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We describe a female infant with X-linked chondrodysplasia punctata (CDPX1) as a result of maternal isodisomy of the X chromosome. Targeted Sanger sequencing and targeted next-generation sequencing of ARSL were used to test for the familial variant. This patient was homozygous for ARSL NM_000047.2: c.1227_1228delinsAT p.(Ser410Cys) familial variant, consistent with a diagnosis of CDPX1. Uniparental disomy is a type of chromosomal variation. Although not necessarily pathogenic, it can cause imprinting disorders and X-linked recessive disorders in females, and be a cause of autosomal recessive conditions when only one parent is a carrier. The patient described highlights that uniparental disomy can be a rare cause of X-linked recessive conditions. This mode of inheritance has not been previously described in this condition.

BACKGROUND: Multiple sulfatase deficiency (MSD) is an ultra-rare neurodegenerative disorder caused by pathogenic variants in SUMF1. This gene encodes formylglycine-generating enzyme (FGE), a protein required for sulfatase activation. The clinical course of MSD results from additive effect of each sulfatase deficiency, including metachromatic leukodystrophy (MLD), several mucopolysaccharidoses (MPS II, IIIA, IIID, IIIE, IVA, VI), chondrodysplasia punctata, and X-linked ichthyosis. While it is known that affected individuals demonstrate a complex and severe phenotype, the genotype-phenotype relationship and detailed clinical course is unknown.; METHODS: We report on 35 cases enrolled in our retrospective natural history study, n=32 with detailed histories. Neurologic function was longitudinally assessed with retrospective scales. Biochemical and computational modeling of novel SUMF1 variants was performed. Genotypes were classified based on predicted functional change, and each individual was assigned a genotype severity score.; RESULTS: The median age at symptom onset was 0.25years; median age at diagnosis was 2.7years; and median age at death was 13years. All individuals demonstrated developmental delay, and only a subset of individuals attained ambulation and verbal communication. All subjects experienced an accumulating systemic symptom burden. Earlier age at symptom onset and severe variant pathogenicity correlated with poor neurologic outcomes.; CONCLUSIONS: Using retrospective deep phenotyping and detailed variant analysis, we defined the natural history of MSD. We found that attenuated cases can be distinguished from severe cases by age of onset, attainment of ambulation, and genotype. Results from this study can help inform prognosis and facilitate future study design. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

A 4-year-old girl presented with congenital patches of scalp alopecia, which on physical examination, was consistent with blaschkolinear alopecic patches with mild epidermal atrophy. Similar atrophic hypopigmented patches were seen on the trunk and proximal extremities. With the clinical suspicion of Conradi-Hunermann-Happle syndrome, genetic testing was performed and revealed a mutation in the EBP gene. Despite characteristic cutaneous findings, no skeletal, ocular, or other anomalies were found on further evaluation.

X-linked dominant chondrodysplasia punctata (CDPX2) is a rare congenital disorder caused by pathogenic variants in EBP on Xp11.23. We encountered a girl and her mother with CDPX2-compatible phenotypes including punctiform calcification in the neonatal period of the girl, and asymmetric limb shortening and ichthyosis following the Blaschko lines in both subjects. Although Sanger direct sequencing failed to reveal a disease-causing variant in EBP, whole genome sequencing (WGS) followed by Manta analysis identified a ~ 4.5 kb insertion at EBP exon 2 of both subjects. The insertion was associated with the hallmarks of retrotransposition such as an antisense poly(A) tail, a target site duplication, and a consensus endonuclease cleavage site, and the inserted sequence harbored full-length SVA_F1 element with 5′- and 3′-transductions containing the Alu sequence. The results imply the relevance of retrotransposition to the human genetic diseases and the usefulness of WGS in the identification of retrotransposition.

Case A 4-year-old girl with spastic gait and hand clumsiness who was diagnosed with cervical myelopathy caused by atlantoaxial dislocation and midcervical severe kyphosis associated with chondrodysplasia punctata (CDP). The patient underwent posterior instrumentation and anterior spinal fusion and successful correction with osseous fusion was obtained 8 months after surgery. In addition, the preoperative neurological symptoms were completely recovered. Conclusion Owing to the characteristics of CDP, the treatment for the cervical lesion is extremely complicated. Successful stabilization and improvement of the neurological symptom were achieved by combining posterior and anterior fusion with instrumentation in this case.

Background Greenberg dysplasia is a rare, autosomal recessive, prenatal lethal bone dysplasia caused by biallelic pathogenic variants in the lamin B receptor (LBR) gene. Pathogenic variants in LBR are also associated with Pelger–Huët anomaly, an autosomal dominant benign abnormality of the nuclear shape and chromatin organization of blood granulocytes, and Pelger–Huët anomaly with variable skeletal anomalies, a mild, regressing to moderate–severe autosomal recessive condition. Conditions with abnormal sterol metabolism and different genetic basis have clinical and radiographic features similar to Greenberg dysplasia, for example X‐linked dominant chondrodysplasia punctata, Conradi–Hünermann type, and CHILD syndrome, and other conditions with unknown genetic etiology display very similar features, for example, dappled diaphyseal dysplasia and Astley–Kendall dysplasia. Methods We present a fetus with typical clinical and radiographic features of Greenberg dysplasia, and review the literature. Results Genetic testing confirmed the diagnosis Greenberg dysplasia: homozygosity for a pathogenic variant in LBR. Conclusion Comparing the clinical and radiographic phenotypes of Greenberg dysplasia, dappled diaphyseal dysplasia, and Astley–Kendall dysplasia, we suggest that these are allelic disorders., Comparing the clinical and radiographic phenotypes of Greenberg dysplasia, dappled diaphyseal dysplasia, and Astley‐Kendall dysplasia, we suggest that these are allelic disorders.

