X-linked Dominant Chondrodysplasia Research Articles

817 Ichthyotic skin lesions of Conradi–Hünermann–Happle syndrome successfully treated with dupilumab

817 Ichthyotic skin lesions of Conradi–Hünermann–Happle syndrome successfully treated with dupilumab

35385 A case of Conradi-Hunermann-Happle syndrome

Conradi-Hunermann-Happle (CHH) syndrome is a rare genodermatosis comprised of cutaneous, ocular, and skeletal abnormalities. CHH syndrome is an X-linked dominant form of chondrodysplasia punctata due to a genetic defect involving the emopamil-binding protein (EBP) gene. We report a case of a female infant with classic cutaneous and extracutaneous manifestations of CHH. Cutaneous manifestations in this patient included ichthyosis and hyperpigmented macules and papules in a Blaschko-linear pattern.

Conradi-Hünermann-Happle syndrome associated with severe hypocalcemia in a newborn.

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.

Retrotransposition disrupting EBP in a girl and her mother with X-linked dominant chondrodysplasia punctata.

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.

Chemical Modifications of Ribosomal RNA.

Cellular RNAs in all three kingdoms of life are modified with diverse chemical modifications. These chemical modifications expand the topological repertoire of RNAs, and fine-tune their functions. Ribosomal RNA in yeast contains more than 100 chemically modified residues in the functionally crucial and evolutionary conserved regions. The chemical modifications in the rRNA are of three types-methylation of the ribose sugars at the C2-positionAbstract (Nm), isomerization of uridines to pseudouridines (Ψ), and base modifications such as (methylation(mN), acetylation (acN), and aminocarboxypropylation (acpN)). The modifications profile of the yeast rRNA has been recently completed, providing an excellent platform to analyze the function of these modifications in RNA metabolism and in cellular physiology. Remarkably, majority of the rRNA modifications and the enzymatic machineries discovered in yeast are highly conserved in eukaryotes including humans. Mutations in factors involved in rRNA modification are linked to several rare severe human diseases (e.g., X-linked Dyskeratosis congenita, the Bowen-Conradi syndrome and the William-Beuren disease). In this chapter, we summarize all rRNA modifications and the corresponding enzymatic machineries of the budding yeast.

Pustular Skin Lesions in an Adult Female Patient with X-linked Dominant Chondrodysplasia Punctata with a Novel Emopamil Binding Protein Mutation: A Rare Skin Manifestation.

Pustular Skin Lesions in an Adult Female Patient with X-linked Dominant Chondrodysplasia Punctata with a Novel Emopamil Binding Protein Mutation: A Rare Skin Manifestation.

Ichthyosiform lesion at birth demystifying familial short stature

Conradi-Hunermann syndrome is a rare genetic condition characterized by skeletal malformations, skin abnormalities, cataracts and short stature. We report a term female infant presenting with a diffuse ichthyosiform erythroderma at birth. Physical examination also showed sparse lusterless hair with cicatricial alopecia, dystrophic nails, facial dysmorphism, and flexion contracture of fingers. Radiological examination revealed a shortening of the right femur and humerus, vertebral defects, scoliosis, and epiphyseal stippling of long bones on the right side. The infant's sister and mother had short stature and bony joint swellings. A clinical diagnosis of X-linked Conradi–Hunermann syndrome was considered based on clinical suspicion and radiological survey. Dermatologists and pediatricians should consider this diagnosis in children with suggestive features.

Abnormal sterol-induced cell wall glucan deficiency in yeast is due to impaired glucan synthase transport to the plasma membrane.

