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Rhizomelic chondrodysplasia punctata (RCDP) are a group of peroxisomal disorders caused by plasmalogen synthesis defects. Patients with RCDP present with rhizomelic short stature, characteristic punctate epiphyseal calcifications, congenital cataracts, severe intellectual disability, seizures, and facial dysmorphism. Pathogenic variants in AGPS result in RCDP type 3 (RCDP3) which is an extremely rare disorder characterized by isolated ADHAPS deficiency. Six patients with RCDP3 have been identified, upto-date. We report two new patients with RCDP3 and their novel variants, c.154dupG (p.Ala52GlyfsTer6) and c.637+1GA, in the AGPS gene. We also present a review of previously reported RCDP3 patients.

Congenital combined vitamin K-dependent clotting factors deficiency (VKCFD) is a rare autosomal recessive disease resulting in hemorrhagic symptoms usually associated with developmental disorders and bone abnormalities. Pathogenic variants in two genes encoding enzymes of the vitamin K cycle, GGCX and VKORC1, can lead to this disorder. We present the case of a male fetus with a brachytelephalangic chondrodysplasia punctata (CDP), absence of nasal bone, growth restriction, and bilateral ventriculomegaly at 18 weeks of gestation. Pathological examination showed a Binder phenotype, hypoplastic distal phalanges, stippled epiphyses, and brain abnormalities suggestive of a brain hemorrhage. Two GGCX pathogenic variants inherited respectively from the mother and the father were identified. To our knowledge, this is the first prenatal description of VKCFD. Even if it remains a rare etiology, which is mostly described in children or adult patients, VKCFD should be considered in fetuses with CDP.

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.

Rhizomelic chondrodysplasia punctata is a rare, often fatal disease that shares many clinical dysmorphologic features with the rare often non-lethal chondrodysplasia punctata due to maternal autoimmune disease. Characteristic findings of both conditions include mid-face hypoplasia, stippled epiphyses of the vertebrae and long bones, and growth failure. A growing association with anti-ribonucleoprotein antibodies is emerging amongst patients with chondrodysplasia punctata due to maternal autoimmune disease and also neonatal lupus that have potential important screening implications. We present a unique case of chondrodysplasia punctata with neonatal lupus in the setting of positive anti-RNP antibodies and negative anti-Ro/SSA and -La/SSB antibodies born to a mother with mixed connective tissue disease and Raynaud's syndrome.

Conradi-Hünermann-Happle syndrome is rare X-linked dominant syndrome associated with stippled epiphyseal calcifications, congenital cataracts, Blaschkoid ichthyosiform scaling, and follicular atrophoderma. This case describes a novel finding of hypocalcemia and hypoparathyroidism in an infant with Conradi-Hünermann-Happle syndrome.

Key Clinical Message We report on a newborn with IUGR, rhizomelic dwarfism, and suspected chondrodysplasia punctata. At birth, OI was suspected; however, a skeletal survey suggested ML II alpha/beta. Sequencing revealed compound heterozygosity for a reported pathogenic and novel but expected pathogenic GNPTAB variant. Molecular testing for autosomal recessive OI identified a SERPINF1 variant.

This manuscript presents a molecularly demonstrated gonadal mosaicism from paternal origin for X-linked dominant chondrodysplasia punctata by single sperm typing. A couple who had experienced two medical terminations of pregnancy of female fetuses was referred to our pre-implantation genetic diagnosis (PGD) centre with the diagnosis of maternally derived gonadal mosaicism. Indeed, genetic analyses of different DNA samples - including semen - from the healthy parents failed to detect the variant found in the fetuses. Six embryos, all male, were obtained during the PGD cycle. The causative variant was not detected in any embryo, whereas five embryos had inherited the 'at-risk' maternal haplotype. The assumption of a maternal gonadal mosaicism was still possible, but this finding allowed us to consider the possibility of a paternal rather than maternal gonadal mosaicism. It prompted us to perform extensive single sperm analyses, demonstrating a low-frequency paternal germline mosaicism, which led to completely different haplotype phasing and PGD counselling. In conclusion, this case further exemplifies that germline mosaicism is a pitfall in PGD where diagnosis largely relies on linkage analysis and suggests that tracing the parental inheritance through polar body analysis and/or single sperm typing experiments is of major importance for adequate genetic counselling and accurate PGD. © 2016 John Wiley & Sons, Ltd.