International audience; X-linked dominant chondrodysplasia punctata (CDPX2 or Conradi-Hünermann-Happle syndrome, MIM #302960) is caused by mutations in the EBP gene. Affected female patients present with Blaschkolinear ichthyosis, coarse hair or alopecia, short stature, and normal psychomotor development. The disease is usually lethal in boys. Nevertheless, few male patients have been reported; they carry a somatic mosaicism in EBP or present with Klinefelter syndrome. Here, we report CDPX2 patients belonging to a three-generation family, carrying the splice variant c.301 + 5 G > C in intron 2 of EBP. The grandfather carries the variant as mosaic state and presents with short stature and mild ichthyosis. The mother also presents with short stature and mild ichthyosis and the female fetus with severe limb and vertebrae abnormalities and no skin lesions, with random X inactivation in both. This further characterizes the phenotypical spectrum of CDPX2, as well as intrafamilial variability, and raises the question of differential EBP mRNA splicing between the different target tissues.

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. 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. 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. 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. 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.

Background Cervical spine deformity in rhizomelic chondrodysplasia punctata (RCDP) has been described with different findings reported in the literature. However, available literature provides limited data from a few cases with magnetic resonance imaging (MRI) of the cervical spine. Our report describes the MRI findings in a group of children with RCDP, aiming to reach a better understanding of this pathology. Methods An Institutional Review Board-approved RCDP Registry was created at our institution with the goal of identifying pertinent medical issues over the lifespan of individuals with RCDP. Records of children within the registry were evaluated, and magnetic resonance images obtained between 2004 and 2015, were available for review. The levels of spinal canal stenosis were recorded and the severity of the stenosis was decided based on adults' parameters. Cord compression and myelomalacia were confirmed on the axial images. Sagittal lumbar spine magnetic resonance images were also evaluated when available, and the presence of tethered cord and fatty filum was recorded. Results Twenty-six children (15 boys and 11 girls) were identified in the RCDP Registry. Eleven children (6 boys and 5 girls) had sagittal MRI of the cervical spine available for review. Age at the time of MRI study was variable (1 wk to 32 mo). All patients except 1 had stenosis of the cervical spinal canal. Myelomalacia of the cord was noted only in this patient. Conclusions This study suggests that, in children with RCDP, cervical spinal stenosis and cord compression are a real risk, and children with this diagnosis should have monitoring for these issues. Tethered cord is also a possible finding that needs to be evaluated. Full sagittal spine MRI is necessary to detect the possible deformities at the cervical and lumbar levels.

Objective To evaluate the complementarity between prenatal ultrasound, computed tomography, and MRI scans for fetuses with Binder phenotype. Methods We carried out a retrospective study from January 1, 2009, to June 30, 2018, of fetuses with Binder phenotype. Prenatal ultrasound (US) data were collected. A systematic survey of the entire skeleton was performed to look for associated abnormalities such as calcifications, brachytelephalangy, and spinal stenosis. Parents were systematically offered fetal skeletal computed tomography (CT). Results Thirteen cases were included. Two cases of perinatal respiratory distress (18%) were observed. Chondrodysplasia punctata was diagnosed from the presence of calcifications, especially of the proximal femoral epiphyses and tarsal bones, in five cases (38%) by US and in 10 cases (83%) by CT. Calcifications of the hyoid bone were detected by CT in three cases (25%) one of which had respiratory distress. Polyhydramnios was associated with the Binder phenotype in four cases (30%) one of which had respiratory distress. One single fetus had combined polyhydramnios and laryngeal calcifications, and he suffered from perinatal respiratory distress. Conclusion An antenatal diagnosis of Binder phenotype is often associated with chondrodysplasia punctata. We recommend the use of fetal CT as a complement to US in this condition.

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.

Among diseases that cause ichthyosis as one of the symptoms, there are some diseases that induce abnormalities in organs other than the skin. Of these, diseases with characteristic signs are regarded as syndromes. Although these syndromes are very rare, Netherton syndrome, Sjögren-Larsson syndrome, Conradi-Hünermann-Happle syndrome, Dorfman-Chanarin syndrome, ichthyosis follicularis, atrichia and photophobia (IFAP) syndrome, and Refsum syndrome have been described in texts as representative ones. It is important to know the molecular genetics and pathomechanisms in order to establish an effective therapy and beneficial genetic counseling including a prenatal diagnosis.

To analyze clinical manifestations and genetic mutation in a child with severe short stature and other malformations.The child has undergone history taking and physical examination. Genome DNA was extracted from peripheral blood samples of the proband and her family members. Candidate genes were captured with Agilent SureSelect and sequenced on an Illumina platform. Suspected mutation was verified by Sanger sequencing.The patient, a six-year-and-10-month old girl, presented with non-symmetrical short stature, dysmorphism, abnormalities of limbs and spine, amblyopia of left eye, and cataract of right eye, in addition with frequent respiratory infection and micturition. Laboratory testing suggested 25-hydroxy vitamin D deficiency (18.9 ng/mL). Spine X-ray showed multiple malformations with centrums. Her mother also featured short stature (138 cm). Her aunt had short stature (130 cm) and limb-length discrepancy. Her little brother was 2.5 years old, and his height was 81 cm (-3.4 SD). Exome sequencing revealed a heterozygous mutation c.184C to T (p.Arg62Trp) in the proband and her mother. The same mutation was not found in her father and brother.The patient was diagnosed with X-linked chondrodysplasia punctata 2. Mutation of the EBP gene probably underlied the disease in this family.

