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Chondrodysplasia Punctata 2, X-Linked

Synonyms: Conradi-Hünermann Syndrome, Happle Syndrome

, MS, CGC, , MS, CGC, and , MD, PhD.

Author Information
, MS, CGC
Certified Genetic Counselor
Department of Human Genetics
The University of Chicago
Chicago, Illinois
, MS, CGC
Certified Genetic Counselor
Department of Human Genetics
The University of Chicago
Chicago, Illinois
, MD, PhD
The Research Institute at Nationwide Children’s Hospital and Department of Pediatrics
The Ohio State University
Columbus, Ohio

Initial Posting: .

Summary

Disease characteristics. The findings in X-linked chondrodysplasia punctata 2 (CDPX2) range from fetal demise with multiple malformations and severe growth retardation to much milder manifestations, including adults with no recognizable physical abnormalities. At least 95% of liveborn individuals with CDPX2 are female with the following findings:

  • Growth deficiency/short stature
  • Distinctive craniofacial appearance
  • Skeletal changes: stippling (chondrodysplasia punctate) on x-rays of the epiphyses of the long bones and vertebrae, the trachea and distal ends of the ribs seen in children prior to completion of normal epiphyseal ossification; rhizomelic (i.e., proximal) shortening of limbs that is often asymmetric; scoliosis
  • Ectodermal changes: linear or blotchy scaling ichthyosis in the newborn that usually resolves in the first months of life leaving linear or whorled atrophic patches involving hair follicles (follicular atrophoderma); coarse hair with scarring alopecia; occasional flattened or split nails; normal teeth
  • Ocular changes: cataracts; microphthalmia and/or microcornea

Intellect is usually normal. Rarely affected males have been identified with a phenotype that includes: hypotonia; moderate to profound developmental delay; seizures; cerebellar (primarily vermis) hypoplasia and/or Dandy-Walker variant; and agenesis of the corpus callosum.

Diagnosis/testing. The diagnosis of CDPX2 rests on the presence of clinical findings consistent with the diagnosis and sterol analysis of plasma, scales from skin lesions, or cultured lymphoblasts or fibroblasts showing increased concentration of 8(9)-cholestenol and 8-dehydrocholesterol. Often a confirmatory mutation is identified in EBP, the only gene in which mutations are known to cause CDPX2.

Management. Treatment of manifestations: Treatment is symptomatic and individualized. For females with typical CDPX2 diagnosed in the newborn period, the following are appropriate: orthopedic management of leg length discrepancy; frequent assessment of kyphoscoliosis; cataract extraction and correction of vision; dermatologic management of skin lesions; sun protection; physical, occupational, and speech therapies, if necessary; standard interventions for congenital heart defects, kidney anomalies, and hearing loss.

Surveillance: Regular follow-up of ophthalmologic abnormalities; regular orthopedic evaluations to monitor kyphoscoliosis, joint problems, and any leg length discrepancy. Routine developmental assessments, hearing evaluations, follow-up with a dermatologist, and monitoring of existing cardiac and/or renal abnormalities.

Genetic counseling. CDPX2 is inherited in an X-linked manner with early gestational male lethality. Women with an EBP germline mutation have a 50% chance of transmitting the disease-causing mutation to each child: EBP mutations in sons are usually lethal; daughters will have a range of possible phenotypic expression. When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low but greater than that of the general population. If the disease-causing mutation cannot be detected in the DNA extracted from the leukocytes of either parent of the proband, three possible explanations are germline mosaicism, somatic mosaicism, or a de novo mutation in the proband. Prenatal diagnosis for pregnancies at increased risk is possible if the family-specific disease-causing mutation is known.

Diagnosis

Clinical Diagnosis

Specific diagnostic criteria for X-linked chondrodysplasia punctata (CDPX2) have not been published. The clinical diagnosis rests on the presence of a number of the following features. The clinical findings are highly variable, secondary principally to random X-chromosome inactivation, often with more severe presentations in newborns and infants and milder findings, including short stature only, in affected older children and adults.