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.

X-linked dominant chondrodysplasia punctata (Conradi-Hunermann-Happle syndrome, CDPX2) caused by mutations in the emopamil-binding protein (EBP) gene and congenital hemidysplasia with ichthyosiform nevus and limb defects (CHILD) syndrome caused by mutation in the NAD(P)H steroid dehydrogenase-like (NSDHL) gene are rare, typically male lethal disorders. CDPX2 skin lesions are characterized by transient severe congenital ichthyosis following the lines of Blaschko, whereas in CHILD syndrome, the lesions show striking lateralization. Here, we report a male CDPX2 patient with postzygotic mosaicism of the EBP gene presenting with lateralized skin lesions with strict midline demarcation as seen in CHILD syndrome (although this diagnosis was ruled out based on analysis of NSDHL), but also partly distributed along Blaschko's lines as seen in CDPX2. The lesions resolved within a few months, but the patient had other abnormalities, including shortening of the limbs, epiphyseal stippling, and forearm asymmetry; he also had problems with respiration and feeding in the first 4 years after birth. Kyphoscoliosis with dysplastic vertebral bodies progressed rapidly and required posterior spinal fusion surgery at 6 years old. These findings provide insights into the pathophysiology of CDPX2 and the mechanism of asymmetric lesion formation during development.

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.

Key Clinical Message A prenatally ascertained case representing the more severe end of the X‐linked dominant chondrodysplasia punctata (CDPX2).

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.

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.

Cholesterol has numerous quintessential functions in normal cell physiology, as well as in embryonic and postnatal development. It is a major component of cell membranes and myelin, and is a precursor of steroid hormones and bile acids. The development of the blood brain barrier likely around 12-18 weeks of human gestation makes the developing embryonic/fetal brain dependent on endogenous cholesterol synthesis. Known enzyme defects along the cholesterol biosynthetic pathway result in a host of neurodevelopmental and behavioral findings along with CNS structural anomalies. In this article, we review sterol synthesis disorders in the pre- and post-squalene pathway highlighting neurodevelopmental aspects that underlie the clinical presentations and course of Smith-Lemli-Opitz Syndrome (SLOS), mevalonic aciduria (MVA) or the milder version hyper-immunoglobulinemia D and periodic fever syndrome (HIDS), Antley-Bixler syndrome with genital anomalies and disordered steroidogenesis (ABS1), congenital hemidysplasia with icthyosiform nevus and limb defects (CHILD) syndrome, CK syndrome, sterol C4 methyl oxidase (SC4MOL) deficiency, X-linked dominant chondrodysplasia punctata 2(CDPX2)/ Conradi Hunermann syndrome, lathosterolosis and desmosterolosis, We also discuss current controversies and share thoughts on future directions in the field.

In the last decades, nine inherited errors of the distal part of cholesterol biosynthesis have been recognized. Affected patients present complex malformation syndromes involving different organs and systems with variable degrees of severity. We report on the phenotype evolution of three patients with enzymatic defects at three distinct steps of such pathway: Smith-Lemli-Opitz syndrome, X-linked dominant chondrodysplasia punctata type 2 and congenital hemidysplasia with ichthyosiform erythroderma and limb defects syndrome. The patients' natural history, from childhood to adulthood, is thoroughly described in order to contribute for a better knowledge of these diseases. Our ultimate goals are to contribute for a better characterization of the long-term course of these metabolic disorders and for the recognition of such diseases in older patients.

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.

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.

The X-linked recessive type of chondrodysplasia punctata (CDPX1) is a skeletal disorder that is characterized by stippled calcification at an epiphyseal nucleus and the surrounding soft tissue, short stature and an unusual face because of nasal hypoplasia. In most of the patients, this condition is noted after birth because of a characteristic face or respiratory problems. Here, we report a fetus with CDPX1. Two-dimensional ultrasound examination revealed unexplained polyhydramnios and a male fetus. Fetal biometry showed shortened long bones. Three-dimensional ultrasonography clearly demonstrated a hypoplastic nose with a depressed nasal bridge and contracture of wrists and fingers. Chromosome analysis of the amniotic fluid cells revealed the 46,Y,del(X)(p22.3) karyotype. Fluorescence in situ hybridization revealed a deletion of subtelomeric sequences at the Xpter and STS gene, but not a deletion of the KAL gene. The genomic copy number analysis demonstrated terminal deletion of 8.33 Mb that included SHOX, CSF2RA, XG, ARSE, NLGN4 and STS genes. We think that our case presents typical features of a fetus with this disorder and will be of great help in prenatal ultrasound diagnosis.