Abnormal sterols disrupt cellular functions through yet unclear mechanisms. In Saccharomyces cerevisiae, accumulation of Δ8-sterols, the same type of sterols observed in patients of Conradi-Hünermann-Happle syndrome or in fungi after amine fungicide treatment, leads to cell wall weakness. We have studied the influence of Δ8-sterols on the activity of glucan synthase I, the protein synthetizing the main polymer in fungal cell walls, its regulation by the Cell Wall Integrity (CWI) pathway, and its transport from the endoplasmic reticulum to the plasma membrane. We ascertained that the catalytic characteristics were mostly unaffected by the presence of abnormal sterols but the enzyme was partially retained in the endoplasmic reticulum, leading to glucan deficit at the cell wall. Furthermore, we observed that glucan synthase I traveled through an unconventional exocytic route to the plasma membrane that is associated with low density intracellular membranes. Also, we found out that the CWI pathway remained inactive despite low glucan levels at the cell wall. Taken together, these data suggest that Δ8-sterols affect cell walls by inhibiting unconventional secretion of proteins leading to retention and degradation of glucan synthase I, while the compensatory CWI pathway is unable to activate. These results could be instrumental to understand defects of bone development in cholesterol biosynthesis disorders and fungicide mechanisms of action.

Conradi–Hünermann–Happle syndrome: report of a novel heterozygous mutation on the emopamil-binding protein gene, c.333delC

Conradi-Hünermann-Happle Syndrome, also called X-linked rhizomelic chondrodysplasia punctata, is a rare genodermatosis that presents with cutaneous, skeletal, and ophthalmological abnormalities. Herein, we report a full-term newborn that presented at birth with scattered blaschkolinear bands of adherent scales and scalp erosions in a spiral distribution. Genetic analysis of emopamil-binding protein gene revealed a previously undescribed heterozygous mutation of c.333delC.

X-linked dominant chondrodysplasia punctata 2 with severe phenotype in one female fetus: a case report

We reported a female fetus diagnosed with X-linked dominant chondrodysplasia punctata 2 with severe phenotype. The fetus was found with abnormal short limbs, thick metaphysis on the right lower limb and a narrow and small thorax by prenatal ultrasound at 24+5 weeks of gestation. Non-invasive prenatal test indicated the risks of trisomies 21, 18 and 13 were low. The pregnancy was terminated at 27 weeks of gestation and postnatal X-ray imaging showed that the fetus had short femur and humerus, a narrow and small thorax, thickened metaphysis with a splashed paint spot pattern, and asymmetric shortened lower limbs. Whole-exome analysis showed that the fetus carried a heterozygous pathogenic mutation c.440G>A (p.Arg147His) in the EBP gene. The mutation was confirmed to be a de novo mutation as neither of her parents carried the same mutation. Thus, the patient was diagnosed as having X-linked dominant chondrodysplasia punctata 2. The severe phenotype of this case migh be related to random X chromosome inactivation. Key words: Chondrodysplasia punctata; Ultrasonography, prenatal; Whole exome sequencing; Female

Structural basis for human sterol isomerase in cholesterol biosynthesis and multidrug recognition

3-β-hydroxysteroid-Δ8, Δ7-isomerase, known as Emopamil-Binding Protein (EBP), is an endoplasmic reticulum membrane protein involved in cholesterol biosynthesis, autophagy, oligodendrocyte formation. The mutation on EBP can cause Conradi-Hunermann syndrome, an inborn error. Interestingly, EBP binds an abundance of structurally diverse pharmacologically active compounds, causing drug resistance. Here, we report two crystal structures of human EBP, one in complex with the anti-breast cancer drug tamoxifen and the other in complex with the cholesterol biosynthesis inhibitor U18666A. EBP adopts an unreported fold involving five transmembrane-helices (TMs) that creates a membrane cavity presenting a pharmacological binding site that accommodates multiple different ligands. The compounds exploit their positively-charged amine group to mimic the carbocationic sterol intermediate. Mutagenesis studies on specific residues abolish the isomerase activity and decrease the multidrug binding capacity. This work reveals the catalytic mechanism of EBP-mediated isomerization in cholesterol biosynthesis and how this protein may act as a multi-drug binder.