International audience; Congenital disorders of glycosylation (CDG) are a group of inborn errors of metabolism presenting with heterogeneous multisystemic clinical manifestations. To date, more than 60 different types of CDG have been reported. ALG3-CDG is very rare, with only nine patients described so far. We report two affected siblings presenting prenatally with skeletal abnormalities associated with dysmorphic features, cerebellar vermis hypoplasia, corpus callosum agenesis, hepatic fibrosis and poor prognosis. This is the first detailed report of an affected fetus including clinical, radiographic and pathological findings. The patients showed some clinical features previously unreported in ALG3-CDG, such as bone dysplasia, cataract, corneal opacities, and pons hypoplasia. Both patients were homozygous for the previously unreported p.Gly96Arg mutation of the ALG3 gene. One patient showed chondrodysplasia punctata (CDP), which has not been previously reported in CDG. An exhaustive genetic and metabolic assessment, performed in order to rule out other possible causes of CDP, showed abnormally raised levels of anti-nuclear antibodies in the mother who, nevertheless, did not show any clinical sign of autoimmune disease during a 7 years follow-up. We speculate that the observed CDP may be explained by the maternal anti-nuclear antibodies; alternatively, a possible link to the underlying metabolic disorder cannot be ruled out. In conclusion, we report the clinical, pathological, biochemical and molecular characterization of two further patients affected by ALG3-CDG, expanding the phenotypic spectrum of this very rare disease.

Multiple sulfatase deficiency (MSD) is an ultra-rare neurodegenerative disorder that results in defective sulfatase post-translational modification. Sulfatases in the body are activated by a unique protein, formylglycine-generating enzyme (FGE) that is encoded by SUMF1. When FGE is absent or insufficient, all 17 known human sulfatases are affected, including the enzymes associated with metachromatic leukodystrophy (MLD), several mucopolysaccharidoses (MPS II, IIIA, IIID, IVA, VI), chondrodysplasia punctata, and X-linked ichthyosis. As such, individuals demonstrate a complex and severe clinical phenotype that has not been fully characterized to date. In this report, we describe two individuals with distinct clinical presentations of MSD. Also, we detail a comprehensive systems-based approach to the management of individuals with MSD, from the initial diagnostic evaluation to unique multisystem issues and potential management options. As there have been no natural history studies to date, the recommendations within this report are based on published studies and consensus opinion and underscore the need for future research on evidence-based outcomes to improve management of children with MSD.

Rhizomelic chondrodysplasia punctata (RCDP) is a rare genetic peroxisome biogenesis disorder with a reported incidence of 1 in 100 000 live births. The 3 genetic subtypes of RCDP are acquired by an autosomal recessive inheritance pattern. RCDP type 1 accounts for greater than 90% of all aggregate cases. Differentiating between the 3 subtypes of RCDP, as well as disorders characterized by similar punctate cartilaginous changes, is essential to guide an appropriate postnatal plan of care. Management strategies are focused toward associated clinical manifestations and require an interdisciplinary approach including ophthalmology, cardiovascular, endocrine, physical and occupational therapy, and neurology. Purposeful and frequent collaboration among all members of the neonatal/pediatric interdisciplinary team is necessary to optimize outcomes for the neonate and the family unit. The purpose of this article is to anticipate the needs of both patients with known and prenatal diagnosis of RCDP type 1 and patients with suspected clinical diagnosis of RCDP type 1 in the immediate neonatal period and to guide the appropriate plan of care. This article presents a case report of type I RCDP, as well as describes genetic influences, symptoms, diagnosis, management, and prognosis.

Raine syndrome is a rare osteosclerotic bone dysplasia characterized by craniofacial anomalies and intracranial calcification. Most patients with Raine syndrome are of Arab ancestry and die during the neonatal period. We herein report a Japanese patient with non-lethal Raine syndrome who presented with characteristic cerebral hyperechogenicity and a hypoplastic nose by fetal ultrasonography. She was admitted to the NICU due to pyriform aperture stenosis. Craniofacial abnormalities, intracranial calcification, osteosclerosis, chondrodysplasia punctata, and a mutation of FAM20C was identified. She was subsequently discharged without surgical intervention and is now 2 years old with mild neurodevelopmental delays. Images of cerebral hyperechogenicity by fetal ultrasonography in a non-lethal case were described herein for the first time. This patient represents a rare occurrence of a child with Raine syndrome born to Japanese parents and confirms that this syndrome is not always lethal. Even if Raine syndrome is suspected in a fetus due to cerebral hyperechogenicity and a hypoplastic nose, cerebral hyperechogenicity without pulmonary hypoplasia does not always predict lethality or severe neurodevelopmental delays. The information provided herein will be useful for prenatal counseling.

Carbohydrate sulfotransferase 11 (CHST11) is a membrane protein of Golgi that catalyses the transfer of sulfate to position 4 of the N-acetylgalactosamine residues of chondroitin. Chondroitin sulfate is the predominant proteoglycan in cartilage, and its sulfation is important in the developing growth plate of cartilage. A homozygous deletion encompassing part of the gene and the embedded miRNAWe performed detailed clinical investigations in family members. Homozygosity mapping using SNP genotype data was performed to map the disease locus and exome sequencing to identify the underlying molecular defect.The limb malformations include brachydactyly, overriding digits and clino-symphalangism in hands and feet and syndactyly and hexadactyly in feet. Skeletal defects include scoliosis, dislocated patellae and fibulae and pectus excavatum. The disease locus is mapped to a 1.6 Mb region at 12q23, harbouring a homozygous in-frame deletion of 15 nucleotides in