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.

Mucopolysaccharide (MPS) metabolism in cultured skin fibroblasts was studied in one case of each of the following osteochondrodysplasias: chondrodysplasia punctata of the rhizomelic type, thanatophoric dysplasia, campomelic dysplasia, and osteogenesis imperfecta congenita. Accumulation of both sulfated and non-sulfated MPS, as well as secretion of total MPS, was normal in chondrodysplasia punctata of the rhizomelic type and in thanatophoric dysplasia. Accumulation of both sulfated and non-sulfated MPS was normal in campomelic dysplasia. Lastly, accumulation of sulfated MPS was normal in osteogenesis imperfecta congenita.

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.

Three brothers, two of them monozygous twins, had epiphyseal dysplasia particularly of the femoral head, a high degree of myopia, and perceptive hearing loss. The parents were related. The disorder may be a rare autosomal recessive condition.

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.

Males with deletions of or within Xp22.3-pter display variable contiguous gene syndromes including manifestations of Léri-Weill syndrome, chondrodysplasia punctata, mental retardation, ichthyosis, Kallmann syndrome, and ocular albinism. Herein, we report on a male infant with a large, cytogenetically visible, terminal Xp deletion defined by extensive FISH and STS marker analysis to encompass 9.6 Mb, and findings of all of the disorders mentioned above. His deletion approximates the largest Xp terminal deletion ever reported in a male individual. Since the extent of terminal Xp deletions viable in males is limited by the position of male lethal genes in Xp22.2 at about 10-11 Mb from the telomere, this patient falls into the category of the most severe male terminal Xp deletion phenotype.

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 Binder syndrome is a maxillonasal dysostosis characterized by midface and nasal hypoplasia, sometimes associated with short terminal phalanges of fingers and toes and transient radiological features of chondrodysplasia punctata. Warfarin- or phenytoin-induced vitamin K deficiency during early pregnancy is a well-established etiology for this syndrome, which occurs nevertheless sporadically in most cases. CASE(S) We describe here the first case, to our knowledge, of Binder syndrome in a child whose mother presented with biliary lithiasis in early pregnancy. The mother proved to have a decrease in clotting factors II, VII, and X, and in prothrombin time, at 11 weeks of gestation, which was highly suggestive of vitamin K deficiency. CONCLUSIONS The biliary lithiasis–induced vitamin K deficiency in early pregnancy is likely to have resulted in Binder syndrome. This observation should prompt physicians to carefully check for vitamin K deficiency in pregnant women presenting with biliary lithiasis, in order to prevent Binder syndrome in the fetus by providing intravenous vitamin K supplementation as soon as possible. Finally, reassuring genetic counseling regarding the genetic risk for future pregnancies is to be provided to the parents. Birth Defects Research (Part A), 2005. © 2005 Wiley-Liss, Inc.

Chondrodysplasia punctata brachytelephalangic type is a common subset of a heterogeneous group of chondrodysplasia punctata. Most affected children generally do not have significant physical disabilities; however, a small number of patients are at risk of cervical canal stenosis with cervical cord compression leading to serious morbidity and early mortality. Very little is known about the in utero manifestation of severe complications. We report an affected child in whom the Binder phenotype was found on antenatal ultrasound and cervical spinal cord compression on fetal magnetic resonance imaging. Prenatal diagnosis of chondrodysplasia punctata brachytelephalangic type and its complications are beneficial for timely, prompt medical intervention.

Chondrodysplasia punctata (CDP) was diagnosed clinically and radiographically in a male child born in Cape Town in 1991. His only sibling, a brother born in 2000 was similarly but more severely affected. The boys' mother had longstanding disseminated lupus erythematosus and epilepsy, for which she had been treated with chloraquine and other therapeutic agents during both pregnancies. The parents were non-consanguineous, and the family history was unremarkable. In addition to these affected brothers, seven previous instances of the association of CDP and maternal lupus erythematosus (MLE) have been reported. On this basis, MLE must be regarded as yet another causative factor in CDP.

