Severe phenotype of X-linked dominant chondrodysplasia punctata.
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ABSTRACT:
SUBMITTER: Damseh N
PROVIDER: S-EPMC5582310 | biostudies-literature | 2017 Sep
REPOSITORIES: biostudies-literature
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Severe phenotype of X-linked dominant chondrodysplasia punctata.
Damseh Nadirah N Chong Karen K Marshall Christian C Kratz Lisa L Teitelbaum Ronni R Shannon Patrick P Kannu Peter P Kannu Peter P
Clinical case reports 20170720 9
A prenatally ascertained case representing the more severe end of the X-linked dominant chondrodysplasia punctata (CDPX2). ...[more]
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Project description:RATIONALE:X-linked dominant chondrodysplasia punctata type 2 (CDPX2) is a condition involving facial, skin, and skeletal dysplasia as a result of a mutation in emopamil binding protein (EBP). It usually presents with mild symptoms in female patients but is fatal in male patients. PATIENT CONCERNS:A fetus was diagnosed with asymmetrical short limbs and a narrow and small thorax by prenatal ultrasound examination at 24+5 weeks gestation. The pregnancy was terminated at 27 weeks of gestation; gross examination, postnatal X-ray and, whole exome analysis were performed to clarify the diagnosis. DIAGNOSIS:A provisional diagnosis of fatal skeletal dysplasia was given and the definite diagnosis of CDPX2 was based on postnatal X-ray and genetic testing of the aborted fetus. INTERVENTION:The pregnancy was terminated at 27 weeks' gestation after a fetal ultrasound indicated a severe abnormal phenotype. OUTCOMES:Whole exome analysis of aborted tissue confirmed EBP mutation in this case. Unlike most case reports, this female patient presented a severe phenotype that was considered to be related to X-chromosome inactivation. LESSONS:Chondrodysplasia punctata (CDP) should be considered if prenatal ultrasound shows high punctuate echoes at the metaphysis of long bones and asymmetrical short lower limbs. Postnatal X-ray and measurement of sterol levels in the amniotic fluid may aid in the diagnosis of CDP, but the condition can be confirmed with genetic testing of a blood sample or aborted tissue after delivery.
| S-EPMC6344186 | biostudies-literature
Project description:BACKGROUND:Chondrodysplasia punctata is a skeletal dysplasia caused by a diverse spectrum of etiologies, with outcomes ranging from antenatal demise to a normal life span. Prenatal detection can be challenging. OBJECTIVE:To review a series of cases of chondrodysplasia punctata associated with nasomaxillary hypoplasia, known as the Binder phenotype, and to highlight prenatal ultrasound and MRI findings, as well as postnatal MRI and radiographic findings. MATERIALS AND METHODS:We retrospectively reviewed ultrasound, MRI and radiographic imaging findings in postnatally confirmed cases of chondrodysplasia punctata from 2001 to 2017. We analyzed prenatal findings and correlated them with maternal history, postnatal imaging, phenotype, genetics and outcome. RESULTS:We identified eight cases, all with prenatal US and six of eight with prenatal MRI between 18 weeks and 32 weeks of gestational age. Reasons for referral included midface hypoplasia in four cases; family history in one case; intrauterine growth restriction in one case; short long-bones, intrauterine growth restriction and multicystic kidney in one case; and multiple anomalies in one case. In six cases, postnatal radiographs were performed. In four cases, postnatal spine MRI imaging was performed. The diagnosis of chondrodysplasia punctata was suggested in prenatal reports in six of eight fetuses. Seven of eight fetuses had Binder phenotype with severe nasomaxillary hypoplasia. Limb length was mildly symmetrically short in four of eight cases and normal in four of eight fetuses. Two of eight fetuses had epiphyseal stippling identified prenatally by US; this was present postnatally in six neonates on radiographs. Hand and foot abnormalities of brachytelephalangy were not detected on the prenatal US or MRI but were present in six of eigth fetuses on postnatal radiographs or physical exam. Four of eight fetuses had prenatal spine irregularity on US from subtle stippling. Six of eight had spine stippling on postnatal radiographs. One fetus had cervicothoracic kyphosis on prenatal US and MRI, and this was postnatally present in one additional neonate. One case had prenatally suspected C1 spinal stenosis with possible cord compression, and this was confirmed postnatally by MRI. There was a maternal history of systemic lupus erythematosus in two and hyperemesis gravidarum in one. Outcomes included one termination and seven survivors. CONCLUSION:Chondrodysplasia punctata can be identified prenatally but findings are often subtle. The diagnosis should be considered when a fetus presents with a hypoplastic midface known as the Binder phenotype. Maternal history of lupus, or other autoimmune diseases or hyperemesis gravidarum can help support the diagnosis.
