P, Obie C, Steel G, Douglas P, Chakraborty PK, Clarke JT, Boneh A, Moser A, Moser H, Valle D. Mutation analysis of PEX7 in 60 probands with rhizomelic chondrodysplasia punctata and functional correlations of genotype with phenotype. Hum Mutat. 2002;20:284–97. [PubMed: 12325024]
4. Brenner B, Tavori S, Zivelin A, Keller CB, Suttie JW, Tatarsky I, Seligsohn U. Hereditary deficiency of all vitamin K-dependent procoagulants and anticoagulants. Br J Haematol. 1990;75:537–42. [PubMed: 2145029]
5. Brunetti-Pierri N, Andreucci MV, Tuzzi R, Vega GR, Gray G, McKeown C, Ballabio A, Andria G, Meroni G, Parenti G. X-linked recessive chondrodysplasia punctata: spectrum of arylsulfatase E gene mutations and expanded clinical variability. Am J Med Genet A. 2003;117A:164–8. [PubMed: 12567415]
6. Brunetti-Pierri N, Hunter JV, Boerkoel CF. Gray matter heterotopias and brachytelephalangic chondrodysplasia punctata: a complication of hyperemesis gravidarum induced vitamin K deficiency? Am J Med Genet A. 2007;143:200–4. [PubMed: 17163521]
7. Carach B, Woods M, Scott P. Maxillonasal dysplasia (Binder syndrome): a lateral cephalometric assessment. Aust Orthod J. 2002;18:82–91. [PubMed: 12462685]
8. Casarin A, Rusalen F, Doimo M, Trevisson E, Carraro S, Clementi M, Tenconi R, Baraldi E, Salviati L. X-linked brachytelephalangic chondrodysplasia punctata: a simple trait that is not so simple. Am J Med Genet A. 2009;149A:2464–8. [PubMed: 19839041]
9. Chitayat D, Keating S, Zand DJ, Costa T, Zackai EH, Silverman E, Tiller G, Unger S, Miller S, Kingdom J, Toi A, Curry CJ. Chondrodysplasia punctata associated with maternal autoimmune diseases: expanding the spectrum from systemic lupus erythematosus (SLE) to mixed connective tissue disease (MCTD) and scleroderma report of eight cases. Am J Med Genet A. 2008;146A:3038–53. [PubMed: 19006208]
10. Cosma MP, Pepe S, Annunziata I, Newbold RF, Grompe M, Parenti G, Ballabio A. The multiple sulfatase deficiency gene encodes an essential and limiting factor for the activity of sulfatases. Cell. 2003;113:445–56. [PubMed: 12757706]
11. Cuillier F, Cartault F, Lemaire P, Alessandri JL. Maxillo-nasal dysplasia (binder syndrome): antenatal discovery and implications. Fetal Diagn Ther. 2005;20:301–5. [PubMed: 15980645]
12. Daniele A, Parenti G, d'Addio M, Andria G, Ballabio A, Meroni G. Biochemical characterization of arylsulfatase E and functional analysis of mutations found in patients with X-linked chondrodysplasia punctata. Am J Hum Genet. 1998;62:562–72. [PMC free article: PMC1376941] [PubMed: 9497243]
13. Eash DD, Weaver DD, Brunetti-Pierri N. Cervical spine stenosis and possible vitamin K deficiency embryopathy in an unusual case of chondrodysplasia punctata and an updated classification system. Am J Med Genet A. 2003;122A:70–5. [PubMed: 12949976]
14. Franco B, Meroni G, Parenti G, Levilliers J, Bernard L, Gebbia M, Cox L, Maroteaux P, Sheffield L, Rappold GA, Andria G, Petit C, Ballabio A. A cluster of sulfatase genes on Xp22.3: mutations in chondrodysplasia punctata (CDPX) and implications for warfarin embryopathy. Cell. 1995;81:15–25. [PubMed: 7720070]
15. Fryburg JS, Kelly TE. Chondrodysplasia punctata, humero-metacarpal type: a second case. Am J Med Genet. 1996;64:493–6. [PubMed: 8862628]