Objective To evaluate the contribution of new imaging techniques in the prenatal diagnosis of skeletal dysplasia. Methods Between May and October 2003, a prospective study was conducted in a single referral center. Three-dimensional ultrasound (3D-US) and three-dimensional helical computer tomography (3D-HCT) were performed after two-dimensional ultrasound (2D-US) in six cases of skeletal dysplasia. Diagnostic accuracy and detailed findings with each of the three techniques were compared with postnatal radiological findings. Results There were three cases of achondroplasia, two cases of osteogenesis imperfecta type II and one case of chondrodysplasia punctata. Termination of pregnancy was performed in five cases and one fetus with osteogenesis imperfecta type II was delivered at term by Cesarean section. 2D-US made the correct diagnosis in four cases. 3D-US and 3D-HCT achieved an accurate diagnosis in all six cases. 3D-HCT and 3D-US identified significantly more abnormalities than did 2D-US (3D-HCT: 94.3% (33/35); 3D-US: 77.1% (27/35); 2D-US: 51.4% (18/35); P < 0.01). The diagnosis was made between 27 and 36 weeks' gestation in all cases. The advantage of 3D-HCT over 3D-US was the possibility of imaging the entire fetus. Conclusion 3D-US and 3D-HCT seem to be useful complementary methods to 2D-US, and may improve accuracy of the prenatal diagnosis of skeletal disorders. These new imaging technologies may have a role in the prenatal multidisciplinary approach to the diagnosis of skeletal dysplasias. Copyright © 2004 ISUOG. Published by John Wiley & Sons, Ltd.

Conradi-Hunermann syndrome (CDPX2) is X-linked dominant disorder appeared with aberrant punctuate calcification. The skeletal cells derived from the marrow stroma are active in maintaining the skeletal formation. We obtained mesenchymal stem cells from a patient with CDPX2 and studied the formation of colony forming unit-fibroblast (CFU-F) in vitro in comparison cells obtained from normal donors. Cultured cells were studied morphologically and subjected to gene expression analysis. Marrow stromal cells (MSC)-chondrodysplasia punctuate (CDP) cells from CDPX2 were identified by their mosaic morphology formed three phenotypically distinct types of CFU-F colonies. One type consisted of normal fibroblasts with developed cell body and cellular processes; the second type contained pathological small cells without processes; and the third type comprised of mixed cells. We compared gene expression by the MSC-CDP to cells from normal donors. Transcription factors analyzed proliferation potential were similar in both normal and mixed colonies of MSC-CDP and similar to normal MSCs. The message expression for cytokines and extra cellular matrix (ECM) proteins revealed similar expression for biglycan, osteocalcin, and osteonectin, while IL-6, IL-11, and M-CSF mRNA levels were significantly higher in normal cells than in MSC-CDP. Mixed cells had elevated levels for IL-6 and M-CSF mRNA, but expressed IL-11 at the normal range. The studied genes were expressed at lower levels by the pathological (MSC-CDP) cells compared to normal ones. Hence, MSC-CDP was demonstrated to display abnormal morphology and transcription of several investigated genes. This study further illuminates the basis of the mosaic pattern of mesenchymal cells derived from a patient affected with CDPX2, and their gene expression involvement.

We describe a mother and two sons with a 6-Mb terminal deletion of the short arm of the X chromosome. The breakpoint was localized to a region between DXS6837 and sAJ243947 in Xp22.33. The two boys were shown to be deleted for the SHOX and ARSE genes on their X chromosome. Both sons were short in stature and showed mild to moderate skeletal abnormalities. The most significant findings in the younger son were severe learning disabilities and attention deficit hyperactivity disorder (ADHD). The older son tested in the mild mental retardation range and was also affected by ADHD. The VCX-A gene, implicated recently in X-linked nonspecific mental retardation, was found to be present in both boys. The mother's stature was greater than one standard deviation below her target height and she had only subtle radiographic evidence of Madelung deformity. Our findings indicate that loss of the Xp22.3 region is not always associated with the classic presentations of Léri-Weill syndrome, or chondrodysplasia punctata, and that one or more genes involved in learning and attention may reside in Xp22.3.