OBJECTIVEChondrodysplasia punctata (CDP), a rare skeletal dysplasia, can lead to cervical spine instability and deformity. However, an optimal neurosurgical intervention has yet to be established. Thus, a retrospective study was conducted to assess the efficacy of various surgical interventions for children with CDP.METHODSThe authors retrospectively reviewed 9 cases of CDP in which cervical decompression with or without posterior fusion was performed between April 2007 and May 2016. Patient demographics, preoperative clinical conditions, radiographic findings, surgical procedures, and the postoperative course were analyzed in detail.RESULTSA total of 12 operations were carried out in 9 patients (8 male, 1 female) during the study period. The patients’ ages at the initial surgery ranged from 2 months to 2 years. Seven of the children had CDPX1, 1 had CDPX2, and 1 had tibia-metacarpal type CDP (CDP-TM). The lesion occurred at the craniovertebral junction (CVJ) in 7 cases and involved a subaxial deformity in 2 cases. The initial surgery was C-1 laminectomy with occipitocervical fusion (OCF) followed by halo external fixation in 5 cases, OCF alone in 1 case, and C-1 laminectomy alone in 3 cases. Three children required additional surgery. In one of these cases, a staged operation was required because the patient’s head was too small to attach a halo ring at the time of the initial procedure (C-1 laminectomy). In another case, OCF was performed 11 months after C-1 laminectomy because of intramedullary signal change on serial MRI, although the child remained asymptomatic. In the third case, additional posterior fusion was performed 17 months after an initial laminectomy and OCF due to newly developed cervical dislocation caudal to the original fusion. This last patient required a third operation 9 months after the second because of deep wound infection. Surgery improved the motor function of all 7 children with CDPX1, but 3 children who had already suffered respiratory failure preoperatively required continued respiratory support. At the time of this report, 7 of the 9 children were alive and in stable condition. One child died due to restrictive respiratory insufficiency, and another died in an accident unrelated to CDP.CONCLUSIONSSurgical decompression with or without fusion for CVJ and subaxial cervical lesions in infants and toddlers with CDP generally saves lives and increases the likelihood of motor function recovery. However, in this case series the patients’ preoperative condition had a strong effect on postoperative respiratory function. The surgery was not straightforward, and a second operation was required in some cases. Nevertheless, the findings indicate that early surgical intervention for CDP with cervical involvement is feasible, suggesting that the role of neurosurgery should be reevaluated.

We present concurrent X-linked chondrodysplasia punctata and ichthyosis vulgaris in adolescent fraternal twin girls, notable for initial presentation with dry skin in adolescence, characterized by dark-brown scale typical of ichthyosis vulgaris and blaschkolinear, atrophic, scaly plaques. This constellation of findings prompted further genetic investigation. Using a multigene approach to examine 39 genes associated with congenital ichthyosis, next-generation sequencing revealed a novel heterozygous missense mutation at a mutational hotspot in the EBP gene c.439C>T (p.R147C) in conjunction with a single nonsense mutation in the FLG gene (p.R501X) in both sisters. These individuals highlight the clinical variability of Conradi-Hunermann-Happle syndrome, illustrate the possibility of co-occurrence of rare and common forms of ichthyosis, and demonstrate the utility of multigene analysis.

Chondrodysplasia punctata is abnormal calcification in the cartilage of developing bones and has been seen in association with deranged vitamin K metabolism. Warfarin, an oral anticoagulant acting on vitamin K dependent clotting factors is known to cause chondrodysplasia punctata. Despite the knowledge of the condition the management of patients with prosthetic heart valves might require use of the drug for anticoagulation. Here, we present a case of a fetal warfarin syndrome in a second born child of a 27 year lady under warfarin for prosthetic heart valve. The pregnancy was complicated by polyhydramnios in third trimester and terminated at term by normal vaginal delivery. The baby was well, except for facial dysmorphism in the form of depressed nasal bridge, narrow nares and suspected left choanal atresia. Radiograph revealed stippled ephiphysis of vertebra, femora and humera supporting diagnosis of fetal warfarin syndrome. The baby did not develop any perinatal complication and was discharged home.

Rhizomelic chondrodysplasia punctata (RCDP) is a group of disorders with overlapping clinical features including rhizomelia, chondrodysplasia punctata, coronal clefts, cervical dysplasia, congenital cataracts, profound postnatal growth retardation, severe intellectual disability, and seizures. Mutations in PEX7, GNPAT, and AGPS, all involved in the plasmalogen-biosynthesis pathway, have been described in individuals with RCDP. Here, we report the identification of mutations in another gene in plasmalogen biosynthesis, fatty acyl-CoA reductase 1 (FAR1), in two families affected by severe intellectual disability, early-onset epilepsy, microcephaly, congenital cataracts, growth retardation, and spasticity. Exome analyses revealed a homozygous in-frame indel mutation (c.495_507delinsT [p.Glu165_Pro169delinsAsp]) in two siblings from a consanguineous family and compound-heterozygous mutations (c.[787CT];[1094AG], p.[Arg263(∗)];[Asp365Gly]) in a third unrelated individual. FAR1 reduces fatty acids to their respective fatty alcohols for the plasmalogen-biosynthesis pathway. To assess the pathogenicity of the identified mutations, we transfected human embryonic kidney 293 cells with plasmids encoding FAR1 with either wild-type or mutated constructs and extracted the lipids from the cells. We screened the lipids with gas chromatography and mass spectrometry and found that all three mutations abolished the reductase activity of FAR1, given that no fatty alcohols could be detected. We also observed reduced plasmalogens in red blood cells in one individual to a range similar to that seen in individuals with RCDP, further supporting abolished FAR1 activity. We thus expand the spectrum of clinical features associated with defects in plasmalogen biosynthesis to include FAR1 deficiency as a cause of syndromic severe intellectual disability with cataracts, epilepsy, and growth retardation but without rhizomelia.

Conradi-Hünermann-Happle syndrome (CDPX2, OMIM 302960) is an inherited X-linked dominant variant of chondrodysplasia punctata (CP) caused by mutations in one gene of the distal pathway of cholesterol biosynthesis. It exhibits intense phenotypic variation and primarily affects the skin, bones and eyes. The ichthyosis following Blaschko's lines, chondrodysplasia punctata and cataracts are the typical clinical findings. The cardinal biochemical features are an increase in 8(9)-cholestenol and 8-dehydrocholesterol (8DHC), which suggest a deficiency in 3β-hydroxysteroid-Δ8,Δ7-isomerase, also called emopamil binding protein (EBP). The EBP gene is located on the short arm of the X chromosome (Xp11.22-p11.23) and encodes a 230 amino acid protein with dual function. Explaining the clinical phenotype in CDPX2 implies an understanding of both the genetics and biochemical features of this disease. CDPX2 displays an X-linked dominant pattern of inheritance, which is responsible for the distribution of lesions in some tissues. The clinical phenotype in CDPX2 results directly from impairment in cholesterol biosynthesis, and indirectly from abnormalities in the hedgehog signaling protein pathways. This article is part of a Special Issue entitled The Important Role of Lipids in the Epidermis and their Role in the Formation and Maintenance of the Cutaneous Barrier. Guest Editors: Kenneth R. Feingold and Peter Elias.