16. Garnier A, Dauger S, Eurin D, Parisi I, Parenti G, Garel C, Delbecque K, Baumann C. Brachytelephalangic chondrodysplasia punctata with severe spinal cord compression: report of four new cases. Eur J Pediatr. 2007;166:327–31. [PubMed: 16937129]
17. Hall JG, Pauli RM, Wilson KM. Maternal and fetal sequelae of anticoagulation during pregnancy. Am J Med. 1980;68:122–40. [PubMed: 6985765]
18. Herman GE, Kelley RI, Pureza V, Smith D, Kopacz K, Pitt J, Sutphen R, Sheffield LJ, Metzenberg AB. Characterization of mutations in 22 females with X-linked dominant chondrodysplasia punctata (Happle syndrome). Genet Med. 2002;4:434–8. [PubMed: 12509714]
19. Hou JW. Detection of gene deletions in children with chondrodysplasia punctata, ichthyosis, Kallmann syndrome, and ocular albinism by FISH studies. Chang Gung Med J. 2005;28:643–50. [PubMed: 16323556]
20. Howe AM, Lipson AH, Sheffield LJ, Haan EA, Halliday JL, Jenson F, David DJ, Webster WS. Prenatal exposure to phenytoin, facial development, and a possible role for vitamin K. Am J Med Genet. 1995;58:238–44. [PubMed: 8533825]
21. Irving MD, Chitty LS, Mansour S, Hall CM. Chondrodysplasia punctata: a clinical diagnostic and radiological review. Clin Dysmorphol. 2008;17:229–41. [PubMed: 18978650]
22. Jaillet J, Robert-Gnansia E, Till M, Vinciguerra C, Edery P. Biliary lithiasis in early pregnancy and abnormal development of facial and distal limb bones (Binder syndrome): a possible role for vitamin K deficiency. Birth Defects Res A Clin Mol Teratol. 2005;73:188–93. [PubMed: 15751048]
23. Khau Van Kien P, Nievelon-Chevallier A, Spagnolo G, Douvier S, Maingueneau C. Vitamin K deficiency embriopathy. Am J Med Genet. 1998;79:66–8. [PubMed: 9738872]
24. Kirkland V, Sundaram UT, Brookshire G, Nino M, Bober M, Braverman N. Chondrodysplasia punctata in infants of mothers with autoimmune diseases. Abstract 518/A. New Orleans, LA: American Society of Human Genetics 56th Annual Meeting; 2006.
25. Konig A, Happle R, Bornholdt D, Engel H, Grzeschik KH. Mutations in the NSDHL gene, encoding a 3beta-hydroxysteroid dehydrogenase, cause CHILD syndrome. Am J Med Genet. 2000;90:339–46. [PubMed: 10710235]
26. Kozlowski K, Basel D, Beighton P. Chondrodysplasia punctata in siblings and maternal lupus erythematosus. Clin Genet. 2004;66:545–9. [PubMed: 15521983]
27. Leicher-Düber A, Schumacher R, Spranger J. Stippled epiphyses in fetal alcohol syndrome. Pediatr Radiol. 1990;20:369–70. [PubMed: 2190164]
28. Malou E, Gekas J, Troucelier-Lucas V, Mornet E, Razafimanantsoa L, Cuvelier B, Mathieu M, Thepot F. X-linked recessive chondrodysplasia punctata. Cytogenetic study and role of molecular biology. Arch Pediatr. 2001;8:176–80. [PubMed: 11232459]
29. Menger H, Lin AE, Toriello HV, Bernert G, Spranger JW. Vitamin K deficiency embryopathy: a phenocopy of the warfarin embryopathy due to a disorder of embryonic vitamin K metabolism. Am J Med Genet. 1997;72:129–34. [PubMed: 9382132]
30. Munroe PB, Olgunturk RO, Fryns JP, Van Maldergem L, Ziereisen F, Yuksel B, Gardiner RM, Chung E. Mutations in the gene encoding the human matrix Gla protein cause Keutel syndrome. Nat Genet. 1999;21:142–4. [PubMed: 9916809]
31. Nino M, Matos-Miranda C, Maeda M, Chen L, Allanson J, Armour C, Greene C, Kamaluddeen M, Rita D, Medne L, Zackai E, Mansour S, Superti-Furga A, Lewanda A, Bober M, Rosenbaum K, Braverman N. Clinical and molecular analysis of arylsulfatase E in patients with brachytelephalangic chondrodysplasia punctata. Am J Med Genet A. 2008;146A:997–1008. [PubMed: 18348268]
