X-Linked Dominant Chondrodysplasia Punctata (original) (raw)
Clinical variation in X-linked dominant chondrodysplasia punctata (X-linked dominant ichthyosis)
British Journal of Dermatology, 2006
Chondrodysplasia punctata is a heterogeneous group of skeletal dysplasias characterized by an anomaly of enchondral bone formation causing stippled calcifications that can be visualized radiologically or sonographically. The X-linked dominant form (Conradi-Hünermann-Happle syndrome, CDPX2) occurs almost exclusively in women and is characterized by asymmetrical limb shortening and cataract as well as a transitory congenital dermatosis presenting as generalized erythroderma with segmental lesions of prominent follicular keratosis. Later, this congenital dermatosis regresses and leaves behind patchy or segmental atrophic skin lesions, mainly follicular atrophoderma. Scarring alopecia is often present. A diffuse, moderate ichthyotic scaling may persist. 1,2 The EBP gene, coding for a D 8 ,D 7-sterol isomerase involved in cholesterol biosynthesis, was identified as the gene mutated in CDPX2. 3,4 To date, at least 45 disease-causing mutations have been reported. The mutation spectrum included 15 nonsense, 16 missense, two deletion, seven frameshift, two splice-site and three intronic mutations, distributed among the five exons as well as introns of the EBP gene, with a majority of mutations encountered in exons 2 and 4. Here we discuss the molecular and clinical correlation of three cases of CDPX2, including a new mutation.
Adult Presentation of X-Linked Conradi-Hünermann-Happle Syndrome
Conradi-Hünermann-Happle syndrome, or X-linked dominant chondrodysplasia punctata type 2 (CDPX2), is a genodermatosis caused by mutations in EBP. While typically lethal in males, females with CDPX2 generally manifest by infancy or childhood with variable features including congenital ichthyosiform eryth-roderma, chondrodysplasia punctata, asymmetric shortening of the long bones, and cataracts. We present a 36-year-old female with short stature, rhizomelic and asymmetric limb shortening, severe scoliosis, a sectorial cataract, and no family history of CDPX2. Whole exome sequencing (WES) revealed a p.Arg63del mutation in EBP, and biochemical studies confirmed a diagnosis of CDPX2. Short stature in combination with ichthyosis or alopecia, cataracts, and limb shortening in an adult should prompt consideration of a diagnosis of CDPX2. As in many genetic syndromes, the hallmark features of CDPX2 in pediatric patients are not readily identifiable in adults. This demonstrates the utility of WES as a diagnostic tool in the evaluation of adults with genetic disorders.
A Case Report of Rhizomelic Chondrodysplasia Punctata
International Journal of Health Sciences and Research, 2015
The authors present a case of a 5 year old, male child born out of 3 rd degree consanguineous marriage affected by the recessive form of chondrodysplasia punctata, a rare condition radiologically characterized by severe proximal shortening and anomalous ossification (epiphyseal stippling) of limbs. Clinical and radiological findings as well as main differential diagnoses are emphasized on the basis of data originating from a brief literature review.
Rhizomelic chondrodysplasia punctata type 1: report of mutations in 3 children from India
Journal of Applied Genetics, 2010
Rhizomelic chondrodysplasia punctata is a rare autosomal recessive disorder characterized by stippled epiphyses and rhizomelic shortening of the long bones. We report 3 subjects of rhizomelic chondrodysplasia punctata from India and the PEX7 mutations identified in them. The common PEX7-L292X allele, whose high frequency is due to a founder effect in the northern European Caucasian population, was not identified in these patients. Instead, 2 novel alleles are described, including 64_65delGC, which was present on a single PEX7 haplotype and could represent a common allele in the Indian population.
Cureus, 2021
Rhizomelic chondrodysplasia punctata (RCDP) is a devastating medical condition for patients and their families. It is a rare peroxisomal autosomal recessive disorder. It was recognized clinically with skeletal abnormalities and intellectual disabilities mainly due to plasmalogen deficiency. Here, we report a case of a 16-day-old girl who was referred to King Abdulaziz Medical City Jeddah, Saudi Arabia because of dysmorphic features. Her growth parameters were below the 3rd centile with short proximal long bones and multiple joint contractures in the extremities. The radiographs showed rhizomelic and shortening of both humeri and femurs. Moreover, punctate ossification was identified in the upper spine, humeri around the shoulders, and femurs around the knees. We observed other classical features, and the genetic testing confirmed the diagnosis of RCDP type 3. Although RCDP is a rare condition, it is a distressing burden necessitating early diagnosis and a holistic approach for manag...