Conradi–Hunermann syndrome: A rare case of chondrodysplasia punctata

Conradi–Hunermann syndrome is a common form of chondrodysplasia punctata, inherited as X-linked dominant disorder of cholesterol metabolism due to mutation of emopamil-binding protein gene resulting in a spectrum of skeletal, cutaneous, and ocular abnormalities. One-day-old premature, cesarean-delivered female neonate admitted with xerotic, featherlike yellow-to-white hyperkeratotic scale all over the body with craniofacial defect, coarse hair, patches of cicatricial alopecia, and absent eyebrows. Baby had rhizomelic shortening of proximal limb, clinodactyly, club foot, talipes equinovarus, and bilateral congenital cataract. Radiological skeletal survey revealed punctate stippled calcification involving left femoral head epiphysis, bilateral tarsal bones, vertebral bodies of multiple thoracolumbar vertebrae, and sternum. Serum level of 8-dehydrocholesterol was elevated. Diagnosis of rare disease can be made on clinical suspicion and radiological survey in resource-limited setting.

New splicing pathogenic variant in EBP causing extreme familial variability of Conradi–Hünermann–Happle Syndrome

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.

Cutis Tricolor

AbstractCutis tricolor is a skin abnormality consisting in a combination of congenital hyper- and hypopigmented skin lesions (in the form of paired macules, patches, or streaks) in close proximity to each other in a background of normal skin. It is currently regarded as a twin-spotting (mosaic) phenomenon. This phenomenon has been reported so far as a purely cutaneous trait, as a part of a complex malformation phenotype (Ruggieri–Happle syndrome), which includes distinct facial features, cataract, skull and vertebral defects, long bones dysplasia, corpus callosum, cerebellar and white matter anomalies, cavum vergae and holoprosencephaly, and other systemic abnormalities. Cutis tricolor has been also reported as a distinct type with multiple, disseminated smaller skin macules (cutis tricolor parvimaculata) or in association with other skin disturbances (e.g., phacomatosis achromico-melano-marmorata) or in the context of other neurocutaneous phenotypes (e.g., ataxia-telangiectasia and phacomatosis pigmentovascularis) or as a sign of complex malformation phenotypes (e.g., microcephaly and dwarfism). More than 20 studies reporting 40 cases are present in the literature with pure cutaneous or syndromic cutis tricolor phenomena and are analyzed in the present study, confirming and expanding the overall phenotype of cutis tricolor. In particular, (1) the skin abnormalities of the cutis tricolor do not evolve over time; (2) there is a typical facial phenotype with long, elongated face, thick and brushy eyebrows, hypertelorism, deep nasal bridge with large bulbous nose, and anteverted nostrils; (3) the skeletal defects are mild-to-moderate and do not progress or cause relevant orthopedic complications; (4) the neurological/behavioral phenotype does not progress and the paroxysmal events (if present) tend to decrease over time; (5) only three patients developed early onset (treatable) cataracts. Different pathologic hypotheses have been postulated, including, early or late postzygotic mutations involving the same gene loci (in the context of the so-called dydymotic theory): such mechanisms can explain the overall skin, bone, lens, and nervous system phenomena of migration of different streaks of clones in the different tissues.

EP13.09: Conradi‐Hünermann‐Happle syndrome, prenatal diagnosis and family generational report

The Conradi-Hünermann-Happle syndrome or Dominant X-Linqued Chondrodysplasia Punctata (CDPX2) is a rare genetic syndrome characterised by dermatological, ocular and skeletal manifestations. A diagnostic approach can be performed with the ultrasound in the prenatal period, however, it is confirmed by a physical examination of classic manifestation and genetic test. It's treatment is multidisciplinary and focused on each alteration it presents, as there is no definitive treatment. This clinical case study is of a pregnant patient with a family history and a genetic diagnosis of the Conradi syndrome. The preliminary diagnosis was performed by doing a pre-natal ultrasound showing skeletal alterations characteristic of this syndrome, later on this diagnostic were confirmed when the child was born and a physical examination was performed as well as. With this clinical case, we can conclude that the ultrasound is reliable to suspect the pre-natal diagnosis in those patients with a history of the disease and to be able to investigate the different manifestation of this pathology.