| S-EPMC6365632 | biostudies-literature
Project description:BACKGROUND: To describe the neurologic profiles of Rhizomelic chondrodysplasia punctata (RCDP); a peroxisomal disorder clinically characterized by skeletal abnormalities, congenital cataracts, severe growth and developmental impairments and immobility of joints. Defective plasmalogen biosynthesis is the main biochemical feature. METHODS: Observational study including review of clinical and biochemical abnormalities, genotype, presence of seizures and neurophysiological studies of a cohort of 16 patients with RCDP. RESULTS: Patients with the severe phenotype nearly failed to achieve any motor or cognitive skills, whereas patients with the milder phenotype had profound intellectual disability but were able to walk and had verbal communication skills. Eighty-eight percent of patients developed epileptic seizures. The age of onset paralleled the severity of the clinical and biochemical phenotype. Myoclonic jerks, followed by atypical absences were most frequently observed. All patients with clinical seizures had interictal encephalographic evidence of epilepsy. Visual evoked (VEP) and brain auditory potential (BAEP) studies showed initial normal latency times in 93% of patients. Deterioration of VEP occurred in a minority in both the severe and the milder phenotype. BAEP and somatosensory evoked potentials (SSEP) were more likely to become abnormal in the severe phenotype. Plasmalogens were deficient in all patients. In the milder phenotype levels of plasmalogens were significantly higher in erythrocytes than in the severe phenotype. Phytanic acid levels ranged from normal to severely increased, but had no relation with the neurological phenotype. CONCLUSION: Neurodevelopmental deficits and age-related occurrence of seizures are characteristic of RCDP and are related to the rest-activity in plasmalogen biosynthesis. Evoked potential studies are more likely to become abnormal in the severe phenotype, but are of no predictive value in single cases of RCDP.
| S-EPMC4228450 | biostudies-literature
Project description:Rhizomelic chondrodysplasia punctate (RCDP) is a rare autosomal recessive peroxisomal disease. The main features of the disease are shortening of the proximal long bones, punctate calcifications located in the epiphyses of long bones and in soft tissues around joints and vertebral column, vertebral clefting, dysmorphic face, and severe growth retardation, whereas cervical spinal stenosis may also rarely be present. Imaging of the brain and spinal cord in patients with this disorder may aid prognosis and guide management decisions. We report the newborn diagnosed as CDP with cervical stenosis. Our aim is to discuss current knowledge on etiopathogenesis as well as radiological and clinical symptoms of diseases associated with CDP.
| S-EPMC3970257 | biostudies-literature
Project description:BackgroundRhizomelic chondrodysplasia punctata (RCDP) is a clinical entity resulting from defects of peroxisomal metabolism whose clinical phenotype is characterized by rhizomelia, calcified foci in periarticular cartilage, coronal lesions of vertebral bodies, cataracts and severe cognitive delay. Usually, survival does not exceed the first decade of life. Transmission is autosomal recessive and is related to mutations in the PEX7, GNPAT or AGPS.MethodsA detailed description of the prenatal ultrasound signs of RCDP found in two successive pregnancies in a consanguineous couple is reported. Molecular genetic investigations included the study of the coding regions and the exon-intron junctions of the GNPAT (high-throughput amplification and sequencing performed with Roche NimbleGen SeqCap Target kit on Illumina platform); the confirmation test was carried out by amplification and Sanger sequencing with automatic capillary sequencer.ResultsIn addition to the typical prenatal ultrasound signs described in the literature in association with RCDP, the presence of prefrontal oedema, never previously described, has been detected in both pregnancies. Moreover, genetic investigations have found a new splicing variant c.924+1G>A of the homozygous GNPAT.ConclusionThe role of mutation in the GNPAT suggests a likely association with the clinical phenotype.
| S-EPMC8404227 | biostudies-literature
Project description:Chondrodysplasia punctata (CDP) is a skeletal abnormality characterized by premature calcification that is usually noticeable in the prenatal period and infancy. Etiologically, the condition is heterogeneous, and the causes include fetal conditions such as chromosome abnormalities, peroxisomal disorders, lysosomal storage disorders, cholesterol synthesis defects and abnormal vitamin K metabolism, as well as maternal diseases such as severe malabsorption and exposure to teratogens. An association between CDP and maternal autoimmune disease was first observed and reported by Curry et al and Costa et al in 1993 and expanded by Chitayat et al in 2010. This review lists the clinical characteristics and radiologic findings of all cases reported to date in English and discuss the possible etiology of this interesting fetal finding.