Females. Clinical features of CDPX2 include:

  • Growth deficiency/short stature
  • Craniofacial appearance
    • Frontal bossing
    • Flat nasal bridge
    • Sparse eyebrows and lashes, often asymmetric
  • Skeletal
    • Stippling (chondrodysplasia punctata) involving the epiphyses of the long bones and vertebrae, the trachea and distal ends of the ribs seen on x-ray. This is the main criterion for diagnosis of this disorder in infants. The presence of stippling is age dependent and cannot be seen once normal epiphyseal ossification occurs during childhood (see Figure 1).
    • Rhizomelic (i.e., proximal) shortening of limbs that is often asymmetric, but occasionally symmetric
    • Postaxial polydactyly in up to 5% of individuals. Polydactyly appears to be most common in CDPX2 among the various types of chondrodysplasia punctata.
    • Scoliosis, occasionally congenital
  • Skin, hair, and nails
    • Scaling ichthyosis on an erythematous base arranged in a linear or blotchy pattern in the newborn period (following lines of X-chromosome inactivation) that usually resolves in the first months of life. This may be followed by linear or whorled atrophic patches involving hair follicles (follicular atrophoderma) (See Figure 2)
    • Coarse hair with scarring alopecia (See Figure 3)
    • Occasional flattened or split nails with normal teeth
  • Ocular
    • Cataracts (in ~2/3; 67%), often congenital, asymmetric and/or sectorial
    • Microphthalmia and/or microcornea
  • Occasional malformations (<10% of patients)
    • Sensorineural or conductive hearing loss
    • Cleft palate
    • Congenital heart disease
    • Renal malformations, including hydronephrosis
    • CNS malformations, including Dandy-Walker variant malformation; uncommon in females but usually present in affected males, especially posterior fossa defects
  • Intelligence. Typically normal
Figure 1

Figure

Figure 1. Radiographs from a female infant with CDPX2 demonstrating epiphyseal stippling (chondrodysplasia punctata)

Radiograph originally published in Herman [2000]; reproduced with permission from Elsevier Ltd.

Figure 2

Figure

Figure 2. A. Typical skin findings of CDPX2 at birth, including scaling and an erythematous eruption that follows lines of X-chromosome inactivation. B. Later hyperpigmentation over the back in a two-month-old female

Photographs originally (more...)

Figure 3

Figure

Figure 3. Scarring, patchy alopecia in a female with CDPX2

Photograph originally published in Herman [2000]; reproduced with permission from Elsevier Ltd.

Males. Classic features of CDPX2 have been reported in:

A total of 11 males with non-mosaic EBP mutations and/or diagnostic sterol abnormalities have been reported with a distinct, primarily neurologic phenotype [Milunsky et al 2003, Kelley et al 2005, Furtado et al 2010, Tan et al 2010] that includes:

  • Neurologic
    • Hypotonia
    • Moderate to profound developmental delay
    • Seizures
    • Cerebellar (primarily vermis) hypoplasia and/or Dandy Walker variant malformation
    • Agenesis of the corpus callosum
  • Facial dysmorphisms
    • Hypertelorism
    • Telecanthus
    • High or prominent nasal bridge
    • Low-set ears
    • Micrognathia
    • Large anterior fontanel
  • Other malformations. Cryptorchidism, hypospadias, pelvocalcyeal obstruction, postaxial polydactyly, 2-3 toe syndactyly, VSD, and ASD
  • Features of classic CDPX2. Cataracts and ichthyosis

Testing

Biochemical testing. Sterol analysis of plasma, scales from skin lesions, or cultured lymphoblasts or fibroblasts is used for diagnosis. Increased concentrations of 8(9)-cholestenol and 8-dehydrocholesterol are essentially diagnostic of CDPX2 [Kelley et al 1999] (Table 1).