Germline mosaicism is a pitfall in PGD for X-linked disorders. Single sperm typing detects very low frequency paternal gonadal mosaicism in a case of recurrent chondrodysplasia punctata misattributed to a maternal origin

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.

Severe X-linked chondrodysplasia punctata in nine new female fetuses.

Conradi-Hünermann-Happle [X-linked dominant chondrodysplasia punctata 2 (CDPX2)] syndrome is a rare X-linked dominant skeletal dysplasia usually lethal in men while affected women show wide clinical heterogeneity. Different EBP mutations have been reported. Severe female cases have rarely been reported, with only six antenatal presentations. To better characterize the phenotype in female fetuses, we included nine antenatally diagnosed cases of women with EBP mutations. All cases were de novo except for two fetuses with an affected mother and one case of germinal mosaicism. The mean age at diagnosis was 22 weeks of gestation. The ultrasound features mainly included bone abnormalities: shortening (8/9 cases) and bowing of the long bones (5/9), punctuate epiphysis (7/9) and an irregular aspect of the spine (5/9). Postnatal X-rays and examination showed ichthyosis (8/9) and epiphyseal stippling (9/9), with frequent asymmetric short and bowed long bones. The X-inactivation pattern of the familial case revealed skewed X-inactivation in the mildly symptomatic mother and random X-inactivation in the severe fetal case. Differently affected skin samples of the same fetus revealed different patterns of X-inactivation. Prenatal 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.

Growth arrest in the ribosomopathy, Bowen–Conradi syndrome, is due to dramatically reduced cell proliferation and a defect in mitotic progression

Bowen–Conradi syndrome (BCS) is a ribosomopathy characterized by severe developmental delay and growth failure that typically leads to death by one year of age. It is caused by a c.257A>G, p.D86G substitution in the ribosomal biogenesis protein, Essential for Mitotic Growth 1 (EMG1). We generated a knock-in of the D86G substitution in mice to characterize the effects of EMG1 deficiency, particularly in the brain, where EMG1 expression is high. Embryos homozygous for the mutation in Emg1 were small for gestational age with neural tube defects, and died between embryonic days 8.5 and 12.5. These embryos exhibited dramatically reduced cell proliferation, which we also detected in autopsy brain tissue and bone marrow of BCS patients, consistent with a requirement for high levels of EMG1 in tissues with rapid cell proliferation. In fibroblasts derived from the BCS mouse embryos, we detected a high proportion of binucleated cells, indicating that a mitotic defect underlies the growth arrest in BCS. These studies add to growing evidence of a link between ribosome biogenesis, mitotic progression, and brain development that is currently unexplored.

Radiographic features of the skeleton in disorders of post-squalene cholesterol biosynthesis.

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.

Emopamil binding protein mutation in conradi-hünermann-happle syndrome representing plaque-type psoriasis.

Conradi-Hünermann-Happle syndrome (CDPX2, OMIM 302960) is an inherited X-linked dominant variant of chondrodysplasia punctata which primarily affects the skin, bones, and eyes. CDPX2 patients display skin defects, including ichthyotic lesions, follicular atrophoderma, cicatricial alopecia, and less frequently ichthyosiform erythroderma, cataracts, and skeletal abnormalities consisting of short stature, asymmetric shortening of the limbs, epiphyseal stippling, and craniofacial defects. CDPX2 results from mutations in emopamil binding protein (EBP) gene. The aim of our study is to identify EBP mutation in a unique case of Conradi-Hünermann-Happle syndrome with rare psoriasiform lesions.