Summary Introduction This paper reviewed the outcome of cantilevered costochondral grafts used for dorsal nasal augmentation in the management of patients treated at the Australian Craniofacial Unit (ACFU), Adelaide over a 29-year period. Materials and methods All patients undergoing dorsal nasal augmentation with costochondral grafts as part of their craniofacial management between 1981 and 2009 were identified using the ACFU database, and their medical notes were reviewed. Results 107 patients (50M, 57F), with a mean age of 12.3 years (range: 2–62 years) and requiring a total of 150 costochondral grafts, were identified from the departmental database. Mean follow-up after nasal augmentation was 5.6 years (1 month-31.5 years). 46% of the patients were diagnosed with Binder syndrome/Chondrodysplasia punctata; other diagnoses included Tessier midline clefts, cleft lip and palate and frontonasal dysplasia. A dorsal midline incision (49%) was the commonest method of access, with 84% of patients having mini-screw fixation for graft stabilisation. Complications included screw palpability, infection, skin necrosis and graft fracture. The commonest reasons for a replacement graft were graft atrophy and fracture, infection and persistent deformity. Conclusion Cantilevered nasal costochondral grafting is an excellent technique for improving nasal contour and function in a wide variety of clinical situations.

Neonatal chondrodysplasia punctata (CDP) is characterized by epiphyseal stippling and midfacial hypoplasia. CDP is usually inherited, but can be acquired because of maternal vitamin K deficiency. We describe an infant with CDP born to a teenager with sickle cell anemia and transfusional iron overload. The mother had severe liver fibrosis, elevated liver iron concentration (34 mg Fe/g), and coagulopathy, but no gestational use of warfarin. Fetal abnormalities were attributed to vitamin K deficiency secondary to liver dysfunction from iron toxicity. Treatment of iron overload among women with sickle cell anemia of childbearing potential is important to avoid possible CDP in newborns.

Chondrodysplasia punctata (CDP) is a heterogenous group of skeletal dysplasias characterized by aberrant bone mineralization, manifesting radiologically as epiphyseal stippling. Among this group, brachytelephalangic dysplasia, a benign form of CDP (CDPX1), is probably under-reported. It is an X-linked recessive disorder and is characterized by a flat nasal tip, short columella and maxillary hypoplasia, involvement of terminal phalanges, and stippled chondrodystrophy. This paper presents a clinical series of 13 patients with brachytelephalangic dysplasia. These patients enrolled during 2002-2006 were re-evaluated and their dysmorphic features were compiled in a predesigned proforma. Skeletal survey, karyotype, cardiac evaluation, and ophthalmic evaluation were planned for all the cases. Out of 13 patients, 10 were males and three were females. All patients had flat facies, a depressed nasal bridge, a hypoplastic nose, a short philtrum, notched alae nasi, brachydactyly, and hypoplastic terminal phalanges. In addition, congenital heart disease, optic nerve hypoplasia, and developmental delay were found in a few patients. Radiography showed hypoplastic terminal phalanges, delayed bone age (1/13), epiphyseal stippling in carpal (3/13) and tarsal bones (2/13), sacral bone (1/13), and bullet-shaped lumbar vertebra (1/13). Cranial neuroimaging, thyroid profile, and karyotype carried out in a few were normal. The present paper discusses various clinical features and associated abnormalities in patients with brachytelephalangic dysplasia (CDPX1) to further delineate the phenotype. The presence of a similar phenotype in females suggests the possibility of another locus or manifestation of disease in heterozygous females. Arylsulfatase E gene analysis would further help in establishing the genotype-phenotype correlation.

Objective Findings from animal studies have suggested that leflunomide may be a human teratogen. In the only human cohort study published to date, an increase in adverse outcomes in pregnancies after exposure to leflunomide was not detected. The aim of the present analysis was to expand on the previously published data with a description of birth outcomes among women who did not meet the previous cohort study criteria but who were exposed to leflunomide either during pregnancy or prior to conception. Methods Data on pregnancy exposures and outcomes were collected from 45 pregnant women who had contacted counseling services of the Organization of Teratology Information Specialists in the US or Canada between 1999 and 2009. Sixteen women were exposed to leflunomide during the first trimester of pregnancy and 29 women were exposed preconception. Results All 16 of the pregnancies with leflunomide exposure during pregnancy and 27 (93%) of the pregnancies with exposure prior to conception resulted in liveborn infants. There were 2 infants with major malformations from mothers who were exposed during pregnancy, and no malformations reported in the preconception group. There was a potential known alternative etiology for at least some of the defects observed. Conclusion These data provide additional reassurance to women who inadvertently become pregnant while taking leflunomide and who undergo the washout procedure, as well as women who discontinue the medication prior to conception but have no prepregnancy documentation of drug clearance. However, until more conclusive data become available, women receiving leflunomide should be advised to use contraceptive methods and avoid pregnancy.