Objective Recognition of prenatal-onset skeletal dysplasias has improved with advances in ultrasound imaging. Skeletal abnormalities can be recognized by two-dimensional (2D) ultrasound, but generating a precise diagnosis can be challenging. We aimed to determine whether three-dimensional (3D) imaging conferred any advantages over 2D imaging in these cases. Methods We studied five women with fetuses of 16–28 gestational weeks referred for abnormal ultrasound skeletal findings. First 2D and then 3D sonography was performed and the results compared. Results The pregnancies resulted in the following skeletal dysplasias: thanatophoric dysplasia, achondrogenesis II/hypochondrogenesis, achondroplasia, chondrodysplasia punctata (rhizomelic form) and Apert's syndrome. For all five fetuses, the correct diagnosis was made in the prenatal period by analysis of the 2D images. In each case the 3D images confirmed the preliminary diagnosis and for many findings it improved the visualization of the abnormalities. Conclusion The 3D imaging had advantages over the 2D imaging when it came to evaluation of facial dysmorphism, relative proportion of the appendicular skeletal elements and the hands and feet. Most importantly, the patient and referring physician appreciated the 3D images of the abnormal findings more readily which aided in counseling and management of the pregnancy. Copyright © 2003 ISUOG. Published by John Wiley & Sons, Ltd.

We report the longterm clinical and radiological progression in three unrelated patients with the tibia-metacarpal form of chondrodysplasia punctata (CDP-TM). The patients were followed for 37, 25, and 32 years, respectively. At follow-up intellectual function was normal, and physical function was well preserved. There was also marked resolution of several significant early radiographic features. The patients attained adult heights of 152, 138, and 148 cm. Two patients had chronic serous otitis media requiring tympanostomy tubes during childhood. One patient suffered persisting back pain related to spinal stenosis and required lumbar laminectomy at the age of 26 years. One patient had hip dysplasia requiring orthopedic surgical intervention. All patients had recurrent patella dislocation. Sterol and very long chain fatty acid profiles, FISH analysis for SHOX gene deletions, blood lymphocyte karyotype, and phytanic acid levels were normal in those tested, and no mutations in arylsulfatase D and E genes were detected. These data suggest that the longterm clinical and functional prognosis in this condition appears to be better than that expected based on initial clinical and radiological findings.

DIENEKE VAN DRIEL,* JUDIT WESSELING, PIETER J.J. SAUER, BERT C.L. TOUWEN, EVELINE VAN DER VEER, AND HUGO S.A. HEYMANS Department of Pediatrics, Beatrix Children’s Hospital, University Hospital Groningen, Groningen, The Netherlands Department of Medical Physiology Section Developmental Neurology, University of Groningen, Groningen, The Netherlands Pathology and Laboratory Medicine, University Hospital Groningen, Groningen, The Netherlands Department of Pediatrics, Emma Children’s Hospital, Academic Medical Center, Amsterdam, The Netherlands

The X-linked dominant Conradi-Hunermann-Happle (CDPX2, MIM 302960) syndrome belongs to the rare, heterogeneous group of diseases called chondrodysplasia punctata. The disease has been connected recently with deficiency of 3beta-hydroxysteroid-Delta8-Delta7-isomerase (also called emopamil-binding protein, EBP), catalysing an intermediate step in the conversion of lanosterol to cholesterol (1, 2). We report a case of CDPX2 with a new missense mutation (C-->G 439) in exon 4, leading to a R147G aminoacid substitution in the EBP.