Table 1. Concentrations of 8(9)-Cholestenol and 8-Dehydrocholesterol Observed in CDPX2

AnalyteCDPX2 Normal
Plasma 8(9)-cholestenol 0.18—186 μg/mL<0.01 μg/mL
(for neonates age 1-2 days)
Plasma 8-dehydrocholesterol<0.01—138 μg/mL<0.01 μg/mL
(for neonates age 1-2 days)

Data from 105 females with presumed CDPX2 [R Kelley, personal communication]

Molecular Genetic Testing

Gene. EBP, encoding 3β-hydroxysteroid-Δ8, Δ7-isomerase, is the only gene in which mutations are known to cause CDPX2 [Braverman et al 1999, Derry et al 1999].

Clinical testing

  • Sequence analysis of the four EBP coding exons and flanking intron sequences identifies a mutation in 85%-95% of females with a clinical diagnosis of CDPX2 and approximately 91% of females with an abnormal sterol profile [Has et al 2000, Herman et al 2002]. Tan et al [2010] identified a mutation in four of four males who had abnormal biochemical results.

    Sequence analysis does not identify deletions in females with CDPX2; however, to date no deletions have been identified in females with this disorder.

    Note: The only deletions described are in females with focal dermal hypoplasia and large deletions that include EBP and PORCN. These females do not have features of CDPX2 [Porter & Herman 2011].

Table 2. Summary of Molecular Genetic Testing Used in Chondrodysplasia Punctata 2, X-Linked

Gene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1
MalesHeterozygous Females
EBPSequence analysis / mutation scanning 2Sequence variants 3Unknown 4, 590% 6

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

2. Sequence analysis and mutation scanning of the entire gene can have similar detection frequencies; however, detection rates for mutation scanning may vary considerably between laboratories based on the specific protocol used.

3. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected.

4. 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.

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

6. Sequence analysis of genomic DNA cannot detect deletion of one or more exons or the entire X-linked gene in a heterozygous female.

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 proband

  • Radiographs showing stippling of the epiphyses of long bones and vertebrae suggest the diagnosis of CDPX2.
  • Biochemical testing revealing an increased concentration of 8(9)-cholestenol in plasma, scales from skin lesions, or cultured lymphoblasts or fibroblasts is diagnostic.
  • Molecular genetic testing using sequence analysis for EBP mutations confirms the diagnosis, especially when biochemical results are equivocal.

Testing for at-risk relatives requires prior identification of the disease-causing mutation in the family.

Note: (1) Females are heterozygotes for this X-linked male lethal disorder. (2) Identification of the disease-causing mutation in females requires either (a) prior identification of the disease-causing mutation in the family or, (b) if an affected relative 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: Prenatal diagnosis by measurement of 8(9)-cholestenol and 8-dehydrocholesterol is also possible; the risk for a false negative result has not been determined.

Clinical Description

Natural History

At least 95% of individuals with X-linked chondrodysplasia punctata 2 (CDPX2) are female. The clinical phenotypes in heterozygous females are highly variable and depend on the pattern of X-chromosome inactivation in relevant tissues (i.e., percentage of wild-type versus mutant active X chromosomes), as well as the exact mutation, and other possible modifying factors. Phenotypes range from fetal demise with multiple malformations and severe growth retardation to much milder manifestations, including adults with no recognizable physical abnormalities. Severity in females varies greatly within families and among individuals with the same mutation, as would be expected for a pathologic process determined, in part, by the random process of X-chromosome inactivation.

Although CDPX2 was for many years presumed to be lethal in males, a small number of affected males have been reported [Crovato & Rebora 1985, Hochman & Fee 1987, De Raeve et al 1989, Tronnier et al 1992, Omobono & Goetsch 1993, Sutphen et al 1995, Aughton et al 2003]. Sutphen et al [1995] describe a male with CDPX2 and a 47,XXY karyotype. Aughton et al [2003] describe a male who is mosaic for the mutation c.238G>A (p.Glu80Lys), which has been reported in affected females. Tan et al [2010] describe three males with novel EBP mutations identified in the mosaic state. The clinical characteristics of males with mosaic EBP mutations are well within the marked variability described in affected females.