Chondrodysplasia punctata (CDP) is a group of skeletal dysplasias manifesting with progressive cervical instability that leads to neurological deficits and eventual death. The major clinical features of CDP also present in a phenocopy known as coumarin embryopathy (CE) which results from coumarin exposure during pregnancy. The objective of this study was to assess treatment strategies employed for children affected by CDP or CE with cervical instability and to determine a strategy on how best to diagnose and treat affected neonates. We performed a systematic review of the English literature for cases reporting cervical spine involvement in CDP and CE and identified 44 such patients. We extracted clinical information on these disorders and identified two patients from our craniovertebral junction database of over 6,000 patients evaluated at our institution. Patients most frequently present with hyperreflexia (21%) and weakness (21%), and there were various conservative treatment strategies. Twenty-one percent of patients who were treated conservatively had neurological complications in their clinical course. There were two deaths reported, one resulting from conservative treatment and one from surgical treatment. We also report long-term follow-up analysis for a patient treated at our institution for the last 30 years and agree with all other reports that suggest that monitoring patients for neurological changes is essential to prevent further neurological injury. This study emphasizes the need for careful neurological and surgical evaluation of pediatric patients with cervical spine abnormalities affected by CDP or CE in order to prevent progressive instability.

Objective: To describe the contribution of 3-dimensional computed tomography (3D-CT) in the prenatal diagnosis of skeletal dysplasias (SD) in a cohort of patients with inconclusive diagnosis by ultrasound (US). Methods: Between May 2007 and February 2010, six pregnant women with suspected fetal SD on US examination but with no specific diagnosis were studied with 3D-CT. The images were evaluated by a multidisciplinary team who proposed a likely diagnosis. Further postnatal workup included clinical and radiological evaluation in all cases. Prenatal and postnatal diagnoses were compared. Results: The use of 3D-CT provided a precise diagnosis confirmed postnatally in 5/6 patients. These included osteogenesis imperfecta type II (n = 2), osteogenesis imperfecta type III (n = 1), chondrodysplasia punctata (n = 1) and thanatophoric dysplasia type I (n = 1). A precise diagnosis could not be made in 1 case – either pre- or postnatally. Conclusion: Prenatal 3D-CT contributed to the diagnosis of the specific fetal SD in the majority of these cases. 3D-CT may have a complementary role to US where fetal SD is suspected, but no specific diagnosis can be made using US alone. Further studies on clinical performance and risk-benefit analysis are needed.

Chondrodysplasia punctate (CDP) is a rare group of disorders with both genetic and non-genetic underlying aetiologies. The genetic causes associated with CDP include peroxisomal disorders, type two mucolipidosis, type 3 mucopolysaccharidosis, GM1 gangliosidosis and chromosomal disorders. Peroxisomal disorders include deficiency of dihydroxyacetone phosphate acyltransferase, encoded by GNPAT, deficiency of the peroxisomal enzyme alkyl-dihydroxyacetone phosphate synthase, encoded by AGPS and Zellweger syndrome. The chromosomal disorders include Turner syndrome, trisomy 21 (Down syndrome), trisomy 18 (Edwards syndrome) and trisomy 9. Among non-genetic causes, teratogen exposure like warfarin and acenocoumarol is well known but for the past few years cases have been reported with maternal autoimmune disease mainly systemic lupus erythematosus and rarely with mixed connective tissue disorder (MCTD). However, the exact mechanism for the occurrence of CDP in MCTD is still unknown. We present here a 35-week appropriate for gestational age baby born to a second gravid mother, a known case of MCTD on treatment with hydroxychloroquine. The baby had mid-facial hypoplasia and bilateral talar region punctuate calcification suggestive of chondrodysplasia punctata. Global data on such cases are very scant. Further research work is needed to explore the association of specific antibody titre with the occurrence of such condition in maternal autoimmune disease.

During the period 1991-2007, autopsy was undertaken in 13 fetuses with warfarin embryopathy. Pregnancy data and radiographic babygrams were available in each instance. Gestational age ranged from 17 to 37 weeks. Eleven of the fetuses had the characteristic nasal hypoplasia, but only three had radiological epiphyseal stippling. Cerebral hemorrhage was a major feature of autopsy in 8 of the fetuses, and it is evident that bleeding is a significant factor in the pathogenesis of warfarin embryopathy. A wide variety of additional visceral manifestations which were observed at autopsy have been tabulated. There was no obvious correlation between maternal or gestational age and the presence and severity of any specific embryopathic feature. No information was available concerning the dose and timing of warfarin administration in this series.

Rhizomelic chondrodysplasia punctata (RCDP) is an autosomal-recessive disorder resulting from mutations in one of three peroxisomal genes essential for ether lipid biosynthesis, PEX7 (RCDP1), GNPAT (RCDP2), and AGPS (RCDP3). Affected patients have characteristic features including shortening of the proximal long bones, epiphyseal stippling, bilateral cataracts, growth and developmental delays. Whereas the majority of patients have RCDP type 1, around 5% have RCDP type 2 or 3. We identified a patient with RCDP type 2 and an apparent homozygous deletion, c.1428delC, after full sequencing of his GNPAT genes. The father was heterozygous for this mutation, while sequencing of the maternal GNPAT genes revealed only wild-type sequence. Southern analyses performed on parental gDNA did not show evidence of a maternal gene deletion. Amplification and fragment analysis of dinucleotide repeat markers spanning chromosome 1 in the patient and both parents revealed paternal uniparental inheritance. We discuss the potential mechanisms causing uniparental disomy (UPD) in this patient and review the literature on chromosome 1 UPD. The absence of non-RCDP clinical features in this patient was consistent with previous literature supporting the absence of imprinted genes on chromosome 1. This first description of RCDP caused by UPD dramatically changes the parental recurrence risk, highlighting the value of obtaining parental genotypes when the proband has a putative homozygous mutation by sequence analysis.

