Lethal Course of X-Linked Dominant Chondrodysplasia punctata in a Male Newborn

Raeve, Linda De; Song, Myeong Ryeol; Dobbeleer, Gilbert De; Spehl, M; Regemorter, N. Van

doi:10.1159/000248418

Cited by 14 publications

(10 citation statements)

References 6 publications

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“…To our knowledge, our patients are the longest‐living males with 3‐β‐hydroxysteroid‐Δ8,Δ7‐isomerase deficiency. Certain published cases have been considered to be independent of CDPX2 [Happle, ; Ikegawa, ; Furtado et al, ; Happle, ; Rope and Carey, ; Barboza‐Cerda et al, ] or mostly, as atypical cases of CDPX2 in males [De Raeve et al, ; Milunsky et al, ; Kelley et al, ; Tan et al, ; Bode et al, ]. However, we concur with the idea that these phenotypes, collectively, actually represent a single condition [Happle, ; Arnold et al, ].…”

Section: Discussionsupporting

confidence: 81%

“…Digital abnormalities are a remarkable feature of the Barboza‐Cerda phenotype; interestingly, an apparently more severe form of this phenotype was previously reported in a boy that was clinically diagnosed with a rare case of CDPX2 [De Raeve et al, ]. The authors described a male newborn with an equivalent syndactyly of 4–5 fingers and toes, together with hypoplasia of all of the middle phalanges.…”

Section: Discussionmentioning

confidence: 93%

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A novel EBP c.224T>A mutation supports the existence of a male‐specific disorder independent of CDPX2

Barboza-Cerda

Wong

Martínez-de-Villarreal

et al. 2014

American J of Med Genetics Pt A

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Mutations in the Emopamil-binding protein (EBP) gene cause X-linked dominant chondrodysplasia punctata 2 (CDPX2), a disorder in which at least 95% of liveborn individuals are female and male intrauterine lethality is assumed. Several affected males with mutations in EBP have been reported. These males exhibit a phenotype similar to CDPX2 due to either somatic mosaicism or a 47, XXY karyotype in association with a null EBP allele. Alternatively, affected males may exhibit a distinct phenotype if they are hemizygous for a hypomorphic allele of EBP. Recently, we described a novel X-linked phenotype associated with digital abnormalities, intellectual disability and short stature, and mapped it to Xp11.4-p11.21. X-exome sequencing was performed to identify the mutated gene responsible for this phenotype. A novel missense variant, c.224T>A (p.I75N), was identified in EBP. SIFT and PolyPhen-2 predicted this change to be deleterious. The pathogenicity of this variant was subsequently supported by increased plasma levels of 8(9)-cholestenol in the proband and his mother. The molecular and biochemical evidence convincingly supports the pathogenicity and association of the p.I75N mutation with this newly described phenotype. This study expands the current phenotypic spectrum of males with hypomorphic EBP mutations and supports to the hypothesis that there exists an X-linked recessive entity independent of CDPX2.

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Section: Discussionsupporting

confidence: 81%

Section: Discussionmentioning

confidence: 93%

A novel EBP c.224T>A mutation supports the existence of a male‐specific disorder independent of CDPX2

Barboza-Cerda

Wong

Martínez-de-Villarreal

et al. 2014

American J of Med Genetics Pt A

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“…However, there was no stippling of the epiphyses noted the patients reported here. A male newborn affected with X-linked dominant chondrodysplasia punctata, hydrocephaly, and blepharophimosis with bilateral cataract has been reported [De Raeve et al, 1989]. This child had a thick ortho-and parakeratotic horny layer covering the skin.…”

Section: Discussionmentioning

confidence: 99%

X-linked dominant chondrodysplasia with platyspondyly, distinctive brachydactyly, hydrocephaly, and microphthalmia

Chassaing

Siani²,

Carles

et al. 2005

Am. J. Med. Genet.