In addition, Milunsky et al [2003] and Furtado et al [2010] reported a neurologic phenotype, distinct from that found in CDPX2, in males with a hemizygous missense EBP mutation. Of the 11 hemizygous or presumed hemizygous males with CDPX2 known to the authors, all have had moderate to severe developmental delay and almost all have clinically important CNS malformations, most notable Dandy-Walker variant, agenesis of the corpus callosum, and major gyral abnormalities. Other unique findings include facial dysmorphisms, skeletal findings (2-3 toe syndactyly, postaxial polydactyly) and urogenital findings (cryptorchidism, hypospadias). Many hemizygous males have chronic ichthyosis, but, as would be predicted, not in patchy distributions.

Growth deficiency/short stature. Individuals with CDPX2 have short stature. Reported heights range from the10th-25th percentile to six standard deviations below the mean.

Craniofacial appearance. The face and head are often asymmetric. Most individuals with CDPX2 have a flattened nasal bridge and frontal bossing. Other distinctive features include downslanting palpebral fissures, ocular hypertelorism, low-set ears, and high-arched palate [Happle 1979, Herman 2000].

Skeletal. Stippling (chondrodysplasia punctata) involving the epiphyses of the long bones and vertebrae and tracheal cartilage and otherwise widespread is seen on x-rays in almost 100% of symptomatic infants; however, this could reflect bias of ascertainment.

Approximately 90% of individuals have asymmetric shortening of limbs (occasionally symmetric), involving mostly the femur, humerus, and other tubular bones [Happle 1979].

Moderate to severe kyphoscoliosis is common and can present in infancy or early childhood. Spinal deformities can progress rapidly; in addition, progressive deformity following surgical vertebral fusion is common [Mason et al 2002]. Contractures, other joint abnormalities, dislocated patella, and postaxial polydactyly have also been reported [Happle 1979, Herman 2000].

Skin, hair, and nails. Scaling ichthyosis, present in newborns in a linear or blotchy pattern, usually resolves in the first weeks or months of life. This erythematous eruption seen at birth often follows the lines of X-chromosome inactivation (i.e., the lines of Blaschko) and has a feather-like edge, but total scaling erythroderma also occurs. As this rash fades, it leaves in a linear or whorled pattern areas of atrophoderma predominantly near hair follicles where scales had been located. Some individuals also have ichthyosis and/or pigmentary abnormalities that persist into childhood.

Hair findings include scarring alopecia in patches, sparse eyelashes and eyebrows, and coarse, lusterless hair.

Minor nail findings include flattening and splitting of the nail plates [Happle 1979, Herman 2000, Hoang et al 2004].

Ocular. Approximately two thirds of individuals have cataracts at birth or develop them early in life. Cataracts are usually unilateral, asymmetric, and/or sectorial [Happle 1979, Happle 1981, Herman et al 2002]. Other eye findings include microphthalmia and/or microcornea.

Neurologic. Intelligence is typically normal in affected individuals unless a CNS malformation is present. Other (rarely seen) neurologic findings can include microcephaly, seizures, and tethered cord [Herman et al 2002].

Ear anomalies and hearing. Rarely, dysplastic auricles and sensorineural hearing loss have been reported in affected individuals [Happle 1979, Herman et al 2002].

Other findings. Individuals with CDPX2 may also have bilateral or unilateral clubfoot and renal or cardiac malformations [Happle 1979, Herman et al 2002]. Hydronephrosis has been seen in several affected girls.

Mortality. Typically life expectancy is normal in individuals with CDPX2 as long as severe scoliosis has not compromised heart and lung function.

Genotype-Phenotype Correlations

There are no confirmed genotype/phenotype correlations.