International audience; We report the prenatal management of a brachytelephalangic chondrodysplasia punctata (CDPX1) case and how postnatal findings confirmed the diagnosis. The mother was initially referred after ultrasound revealed an abnormal fetal mid-face and punctuation of upper femoral epiphyses. Chondrodysplasia punctata (CP) with Binder anomaly was suspected. 3D-HCT revealed brachytelephalangy suggesting CDPX1. At birth, mid-face hypoplasia was marked. Postnatal imaging and genetic analysis confirmed the initial diagnosis. Binder anomaly is probably always associated with CP. The newly revised CP classification facilitates the diagnosis. The main etiologies are metabolic and chromosomal abnormalities, and arylsulfatase E enzyme dysfunction. Thus, screening for arylsulfatase E mutation is mandatory for an accurate diagnosis and can lead to better delineation among CP etiologies associated with a Binder phenotype.

Radiological and clinical comparisons of multiple epiphyseal dysplasia were made in four children and five puppies. On the basis of these, it is assumed that the disease in children and puppies is closely related. Two six-week-old beagle puppies with epiphyseal dysplasia were examined histologically. It was found that bone changes developed primarily in the hyaline cartilage. Two forms of pathological tissue were demonstrated in the cartilage. One was an acellular structureless mass which underwent secondary calcification. The other form was located outside the first and consisted of abnormal intercellular calcified hyaline cartilage. Bones with pronounced stippled radiographical appearance (punctate epiphyseal dysplasia) showed massive calcifications of clear-cut demarcated acellular masses. Bone with pronounced mottled radiographical appearance (multiple epiphyseal dysplasia) showed zones of abnormal intercellular calcified hyaline cartilage. However, both forms of pathological tissue were found in bones with radiographical stippled calcification and in those with radiographical mottled calcification.

Chondrodysplasia punctata (CDP) is etiologically a heterogeneous condition and has been associated with single gene disorders, chromosome abnormalities and teratogenic exposures. The first publication of the association between CDP and maternal autoimmune connective tissue disorder was by Curry et al. 1993]. Chondrodysplasia punctata associated with maternal collagen vascular disease. A new etiology? Presented at the David W. Smith Workshop on Morphogenesis and Malformations, Mont Tremblant, Quebec, August 1993] and subsequently, other cases have been reported. We report on eight cases of maternal collagen vascular disease associated with fetal CDP and included the cases reported by Curry et al. 1993. Chondrodysplasia punctata associated with maternal collagen vascular disease. A new etiology? Presented at the David W. Smith Workshop on Morphogenesis and Malformations, Mont Tremblant, Quebec, August 1993] and Costa et al. [1993]. Maternal systemic lupus erythematosis (SLE) and chondrodysplasia punctata in two infants. Coincidence or association? 1st Meeting of Bone Dysplasia Society, Chicago, June 1993] which were reported in an abstract form. We suggest that maternal autoimmune diseases should be part of the differential diagnosis and investigation in newborns/fetuses with CDP. Thus, in addition to cardiac evaluation, fetuses/newborn to mothers with autoimmune diseases should have fetal ultrasound/newborn examination and if indicated, X-rays, looking for absent/hypoplastic nasal bone, brachydactyly, shortened long bones and epiphyseal stippling.

This paper suggests that there is probably a dominant, sex-linked type of chondrodysplasia punctata. Clinical data are reported for three girls with such a disorder. Two of their mothers showed a mild form of cicatricial alopecia. The pathognomonic dermatological findings in the children include erythematous skin changes and striated ichthyosiform hyperkeratosis during the first months of life. Later on, patterned ichthyosis, follicular atrophoderma, coarse, lusterless hair and cicatricial alopecia become evident. It is assumed that about one fourth of all cases with chondrodysplasia punctata reported in the literature belong to the dominant sex-linked type.

Objective To determine the pathogenicity of a novel conserved missense mutation, p.Ser98Phe, in the emopamil binding protein (EBP) gene in order to perform a prenatal diagnostic test for X-linked dominant chondrodysplasia punctata (CDPX2) in a male foetus at 50% risk. Methods Family members were tested for p.Ser98Phe using PCR and sequence analysis of leucocyte or buccal cell DNA. Haplotype analysis was employed to identify the grandparental chromosome on which p.Ser98Phe had arisen. In silico protein analyses were used to predict whether p.Ser98Phe significantly altered the EBP protein structure. Results The mutation was detected in the proband and her affected mother but not in the maternal grandmother, who was thought to be mildly affected. However, haplotype analysis showed that p.Ser98Phe had arisen de novo on the grandpaternal X chromosome. Protein secondary structure predictions suggested that p.Ser98Phe alters the properties of the helix within which it is located. Conclusion We concluded that p.Ser98Phe is likely to be pathogenic and proceeded with prenatal testing. The male foetus had not inherited p.Ser98Phe and his unaffected status was confirmed at birth. This family demonstrates some of the difficulties in interpreting the significance of novel missense mutations, particularly when results are needed urgently for prenatal diagnosis. Copyright © 2008 John Wiley & Sons, Ltd.

International audience; no abstract

International audience; Disorders of post-squalene cholesterol biosynthesis are inborn errors of metabolism characterised by multiple congenital abnormalities, including significant skeletal involvement. The most frequent and best-characterised example is the Smith-Lemli-Opitz syndrome. Nine other disorders are known, namely autosomal-recessive Antley-Bixler syndrome, Greenberg dysplasia, X-linked dominant chondrodysplasia punctata, X-linked recessive male emopamil-binding protein deficiency, CHILD syndrome, CK syndrome, sterol C4 methyloxidase-like deficiency, desmosterolosis and lathosterolosis. This study provides an overview of the radiologic features observed in these diseases. A common pattern of limb abnormalities is recognisable, including polydactyly, which is typically post-axial and rarely interdigital and can involve all four limbs, and syndactyly of the toes. Chondrodysplasia punctata is specifically associated with a subgroup of disorders of cholesterol biosynthesis (Greenberg dysplasia, CHILD syndrome, X-linked dominant chondrodysplasia punctata, male emopamil-binding protein deficiency). The possible occurrence of epiphyseal stippling in the Smith-Lemli-Opitz syndrome, initially reported, does not appear to be confirmed. Stippling is also associated with other congenital disorders such as chromosomal abnormalities, brachytelephalangic chondrodysplasia punctata (X-linked recessive chondrodysplasia punctata, disruptions of vitamin K metabolism, maternal autoimmune diseases), rhizomelic chondrodysplasia punctata (peroxisomal disorders) and lysosomal storage disorders. In the differential diagnosis of epiphyseal stippling, a moth-eaten appearance of bones, asymmetry, or presence of a common pattern of limb abnormalities indicate inborn errors of cholesterol biosynthesis. We highlight the specific differentiating radiologic features of disorders of post-squalene cholesterol biosynthesis.