Type 1 rhizomelic chondrodysplasia punctata with a homozygous PEX7 mutation
Journal of pediatric endocrinology & metabolism : JPEM, 2017
Rhizomelic chondrodysplasia punctata (RCDP) is a rare peroxisomal disease characterised by punctate calcifications of non-ossified cartilage epiphyseal centres. The main biochemical marker of all RCDP types is a decrease in the levels of plasmalogens. Additionally, the accumulation of phytanic acid can be used as a differential marker between types of RDCP. Due to the biochemical overlap between types 1 and 5 RCDP, a genetic analysis of these genes should be performed in patients to identify the type. A 2-month-19-day-old male child presented with symptoms of limited movement and discomfort with movement in the extremities. His sister, who had similar clinical findings, was diagnosed with tetralogy of Fallot and died at 6 months of age. A physical examination revealed an atypical facial appearance, bilateral cataracts, sensitivity to touch in the extremities, shortness in the proximal segments of the long bones, limited movement in both knees and elbows and axial hypotonicity. Labor...
Severe X-linked chondrodysplasia punctata in nine new female fetuses
Prenatal Diagnosis, 2015
Objectives Conradi-Hünermann-Happle [X-linked dominant chondrodysplasia punctata 2 (CDPX2)] syndrome is a rare X-linked dominant skeletal dysplasia usually lethal in men while affected women show wide clinical heterogeneity. Different EBP mutations have been reported. Severe female cases have rarely been reported, with only six antenatal presentations. Methods To better characterize the phenotype in female fetuses, we included nine antenatally diagnosed cases of women with EBP mutations. All cases were de novo except for two fetuses with an affected mother and one case of germinal mosaicism. Results The mean age at diagnosis was 22 weeks of gestation. The ultrasound features mainly included bone abnormalities: shortening (8/9 cases) and bowing of the long bones (5/9), punctuate epiphysis (7/9) and an irregular aspect of the spine (5/9). Postnatal X-rays and examination showed ichthyosis (8/9) and epiphyseal stippling (9/9), with frequent asymmetric short and bowed long bones. The X-inactivation pattern of the familial case revealed skewed X-inactivation in the mildly symptomatic mother and random X-inactivation in the severe fetal case. Differently affected skin samples of the same fetus revealed different patterns of X-inactivation.
X-linked recessive chondrodysplasia punctata due to a new point mutation of the ARSE gene
American Journal of Medical Genetics, 1997
X-linked chondrodysplasia punctata (CDPX1), due to mutations of the arylsulfatase E (ARSE) gene, is a congenital disorder characterized by abnormalities in cartilage and bone development. We performed mutational analysis of the ARSE gene in a series of 16 male patients, and we found mutations in 12 subjects. Clinical variability was observed among the patients, including severe presentations with early lethality in one of them, and symptoms such as cataract and respiratory distress. This indicates that the clinical spectrum of CDPX1, commonly considered a relatively mild form of chondrodysplasia punctata, is wider than previously reported. Different types of mutations were found among the patients examined. Three missense mutations (I80N, T481M, P578S) were expressed in Cos7 cells to study the effects on arylsulfatase E catalytic activity. These mutations caused impaired enzymatic activity suggesting that they are responsible for the disease. Two nonsense mutations, W581X in four patients and R540X in one, were found. One patient showed an insertion (T616ins). In three patients we found deletions of the ARSE gene: in one the deletion involved only the 3 0 end of the gene, while in two the ARSE gene was completely deleted.
NEW CASE OF CONRADI HUNERMANN SYNDROME IN A NEWBORN MALE.
Chondrodysplasia punctata type 2, also known as Conradi-Hunermann-Happle syndrome, is a rare genetic disorder. This disorder is characterized by bone, skin and eye abnormalities.It occurs almost exclusively in females as it is usually lethal in males before birth. We report a new original observation of a newborn full term male, presenting a facial dysmorphism and skeletal abnormalities. X-rays showed bilateral symmetrical punctate calcifications of femoral, tibial, fibular and ankle epiphyses. The diagnosis of X-linked chondrodysplasia punctata type 2 (CDX2) has been suggested and confirmed by biochemical study and molecular analysis. This case is important as it is a milestone for further future research.