Ikegawa et al [2000] suggested that EBP mutations resulting in truncated proteins cause typical CDPX2 manifestations including skeletal, skin, and ocular findings, while missense mutations may result in a milder phenotype lacking some of these classic findings. However, other studies have shown no such correlation [Braverman et al 1999, Herman et al 2002].

The wide variation in phenotype is most likely due to X-chromosome inactivation patterns [Shirahama et al 2003], making genotype-phenotype correlations difficult to study. Although a genotype-phenotype correlation is more likely to be detected among hemizygous males with a hypomorphic mutation, few EBP-deficient males are known at this time.

Penetrance

No unaffected males or females with an EBP mutation have been reported; thus penetrance appears to be complete. Some women have been so mildly affected that they were identified only after having had a child with more severe features in whom CDXP2 was diagnosed. Although these adult women have subtle findings, their findings are sufficient to consider them affected.

Anticipation

Although increasing severity of phenotype in successive generations has been observed in a few instances, this is more likely secondary to germline mosaicism or variation in X-chromosome inactivation than true genetic anticipation [Has et al 2000, Herman et al 2002, Shirahama et al 2003].

Nomenclature

X-linked chondrodysplasia punctata (CDPX2) has also been referred to as:

Prevalence

Based on rates of biochemical diagnosis of CDPX2 compared to Smith-Lemli-Opitz syndrome (incidence of 1 in 75-100,000 births) in one laboratory, the recognized incidence of CDPX2 is no more than one fifth the rate for Smith-Lemli-Opitz syndrome, or no greater than approximately one in 400,000 births. This number may be an underestimate because of individuals with milder features who may not be accurately diagnosed.

Differential Diagnosis

Several disorders described below demonstrate features similar to those of chondrodysplasia punctata and/or manifest stippling on radiographs and various combinations of limb asymmetry, short stature, intellectual disability, cataracts, and skin changes. The key radiologic finding of chondrodysplasia punctata (CDP) occurs in various metabolic disorders, skeletal dysplasias, chromosome abnormalities, and teratogen exposures.

  • Rhizomelic chondrodysplasia punctata (RCDP), type 1, 2, or 3. This group of disorders shares with CDPX2 the features of rhizomelic shortening of the limbs, punctate calcifications in cartilage with epiphyseal and metaphyseal abnormalities (chondrodysplasia punctata), vertebral abnormalities (notching but not commonly CDP), and cataracts that are usually present at birth or appear in the first few months of life. Birth size is often in the lower range of normal, but postnatal growth deficiency is profound, intellectual disability severe, and seizures common. The skeletal findings and cataracts are more symmetric than in CDPX2. Most children with RCDP do not survive the first decade of life, and a substantial proportion die in the neonatal period. All types of RCDP are inherited in an autosomal recessive manner; type 1 is the most common. (See Rhizomelic Chondrodysplasia Punctata Type 1.)

    Biochemical diagnosis is based on a deficiency of plasmalogens in erythrocyte membranes and confirmed by demonstration of a mutation in one of three genes: PEX7, encoding the PTS2 peroxisomal protein import system (RCDP type 1); GNPAT, encoding dihydroxyacetonephosphate acyltransferase (RCDP type 2); or AGPS, encoding alkyldihydroacetonephosphate synthase (RCDP type 3).
  • X-linked recessive chondrodysplasia punctata, or brachytelephalangic type (CDPX1) is caused by defects in arylsulfatase E (ARSE), a vitamin K-dependent enzyme. Affected males have hypoplasia of the distal phalanges without limb shortening or cataracts. The diagnosis is confirmed by molecular genetic testing. Contiguous gene deletions involving ARSE and other genes in this region result in more complex phenotypes, including, variously, additional findings of ichthyosis, anosmia, hypogonadism, short stature, and corneal opacities.
  • Chondrodysplasia punctata, tibia-metacarpal and humero-metacarpal types are inherited in an autosomal dominant manner. The gene defect(s) are unknown. Affected individuals have short limbs due primarily to shortening of the metacarpals and tibiae/humeri. No skin or eye changes are present, and prognosis is good.
  • Warfarin embryopathy and other vitamin K deficiencies (including vitamin K epoxide reductase deficiency) are phenotypically similar to CDPX1 with especially severe hypoplasia of the nasal bone (“Binder anomaly”).
  • Maternal systemic lupus erythematosus (SLE) can cause CDP with rhizomelic limb shortening.