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We describe a family with an X-linked dominant chondrodysplasia. Four males and six females were affected through four generations. Identification of skeletal abnormalities and hydrocephaly during the pregnancy of three male fetuses led to termination of the pregnancies. A fourth affected male died at 6 days of life. The four patients had chondrodysplasia, hydrocephaly, and facial features with microphthalmia. Radiographs showed severe platyspondyly and various bone abnormalities including a distinctive metaphyseal cupping of the metacarpals, metatarsals, and phalanges. The affected females were less affected and showed small stature, sometimes associated with body asymmetry and mild mental retardation. This condition appears to be a previously unrecognized X-linked dominant chondrodysplasia.

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“…The phenotype in males has not been well delineated. The few cases reported have had either clinical findings similar to those observed in affected females, or skeletal and CNS anomalies resulting in neonatal death [De Raeve et al, 1989].…”

Section: Introductionmentioning

confidence: 86%

“…CDPX2 is presumed lethal in males [Wettke-Schafer and Kantner, 1983], although about 10 affected males have been reported [Crovato and Rebora, 1985;Hochman and Fee, 1987;Sillevis Smitt et al, 1987;De Raeve et al, 1989;Tronnier et al, 1992;Omobono and Goetsch, 1993;Happle, 1995;Sutphen et al, 1995;Aughton et al, 2001]. CDPX2 is a postsqualene cholesterol biosynthetic disorder due to 3-b-hydroxysteroid-D8,D7-isomerase deficiency caused by mutations in the emopamil binding protein (EBP) gene [Braverman et al, 1999].…”

Section: Introductionmentioning

confidence: 99%

Molecular, biochemical, and phenotypic analysis of a hemizygous male with a severe atypical phenotype for X‐linked dominant Conradi‐Hunermann‐Happle syndrome and a mutation in EBP

Milunsky

Maher

Metzenberg

2002

American J of Med Genetics Pt A

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X-linked dominant Conradi-Hunermann-Happle syndrome (CDPX2; MIM 302960) is a rare chondrodysplasia punctata primarily affecting females. CDPX2 is presumed lethal in males, although a few affected males have been reported. CDPX2 is a cholesterol biosynthetic disorder due to 3-beta-hydroxysteroid-delta8,delta7-isomerase deficiency caused by mutations in the emopamil binding protein (EBP) gene. A 2.5-year-old Caucasian male was followed from the age of 6 weeks and noted to have significant developmental delay, hypotonia, seizures, and patchy hypopigmentation. Multiple congenital anomalies included a unilateral cataract, esotropia, crossed renal ectopia, stenotic ear canals, and failure to thrive, requiring G-tube placement. Multiple minor anomalies and ptosis were noted. No skeletal asymmetry or chondrodysplasia punctata were noted on skeletal survey at 6 weeks and 13 months. An extensive genetic work-up including cholesterol (126-176 mg/dl) and 7-dehydrocholesterol was unrevealing. However, the levels of 8(9)-cholestenol and 8-dehydrocholesterol were mildly increased in plasma, which was confirmed in cultured fibroblasts. This prompted molecular analysis of the EBP gene, which revealed a novel hemizygous (nonmosaic) mutation in exon 2 (L18P). Two restriction digests were developed that confirmed this mutation in skin fibroblasts, blood, and buccal cells (all nonmosaic). We determined that the patient's mother (adopted) also has the L18P mutation enabling prenatal diagnosis of a normal male fetus. She has normal stature, no asymmetry, no cataracts at this time, and has a patch of hyperpigmentation on her chest best visualized on Woods lamp examination, characteristic of CDPX2. The mild maternal phenotype has been described previously. However, this nonmosaic missense mutation has resulted in a severe phenotype in her surviving son.

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Lethal Course of X-Linked Dominant Chondrodysplasia punctata in a Male Newborn

Cited by 14 publications

References 6 publications

A novel EBP c.224T>A mutation supports the existence of a male‐specific disorder independent of CDPX2

A novel EBP c.224T>A mutation supports the existence of a male‐specific disorder independent of CDPX2

X-linked dominant chondrodysplasia with platyspondyly, distinctive brachydactyly, hydrocephaly, and microphthalmia

Molecular, biochemical, and phenotypic analysis of a hemizygous male with a severe atypical phenotype for X‐linked dominant Conradi‐Hunermann‐Happle syndrome and a mutation in EBP

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