Here we report an 8-year-old male patient who had mesomelic shortening of forearms and legs, brachytelephalangia and ichthyotic skin lesions. Chromosomal analysis showed an X;Y translocation involving the short arm of the X chromosome (Xp). Fluorescence in situ hybridization (FISH) and molecular studies localized the breakpoints on Xp22.3 in the immediate vicinity of the KAL gene demonstrating deletions of steroid sulfatase (STS), arylsulfatase E (ARSE), and short stature homeo box (SHOX) genes. It was suspected that the patient was suffering from chondrodysplasia punctata because of a loss of the arylsulfatase E (ARSE) gene. However, no stippled epiphyses were to be seen in the neonatal radiograph. Interestingly, this patient is the first case with a proven loss of the ARSE gene without chondrodysplasia punctata, assuming that chondrodysplasia punctata is not an obligatory sign of ARSE gene loss. Brachytelephalangia was the only result of ARSE gene deletion in this case. The patient's mother also had dwarfism and showed Madelung deformity of the forearms. She was detected as a carrier of the same aberrant X chromosome. The male patient did not show Madelung deformity, demonstrating that Lerri-Weill syndrome phenotype may be still incomplete in children with SHOX gene deletion. The wide clinical spectrum in the male and the Leri-Weill phenotype in his mother are the results of both a deletion involving several sulfatase genes in Xp22.3 and the SHOX gene located in the pseudoautosomal region. Nevertheless, there is no explanation for the absence of chondrodysplasia punctata despite the total loss of the ARSE gene. Further studies are necessary to investigate genotype/phenotype correlation in cases with translocations or microdeletions on Xp22.3, including the ARSE and the SHOX gene loci.

Rhizomelic chondrodysplasia punctata (RCDP) is a rare peroxisomal disorder leading to multiple developmental malformations, including skeletal deformity. Specifically, involvement of the vertebral bodies has been described. Presented here is a case of a two-year-old female child with RCDP leading to advanced cervical stenosis as detected on magnetic resonance imaging (MRI) studies of the cervical spine. The practicing clinician should be aware of the possibility of cervical stenosis secondary to RCDP and its impact on the management of the patient with this rare disease process.

We present a male autopsied case of chondrodysplasia punctata with abnormal face, symmetrical proximal limb shortness, severe psychomotor developmental delay, respiratory muscle weakness, and death at the age of 2 years. Although his clinical manifestations were similar to those of rhizomelic chondrodysplasia punctata (RCDP), biochemical studies using skin fibroblasts did not document the peroxisomal dysfunction described in RCDP. In addition, the sterol profile, for which abnormalities have recently been reported in cases of X-linked dominant form chondrodysplasia punctata (CDPX2), was normal both in the liver and in the fibroblasts. This patient may represent a new lethal form of chondrodysplasia punctata.

Neonatal lupus erythematosus (NLE) is characterized by the transplacental passage of maternal anti-Ro and/or anti-La antibodies and characteristic illnesses in the foetus/neonate. Most attention has focused on the most serious complication- cardiac involvement. This article will focus on non-cardiac involvement. Skin involvement (cutaneous NLE) is present in 15-25% of children with NLE. The rash of NLE tends to be photosensitive but may be present at birth or in non-sun exposed areas. It is most frequently seen around the eyes, not in the malar area, but also occurs in other parts of the body. The pathology resembles the rash of subacute cutaneous lupus erythematosus. Anti-Ro antibodies are present in >95% with the remaining mothers having anti-U1RNP antibodies only. Asymptomatic elevation of liver function tests, which may be associated with evidence of cholestasis, is seen in 10-25% of cases of NLE. Mild hepatomegaly and less commonly splenomegaly may be present. Liver involvement seen in isolation or associated with other features. The pathology resembles idiopathic neonatal giant cell hepatitis. Any haematological lineage, neutropenia and thrombocytopenia most commonly, may be affected by NLE. Haematological involvement is almost always asymptomatic. There are protean manifestations of neurologic involvement in NLE: hydrocephalus, non-specific white matter changes, calcification of the basal ganglia and a 'vasculopathy'. The most unusual feature of NLE is the radiographic finding of stippling of the epiphyses (chondrodysplasia punctata). Overall, non-cardiac involvement of NLE is more common than cardiac. The study of these manifestations may lead to new insight into how autoantibodies lead to disease.