Autosomal recessive chondrodysplasia with severe short stature caused by a biallelic COL10A1 variant
Journal of Medical Genetics
BackgroundHeterozygous mutations in COL10A1 underlie metaphyseal chondrodysplasia, Schmid type (MCDS), an autosomal dominant skeletal dysplasia.ObjectiveTo identify the causative variant in a large consanguineous Pakistani family with severe skeletal dysplasia and marked lower limb deformity.MethodsWhole exome sequencing was completed followed by Sanger sequencing to verify segregation of the identified variants. In silico variant pathogenicity predictions and amino acid conservation analyses were performed.ResultsA homozygous c.133 C>T (p.Pro45Ser) variant was identified in COL10A1 in all six severely affected individuals (adult heights 119–130 cm, mean ~−6.33 SD). The individuals heterozygous for the variant had mild phenotype of short stature (adult heights 140–162 cm, mean ~−2.15 SD) but no apparent skeletal deformities. The variant was predicted to be pathogenic by in silico prediction tools and was absent from public databases and hundred control chromosomes. Pro45 is conse...
American Journal of Medical Genetics, 1993
This is a follow-up report on a male patient with a 46,Y,r(X) karyotype. Although he had no clinico-radiological features of X-linked recessive chondrodysplasia punctata (CDPXl), molecular studies revealed an Xp terminal deletion involving the putative region for the CDPXl locus (PABX-DXS31). We suspect that the absence of CDPXl may be attributable to the nature of the disease and the extreme short stature of the patient (mean -5.6 S.D.). 0 1993 Wiley-Liss, Inc.
American Journal of Medical Genetics Part A, 2005
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 asymetry and mild mental retardation. This condition appears to be a previously unrecognized X-linked dominant chondrodysplasia. ß 2005 Wiley-Liss, Inc.
Clinical Genetics, 2008
Rhizomelic chondrodysplasia punctata (RCDP), a peroxisomal disorder, is considered to be a lethal neonatal autosomal recessive chondrodysplasia. We report five patients, three of whom survived beyond 1 year, and we summarize the findings in 21 patients from a literature review who survived beyond 1 year. In those patients that survive, there is a high association of spasticity, psychomotor retardation, grovth failure, seizures, thermoregulatory instability, feeding difficulty, and recurrent otitis media and pneumonia. Three of our five patients had no radiographic evidence of vertebral body clefts, a finding which has previously been considered invariable in RCDP. Three of our patients had distinctive facies that differ from the classic Conradi-Hunermann facies.
Biochemical abnormalities in rhizomelic chondrodysplasia punctata
Journal of Pediatrics, 1988
Biochemical studies with emphasis on peroxisomal functions were conducted in six patients with well-documented rhizomelic chondrodysplasia punctata (RCDP) and compared with findings in patients with Zellweger syndrome and neonatal adrenoleukodystrophy (ALD). Patients with RCDP had three characteristic biochemical abnormalities: (I) profound defect in plasmalogen (ether lipid) synthesis, which is significantly greater than the analogous defect in Zellweger syndrome or neonatal ALD; (2) reduction of phytanic acid oxidation activity to I% to 5% of control, similar to that observed in Refsum disease, Zellweger syndrome, and neonatal ALD; (3) presence of the unprocessed form of peroxisomal 3-oxoacyl-coenzyme A thiolase in the postmortem liver of two patients. Other peroxisomal functions were normal, Including levels of very long chain fatty acids, pipecolic acid, and bile acid intermediates, and immunoblot studies of peroxlsomal acyl-CoA oxidase and bifunctional enzyme in postmortem liver. Unlike what is observed in Zellweger syndrome and neonatal ALD, catalase activity in cultured skin fibroblasts was sedimentable, indicating that peroxisome structure is not grossly deficient in RCDP. The biochemical abnormaltles in RCDP were consistent and set it apart from all the other known peroxisomal disorders. (J PEDIATR 1988;112:726-33) The term chondrodysplasia punctata is applied to puncrate epiphyseal and extraepiphyseal calcifications on roentgenograms of infants. First described by Conradi in 1914,1 the finding is nonspecific. It can result from maternal use of warfarin during pregnancy, 2 and is observed in Zellweger cerebrohepatorenaI syndrome 3 and other syndromes.