International audience; ObjectivesConradi-Hunermann-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. MethodsTo 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. ResultsThe mean age at diagnosis was 22weeks 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. ConclusionPrenatal detection of asymmetric shortening and bowing of the long bones and cartilage stippling should raise the possibility of CPDX2 in female fetuses, especially because the majority of such cases involve de novo mutations.

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 erythroderma, 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 is the case with many genetic syndromes, the hallmark features of CDPX2 in pediatric patients are not readily identifiable in adults. This case demonstrates the utility of WES as a diagnostic tool in the evaluation of adults with genetic disorders.

Insig-1 and Insig-2 are regulatory proteins that restrict the cholesterol biosynthetic pathway by preventing proteolytic activation of SREBPs and by enhancing degradation of HMG-CoA reductase. Here, we created Insig–double-knockout (Insig-DKO) mice that are homozygous for null mutations in Insig-1 and Insig-2. After 18.5 days of development, 96% of Insig-DKO embryos had defects in midline facial development, ranging from cleft palate (52%) to complete cleft face (44%). Middle and inner ear structures were abnormal, but teeth and skeletons were normal. The animals were lethargic and runted; they died within 1 day of birth. The livers and heads of Insig-DKO embryos overproduced sterols, causing a marked buildup of sterol intermediates. Treatment of pregnant mice with the HMG-CoA reductase inhibitor lovastatin reduced sterol synthesis in Insig-DKO embryos and reduced the pre-cholesterol intermediates. This treatment ameliorated the clefting syndrome so that 54% of Insig-DKO mice had normal faces, and only 7% had cleft faces. We conclude that buildup of pre-cholesterol sterol intermediates interferes with midline fusion of facial structures in mice. These findings have implications for the pathogenesis of the cleft palate component of Smith-Lemli-Opitz syndrome and other human malformation syndromes in which mutations in enzymes catalyzing steps in cholesterol biosynthesis produce a buildup of sterol intermediates.

Objective To report our experience of the prenatal diagnosis of X-linked dominant chondrodysplasia punctata (CDPX2) and highlight its variable phenotypic presentation. Methods We report the sonographic features of three female fetuses affected with CDPX2. The ultrasound, radiographic and pathological findings were compared. Results Family 1: Two affected pregnancies, both terminated. Fetus 1: Presented with epiphyseal stippling involving the vertebrae, upper and lower limbs, asymmetric shortening of the long bones and flat facial profile. Fetus 2: Prenatal findings included premature epiphyseal stippling, paravertebral cartilaginous calcific foci, mild shortening of the long bones and flat facies. Mutation analysis of the mother and both fetuses revealed mutation in the emopamil-binding protein (EBP) gene. Family 2: Prenatal sonography showed scattered epiphyseal stippling, minimal vertebral segmentation anomalies, mild asymmetric limb shortening and flat facies. Female infant delivered at 39 weeks of gestation. Biochemical analysis in all three fetuses showed increased levels of serum 8(9)-cholestenol consistent with delta (8), delta (7)-isomerase deficiency and CDPX2. Conclusion Prenatal diagnosis of CDPX2 is difficult because of marked phenotypic variation. Epiphyseal stippling, ectopic paravertebral calcifications, asymmetric shortening of long bones and dysmorphic flattened facies are crucial for prenatal diagnosis. DNA analysis of the CDPX2 gene and biochemical determination of the serum 8(9)-cholestenol level are important for diagnosis, especially if future pregnancies are planned. Copyright © 2006 John Wiley & Sons, Ltd.

Background: The classic rhizomelic chondrodysplasia punctata (RCDP) phenotype involves a typical facial appearance, cataracts, skeletal dysplasia causing disproportionate somatic growth failure, microcephaly, and severe psychomotor defects. Biochemical abnormalities include impaired plasmalogen biosynthesis in all forms of RCDP and accumulation of phytanic acid in RCDP type 1. A subset of patients has a milder clinical and biochemical phenotype, with less severe neurologic impairment and an incomplete deficiency in plasmalogens. The impact of plasmalogen deficiency on neurologic function is severe, causing spasticity and mental defects, but its pathomechanism is still unknown. The authors specifically focused on myelination because myelin is rich in ethanolamine plasmalogens. Objective: To define the neuroimaging characteristics of the genetic peroxisomal disorder RCDP. Methods: Twenty-one MR images of the brain and cervical spine of 11 patients were evaluated and correlated with neurologic and biochemical profiles. Results: No abnormalities on MRI were seen in the patients with a mild phenotype of RCDP, whereas delayed myelination, ventricular enlargement and increased subarachnoidal spaces, supratentorial myelin abnormalities, and cerebellar atrophy were observed in patients with the severe phenotype of both RCDP type 1 and 3. The severity of both the MRI abnormalities and the clinical phenotype is correlated with the plasmalogen level. Conclusions: The severe phenotype of rhizomelic chondrodysplasia punctata (RCDP) is accompanied by a specific pattern of both developmental and regressive MRI abnormalities. Plasmalogen levels seem to play an important role in the pathophysiology of CNS abnormalities in RCDP. Increased phytanic acid appears not to be the cause of cerebellar atrophy.