The following syndrome demonstrates other overlapping features of CDPX2 and may need to be considered.

  • CHILD (congenital hemidysplasia, ichthyosis, and limb defects) syndrome is also X-linked, apparently male-lethal, and associated with skin and limb abnormalities. (See NSDHL-Related Disorders.) The skin lesions typically present at birth and often persist, but can develop at any age, often at a site of skin damage. The skin lesions histologically are ichthyosiform nevi and, more often than not, do not conform to lines of Blaschko [Happle 1981, Herman 2000, Bornholdt et al 2005]. Ipsilateral limb defects, often reduction in type, are found with epiphyseal stippling noted in infancy. Alopecia and internal malformations may occur, and occasional skin lesions on the “unaffected” side or even symmetric lesions have been reported. Cataracts have not been reported.

    CHILD syndrome is caused by mutations in NSDHL that encodes a cholesterol biosynthetic 4-methylsterol dehydrogenase [König et al 2000]. The enzyme, part of a 4-methylsterol demethylase complex, occurs one step proximal to the EBP sterol isomerase.

    Both CHILD syndrome and CDPX2 cause pathognomonic abnormalities in plasma or tissue sterol levels. Individuals with CHILD syndrome have increased levels of 4-methyl- and carboxysterols in cultured lymphoblasts, but only occasionally in plasma, whereas those with CDPX2 have increased levels of 8(9)-cholestenol and 8-dehydrocholeterol. In cultured lymphoblasts, both disorders manifest a paradoxical increase in the distal sterol metabolite lathosterol, including hemizygous males with an EBP mutation. The embryologic cause of the CHILD phenotype, common in NSDHL deficiency and rare in EBP deficiency, is unknown. Interestingly, fibroblasts cultured from normal skin from both the hemidysplastic and normal sides of the body can manifest the classic, abnormal sterol profile.

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

No published guidelines exist to establish the extent of disease or proper management in an individual with X-linked chondrodysplasia punctata 2 (CDPX2). The following recommendations are based on current literature and the authors’ experience.

Evaluations Following Initial Diagnosis

  • Physical examination with attention to growth parameters, skin, hair, and skeleton, as well as possible internal malformations (CNS, cardiac, renal)
  • Full skeletal survey and orthopedic evaluation to assess limb length differences, kyphoscoliosis, and other skeletal abnormalities, including polydactyly
  • Pulmonary evaluation, if scoliosis compromises respiratory function
  • Dermatologic evaluation to exclude other causes of the phenotype
  • Ophthalmologic evaluation for congenital cataracts and other eye abnormalities
  • Developmental assessment (after the newborn period)
  • Echocardiogram for possible congenital heart defect at the time of diagnosis
  • Renal ultrasound examination for possible kidney anomalies
  • Hearing evaluation to detect hearing loss

Treatment of Manifestations

Treatment is symptomatic and should be tailored to each patient. For females with typical CDPX2 diagnosed in the newborn period:

  • Orthopedic management of leg length discrepancy; surgical correction of polydactyly; frequent assessment of kyphoscoliosis, which can progress rapidly at any age
  • Cataract extraction and correction of vision
  • Dermatologic management of skin lesions
  • Physical, occupational, and speech therapies, if necessary
  • Standard interventions for congenital heart defects, kidney anomalies, and hearing loss

Surveillance

Appropriate surveillance includes:

  • Regular follow-up of ophthalmologic abnormalities
  • Regular orthopedic evaluations to monitor kyphoscoliosis or joint problems and assess linear growth and any leg length discrepancy
  • Ongoing developmental assessments
  • Ongoing follow-up with dermatologist
  • Routine monitoring of any existing cardiac and/or renal abnormalities
  • Regular hearing evaluations

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing 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.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

X-linked chondrodysplasia punctata 2 (CDPX2) is inherited in an X-linked manner with male lethality.