We present a 6-week-old black girl with Conradi–Hunerman–Happle syndrome (CHS). The mother had no past medical history of illness, and the pregnancy progressed normally to a spontaneous vaginal delivery at 36 weeks. There was no known significant family history. A diagnosis of chondrodysplasia punctata was made at birth from physical examination and X-ray findings. On physical examination at 6 weeks, a koala face, a saddle nose, and a right-sided cataract were noted (Fig. 1a,b). There was unilateral left-sided ichthyosis well demarcated at the midline, with whorled brown fine scale following Blashko's lines on the patient's right side. Orthopedic complications were bilateral but were more pronounced on the left side. There was bilateral shortening of the humerus, with polydactyly of the right hand, arachnodactyly of the left fingers, bilateral clubbing, and mild contractures of the feet. X-Rays showed multiple calcifications along the spine, proximal and distal femoral epiphysis, and proximal humeral epiphysis (Fig. 2). Figure 1. Six-week-old black girl with X-linked dominant chondrodysplasia punctata (XCDP2). The patient has a koala face, a saddle nose (a), and a right-sided cataract (b). There is unilateral left-sided ichthyosis well demarcated at the midline. The ichthyosis consists of whorled brown fine scale following Blashko's lines on the patient's right side, including the abdomen, thigh, upper back, and upper and lower extremities. There is bilateral shortening of the humerus, polydactyly of the right hand, arachnodactyly of the left fingers, bilateral clubbing, and mild contractures of the feet Download figure to PowerPoint Figure 2. X-Rays showing multiple calcifications along the spine, proximal and distal femoral epiphysis, and proximal humeral epiphysis in the patient with X-linked dominant chondrodysplasia punctata (XCDP2) Download figure to PowerPoint The patient was treated with emollients (aquaphor) twice daily with continuing improvement in ichthyosis. The clubbed feet were treated with splinting and the polydactyly was corrected by surgery. Ophthalmology was to follow the patient for her right-sided cataract. At the patient's 4-month follow-up, the ichthyosis showed a marked improvement with some residual hypo- pigmented atrophoderma noted. The distribution remained unchanged. Biopsies taken of ichthyotic lesions showed compact hyperkeratosis and follicular plugging. Vesicles within the stratum corneum contained amorphous material (Fig. 3a,b). The granular cell layer was thickened with retained oval nuclei. The epidermal and adnexal epithelium were disorganized. Increased apoptotic/dyskeratotic keratinocytes were seen within the epidermis, but were most evident within the follicular epithelium. Figure 3. (a, b) Sections from biopsy specimens of the X-linked dominant chondrodysplasia punctata (XCDP2) patient showing compact hyperkeratosis and follicular plugging. Vesicles within the stratum corneum contain amorphous material. The granular cell layer is thickened with retained oval nuclei. The epidermal and adnexal epithelium are disorganized. Increased apoptosis/dyskeratosis are seen within the epidermis, but are most evident within the follicular epithelium (400×, 400×) Download figure to PowerPoint Ultrastructural studies showed saccular dilations of the acellular space within the stratum corneum. These acellular spaces were filled with unprocessed lamellated pleated sheets and vesicle complexes and processed lamellae. Dyskeratotic cells were seen within the stratum spinosum. Red blood cell (RBC) plasmalogen levels and polyunsaturated fatty acids (PUFA), including decosahexaenoic acid (DHA), were within normal limits. Plasma very long chain fatty acids (VLCFA), including C26 : 0/C22 : 0 ratios, phytanic and pristanic acids, plasmalogen, and phytanic/pristanic ratios, trihydroxycholestanic acid (THCA) and dihydroxycholestanoic acid (DHCA) including their ratios, THCA/cholic acid and DHCA/chenodeoxycholic acid, and PUFAs including DHA were within normal limits. Urine organic acids and piecolic acid were within normal limits. Despite these normal values, there was an increase in cholest-8(9)-en-3β-ol of 6.8 μg/mL (normal, 0.01–0.10 μg/mL) and an increase in 8-dehydrocholesterol (5.1 μg/mL) (normal

ultrasonography in a fetus at 16 weeks’ gestation. Generalized shortening of the long bones, with bowing of the femora and tibiae, a flat midface, small mouth, and micrognathia, were demonstrated. Radiologic findings of vertebral coronal clefts, shortened tibiae, elongated fibulae, and calcific stippling confirmed the diagnosis of CP-MT. Skeletal dysplasias are a heterogeneous group of bone growth disorders that result in an abnormal shape and size of the skeleton. CP-MT refers to a category of skeletal dysplasias with stippled calcification and abnormalities of vertebrae, long bones, and viscera. This report describes the ultrasonographic, radiographic, and pathologic findings in a fetus aborted during the second trimester of pregnancy because of a skeletal dysplasia. This fetus showed findings of CP-MT as described by Rittler and associates.1