| S-EPMC5918624 | biostudies-literature
Project description:X-linked chondrodysplasia punctata (CDPX) is a congenital disorder characterized by abnormalities in cartilage and bone development. Mutations leading to amino acid substitutions were identified recently in CDPX patients, in the coding region of the arylsulfatase E (ARSE) gene, a novel member of the sulfatase gene family. Transfection of the ARSE full-length cDNA, in Cos7 cells, allowed us to establish that its protein product is a 60-kD precursor, which is subject to N-glycosylation, to give a mature 68-kD form that, unique among sulfatases, is localized to the Golgi apparatus. Five missense mutations found in CDPX patients were introduced into wild-type ARSE cDNA by site-directed mutagenesis. These mutants were transfected into Cos7 cells, and the arylsulfatase activity and biochemical properties were determined, to study the effect of these substitutions on the ARSE protein. One of the mutants behaves as the wild-type protein. All four of the other mutations resulted in a complete lack of arylsulfatase activity, although the substitutions do not appear to affect the stability and subcellular localization of the protein. The loss of activity due to these mutations confirms their involvement in the clinical phenotype and points to the importance of these residues in the correct folding of a catalytically active ARSE enzyme.
| S-EPMC1376941 | biostudies-other
Project description:BackgroundX-linked recessive chondrodysplasia punctate (CDPX1) is a rare congenital disorder of bone and cartilage development, caused by a mutation in the arylsulfatase E (ARSE) gene located on chromosome Xp22.3. Although most of the affected men had mild symptoms, some had more severe symptoms, and had a poor prognosis.Case presentationWe present the case of a male fetus diagnosed with CDPX1. Ultrasound clearly showed that hypoplasia of the midface, flatness of face, low flatness of the nose, collapse of the tip of the nose, accompanied by severe spinal stenosis and secondary ossification center of the femoral metaphysis appeared in advance. Chromosome analysis of the amniotic fluid cells revealed 46, XY. Whole exome sequencing showed that there was a novel missense mutation of c.640G > A in ARSE gene on X chromosome. Three protein function prediction software FATHMM、Polyphen-2、PROVEAN have shown that the novel missense mutation of c.640G > A in this study was pathogenic.ConclusionsOur case is a novel mutation and presents a typical characterization of the disease, which can expand the spectrum of mutations of the ARSE gene and is helpful for prenatal ultrasound diagnosis of this disease.
| S-EPMC6647267 | biostudies-literature
Project description:Peroxisomes are involved in various metabolic reactions. Rhizomelic chondrodysplasia punctata (RCDP) type 1 is one of the peroxisomal biogenesis disorders caused by mutations in the PEX7 gene and is inherited in an autosomal recessive manner. We present a nine-year-old boy with skeletal abnormalities and dysmorphic facial appearance. The patient was born to parents who were first cousins. Very-long-chain fatty acids and pristanic acid levels were in the normal range, but an elevated phytanic acid level was detected by gas chromatography/mass spectrometry. The PEX7 gene was sequenced in the patient and his parents. A novel homozygous mutation, c.192delT (p.F64Lfs*10), was identified in the patient and was present in heterozygosity in both parents. In conclusion, the clinical presentation and peroxisome profile of the patient suggest that this novel mutation leads to RCDP type 1.
| S-EPMC4439895 | biostudies-literature
Project description:X-Linked recessive chondrodysplasia punctata (CDPX1) is a rare skeletal dysplasia characterized by stippled epiphyses, brachytelephalangy, and nasomaxillary hypoplasia. CDPX1 is caused by function loss of arylsulfatase E (ARSE, also known as ARSL). Pathogenic mutations in ARSE are responsible for CDPX1 in newborns or adults; however, studies have not fully explored prenatal cases. In the current study, a novel missense mutation (c.265A > G) in ARSE was identified in a fetus with short limbs using whole-exome sequencing (WES). Bioinformatic analysis showed that the variant was pathogenic, and RT-qPCR, Western blot, and enzymatic assays were performed to further explore pathogenicity of the variant. The findings showed that the variant decreased transcription and protein expression levels and led to loss of enzymatic activity of the protein. The novel mutation c.265A > G in ARSE was thus the genetic cause for the phenotype presented by the fetus. The current study presents a prenatal case in Chinese population using functional analysis of ARSE, which helps the family to predict recurrence risks for future pregnancies and provides more information for understanding this rare condition. The findings show that WES is a feasible method for prenatal diagnosis of fetuses with CDPX1.
| S-EPMC8498588 | biostudies-literature