32. Parenti G, Buttitta P, Meroni G, Franco B, Bernard L, Rizzolo MG, Brunetti-Pierri N, Ballabio A, Andria G. X-linked recessive chondrodysplasia punctata due to a new point mutation of the ARSE gene. Am J Med Genet. 1997;73:139–43. [PubMed: 9409863]
33. Patel MS, Callahan JW, Zhang S, Chan AK, Unger S, Levin AV, Skomorowski MA, Feigenbaum AS, O'Brien K, Hellmann J, Ryan G, Velsher L, Chitayat D. Early-infantile galactosialidosis: prenatal presentation and postnatal follow-up. Am J Med Genet. 1999;85:38–47. [PubMed: 10377011]
34. Pauli RM, Lian JB, Mosher DF, Suttie JW. 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. 1987;41:566–83. [PMC free article: PMC1684308] [PubMed: 3499071]
35. Puetz J, Knutsen A, Bouhasin J. Congenital deficiency of vitamin K-dependent coagulation factors associated with central nervous system anomalies. Thromb Haemost. 2004;91:819–21. [PubMed: 15045146]
36. Rost S, Fregin A, Ivaskevicius V, Conzelmann E, Hortnagel K, Pelz HJ, Lappegard K, Seifried E, Scharrer I, Tuddenham EG, Muller CR, Strom TM, Oldenburg J. Mutations in VKORC1 cause warfarin resistance and multiple coagulation factor deficiency type 2. Nature. 2004;427:537–41. [PubMed: 14765194]
37. Sardiello M, Annunziata I, Roma G, Ballabio A. Sulfatases and sulfatase modifying factors: an exclusive and promiscuous relationship. Hum Mol Genet. 2005;14:3203–17. [PubMed: 16174644]
38. Savarirayan R, Boyle RJ, Masel J, Rogers JG, Sheffield IJ. Long-term follow-up in chondrodysplasia punctata, tibial metacarpal type, demonstrating natural history. Am J Med Genet A. 2004;124A:148–57. [PubMed: 14699613]
39. Schulz SW, Bober M, Johnson C, Braverman N, Jimenez SA. Maternal mixed connective tissue disease and offspring with chondrodysplasia punctata. Semin Arthritis Rheum. 2010;39:410–6. [PMC free article: PMC2844477] [PubMed: 19110299]
40. Shanske AL, Bernstein L, Herzog R. Chondrodysplasia punctata and maternal autoimmune disease: a new case and review of the literature. Pediatrics. 2007;120:e436–41. [PubMed: 17671048]
41. Sheffield LJ, Osborn AH, Hutchison WM, Sillence DO, Forrest SM, White SJ, Dahl HH. Segregation of mutations in arylsulphatase E and correlation with the clinical presentation of chondrodysplasia punctata. J Med Genet. 1998;35:1004–8. [PMC free article: PMC1051512] [PubMed: 9863597]
42. Tim-aroon T, Jaovisidha S, Wattanasirichaigoon D. A new case of maternal lupus-associated chondrodysplasia punctata with extensive spinal anomalies. Am J Med Genet A. 2011;155A:1487–91. [PubMed: 21567922]
43. Toriello HV, Higgins JV, Miller T. Provisionally unique autosomal recessive chondrodysplasia punctata syndrome. Am J Med Genet. 1993;47:797–9. [PubMed: 8267015]
44. Van Driel D, Wesseling J, Sauer PJ, Touwen BC, van der Veer E, Heymans HS. Teratogen update: Fetal effects after in utero exposure to coumarins overview of cases, follow-up findings, and pathogenesis. Teratology. 2002;66:127–40. [PubMed: 12210474]
45. Wolpoe ME, Braverman N, Lin SY. Severe tracheobronchial stenosis in the X-linked recessive form of chondrodysplasia punctata. Arch Otolaryngol Head Neck Surg. 2004;130:1423–6. [PubMed: 15611404]

Revision History

• 3 November 2011 (me) Comprehensive update posted live

• 22 April 2008 (me) Review posted live

• 16 November 2007 (nb) Original submission