We report for the first time that CHILD syndrome (MIM 308050), an X-linked dominant, male-lethal trait characterized by an inflammatory nevus with striking lateralization and strict midline demarcation, as well as ipsilateral hypoplasia of the body is caused by mutations in the gene NSDHL located at Xq28 (NAD(P)H steroid dehydrogenase-like protein) encoding a 3β-hydroxysteroid dehydrogenase functioning in the cholesterol biosynthetic pathway. SSCA and genomic sequence analysis of NSDHL identified in 6 patients with CHILD syndrome, including one boy as well as a mother and her daughter, mutations potentially impairing protein function. This phenotype is distinct from, but shares various clinical and biochemical findings with chondrodysplasia punctata (CDPX2, MIM 302960). CDPX2 is due to mutations affecting a Δ8-Δ7 sterol isomerase (EBP, emopamil binding protein, at Xp11.22 - p11.23) that functions downstream of NSDHL in a later step of cholesterol biosynthesis. EBP was unaffected in the patients analyzed by us demonstrating that CHILD syndrome and CDPX2 are not caused by allelic mutations. Two mouse X-linked dominant male-lethal traits, bare patches (Bpa) and striated (Str) had previously been associated with mutations in Nsdhl. They provide animal models for the study of CHILD syndrome, a further human condition due to mutations in a gene of the cholesterol synthesis pathway. Am. J. Med. Genet. 90:339–346, 2000. © 2000 Wiley-Liss, Inc.

CHILD (congenital hemidysplasia, ichthyosis, and limb defects) syndrome is a rare, usually sporadic disorder associated with unilateral distribution of ichthyosiform skin lesions, limb defects, punctate calcifications of cartilaginous structures, and visceral anomalies. CHILD syndrome shares some manifestations with X-linked dominant Conradi-Hunermann syndrome (CDPX2), although the skeletal defects and skin lesions in CDPX2 are bilateral and asymmetric. Because CDPX2 patients have abnormal 8-dehydrosterol metabolism caused by mutations in 3beta-hydroxysteroid-delta8,delta7-isomerase, we measured plasma sterols in a patient with CHILD syndrome and found levels of 8-dehydrocholesterol and 8(9)-cholestenol increased to the same degree as in CDPX2 patients. Subsequently, we identified a nonsense mutation in exon 3 of the patient's 3beta-hydroxysteroid-delta8,delta7-isomerase gene. We speculate that at least some cases of CHILD syndrome are allelic with CDPX2 caused by 3beta-hydroxysteroid-delta8,delta7-isomerase deficiency.

Chondrodysplasia punctata (CDP) is a heterogeneous group of skeletal dysplasias characterized by stippled epiphyses. A subtype of CDP, X-linked dominant chondrodysplasia punctata (CDPX2), known also as Conradi-Hunermann-Happle syndrome, is a rare skeletal dysplasia characterized by short stature, craniofacial defects, cataracts, ichthyosis, coarse hair, and alopecia. The cause of CDPX2 was unknown until recent identification of mutations in the gene encoding Delta(8),Delta(7) sterol isomerase emopamil-binding protein (EBP). Twelve different EBP mutations have been reported in 14 patients with CDPX2 or unclassified CDP, but with no evidence of correlation between phenotype and nature of the mutation. To characterize additional mutations and investigate possible phenotype-genotype correlation, we sequenced the entire EBP gene in 8 Japanese individuals with CDP; 5 of them presented with a CDPX2 phenotypes. We found EBP mutations in all 5 CDPX2 individuals, but none in non-CDPX2 individuals. Three of these CDPX2 individuals carried novel nonsense mutations in EBPand the other two, separate missense mutations that had been reported also in different ethnic groups. Our results, combined with previous information, suggest all EBP mutations that produce truncated proteins result in typical CDPX2, whereas the phenotypes resulted from missense mutations are not always typical for CDPX2. Patients with nonsense mutations showed abnormal sterol profiles consistent with a defect in Delta(8), Delta(7) sterol isomerase. X-inactivation patterns of the patients showed no skewing, an observation that supports the assumption that inactivation of the EBP gene occurs at random in affected individuals.