Risk to Family Members

Parents of a female proband

  • If the proband is a female and if pedigree analysis reveals that she is the only affected family member, it is reasonable to offer molecular genetic testing to both of her parents to determine risks to family members.
  • If the proband’s father is asymptomatic, it is possible, but not likely, that he has the mutation in some cells in his body (somatic mosaicism). If her father is asymptomatic and does not have somatic mosaicism for the altered gene, the possible genetic explanations for the origin of the proband's gene mutation are the same as for a male proband with a negative family history.

Parents of a male proband

  • CDPX2 is presumed lethal in males, though a small number of affected males have been reported.
  • 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 that 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, four possible genetic explanations exist:

  • The proband has a de novo EBP mutation. In this instance, the proband’s mother does not have a gene mutation and the only other family members at risk are the offspring of the proband. De novo EBP mutations have been reported.
  • The mother has inherited the mutation from her mother.
  • The proband’s mother has a de novo mutation. One of three types of de novo mutations may be present in the mother:
    a.

    A germline EBP mutation that was present at the time of her conception, is present in every cell of her body, and is detectable in her leukocytes; however, because of variability in X-chromosome inactivation patterns, the mother may have very subtle to no features of CDPX2;

    b.

    A somatic EBP mutation that occurred in one cell after conception that populated some tissues in her body including her germline. This may cause very subtle to no features of CDPX2 and has been reported in individuals with CDPX2 [Has et al 2000];

    c.

    An EBP mutation that is present only in her ovaries (termed "germline mosaicism") in which some germ cells have the mutation and some do not, and in which the mutation is often not detectable in DNA extracted from leukocytes. Germline mosaicism has been reported in families with CDPX2 [Has et al 2000].

In all above instances (a, b, and c), each of the proband’s mother’s offspring is at risk of inheriting the mutation; none of the proband’s mother’s sibs, however, is at risk of inheriting the altered gene.

Sibs of a proband. The risk to the sibs of a proband depends on the genetic status of the parents.

  • If a parent has a germline mutation, the chance in each pregnancy of transmitting the mutation is 50%.
  • When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low but greater than that of the general population.

Offspring of a female proband. Women with an EBP germline mutation have a 50% chance of transmitting the disease-causing mutation to each child: EBP mutations in sons are usually lethal; daughters will have a range of possible phenotypic expression.

Offspring of a male proband. Affected males would transmit the disease-causing mutation to all of their daughters and none of their sons; however, to the authors’ knowledge, no affected males have been reported to reproduce.

Other family members of a proband. If a parent of the proband also has a disease-causing mutation, his/her female family members may be at risk of being carriers (asymptomatic or symptomatic) and his/her family members may be at risk of being affected depending on their genetic relationship to the proband.

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 affected, have the disease-causing mutation, or are at risk of having the disease-causing mutation.

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.

Prenatal Testing

If the disease-causing mutation has been identified in the family, prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis (usually performed at ~15-18 weeks’ gestation) or chorionic villus sampling (usually performed at ~10-12 weeks’ gestation).

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 an option for some families in which the disease-causing mutation has been identified in an affected family member.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Foundation for Ichthyosis and Related Skin Types, Inc. (FIRST)
    2616 North Broad Street
    Colmar PA 18915
    Phone: 215-997-9400
    Fax: 215-997-9403
    Email: info@firstskinfoundation.org
  • Little People of America, Inc. (LPA)
    250 El Camino Real
    Suite 201
    Tustin CA 92780
    Phone: 888-572-2001 (toll-free); 714-368-3689
    Fax: 714-368-3367
    Email: info@lpaonline.org
  • MAGIC Foundation
    6645 West North Avenue
    Oak Park IL 60302
    Phone: 800-362-4423 (Toll-free Parent Help Line); 708-383-0808
    Fax: 708-383-0899
    Email: info@magicfoundation.org
  • International Skeletal Dysplasia Registry
    Cedars-Sinai Medical Center
    116 North Robertson Boulevard, 4th floor (UPS, FedEx, DHL, etc)
    Pacific Theatres, 4th Floor, 8700 Beverly Boulevard (USPS regular mail only)
    Los Angeles CA 90048
    Phone: 310-423-9915
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Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. Chondrodysplasia Punctata 2, X-Linked: Genes and Databases

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for Chondrodysplasia Punctata 2, X-Linked (View All in OMIM)

300205EMOPAMIL-BINDING PROTEIN; EBP
302960CHONDRODYSPLASIA PUNCTATA 2, X-LINKED DOMINANT; CDPX2

Molecular Genetic Pathogenesis

X-linked chondrodysplasia punctata 2 (CDPX2) is caused by a deficiency of 3β-hydroxysteroid-Δ8, Δ7-isomerase or “sterol-Δ8-isomerase,” which converts 8(9)-cholestenol to lathosterol during cholesterol biosynthesis. Lathosterol is then converted to 7-dehydrocholesterol, which is a primary precursor for synthesizing both cholesterol and vitamin A [Kelley et al 1999]. Human sterol-Δ8-isomerase is encoded by the EBP (emapomil-binding protein) gene [Braverman et al 1999, Derry et al 1999]. EBP is presumably subjected to X-chromosome inactivation, which is responsible for the variability in phenotypes among females.

Normal allelic variants. EBP comprises approximately 7.0 kb of genomic DNA and consists of five exons, of which only four are coding exons. It encodes a 230-aa protein, which is thought to be an integral endoplasmic reticulum membrane protein that contains four potential transmembrane domains and a potential site for cAMP-dependent protein kinase phosphorylation. The synonymous c.15G>T (p.Ala5Ala) rs3048 normal variant in exon 2 is the only non-pathologic sequence change reported with a high frequency in EBP. This variant has a frequency of 39%, 21%, 48%, and 46% in the white, African, Japanese, and Chinese populations, respectively.

Pathologic allelic variants. Over 55 EBP mutations have been reported in individuals with CDPX2. Mutations have been found in all of the coding exons of EBP, with a majority of mutations found in exons 2 and 4. Small deletions and insertions, splice site mutations, frameshifts, along with missense and nonsense mutations have been reported. Functional studies have confirmed the pathogenesis of a small number of missense mutations [Braverman et al 1999]. A number of mutations appear to be recurrent, and mutations commonly occur at CpG dinucleotides, representing likely “hot spots” [Herman et al 2002].

Table 3. Selected EBP Allelic Variants

Class of Variant AlleleDNA Nucleotide ChangeProtein Amino Acid Change
Normalc.15G>T 1p.Ala5Ala
Pathologicc.238G>Ap.Glu80Lys

Note on variant classification: Variants listed in the table have been provided by the author(s). GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1. www​.ncbi.nlm.nih.gov/projects/SNP

Normal gene product. EBP encodes 3β-hydroxysteroid-Δ8, Δ7-isomerase, an enzyme important in cholesterol biosynthesis. This enzyme converts 8(9)-cholestenol to lathosterol, which is then converted to 7-dehydrocholesterol, a primary precursor for synthesizing cholesterol and vitamin A [Kelley et al 1999].

Abnormal gene product. Decreased function of the 3β-hydroxysteroid-Δ8, Δ7-isomerase causes the accumulation of sterol intermediates above the enzymatic block, as well as reduced cellular cholesterol. Plasma cholesterol levels in affected heterozygous females are usually normal. The exact mechanism(s) producing the clinical features seen in females with CDPX2 are not known.

References

Literature Cited

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Chapter Notes

Revision History

  • 31 May 2011 (me) Review posted live
  • 13 July 2009 (md) Original submission
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