Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027960 (mole)
 21,279 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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 3beta-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 delta8-delta7 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.
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PMID:Mutations in the NSDHL gene, encoding a 3beta-hydroxysteroid dehydrogenase, cause CHILD syndrome. 1071 Feb 35

The CHILD syndrome (MIM 308050), an acronym for congenital hemidysplasia with ichthyosiform nevus and limb defects, is an X-linked dominant trait with lethality for male embryos. Recently, we elucidated the underlying gene defect by demonstrating point mutations in NSDHL (NAD[P]H steroid dehydrogenase-like protein) at Xq28 in 6 patients with classic CHILD syndrome. The most striking clinical feature is an inflammatory nevus that usually shows a unique lateralization with strict midline demarcation. Ipsilateral defects involve all skeletal structures and internal organs such as the brain, the lung, the heart, or the kidney. As an exception to this rule, in some cases the CHILD nevus may occur in a more or less bilateral distribution. In 1997 Fink-Puches et al described a case of CHILD nevus with an almost symmetric arrangement. To test the correctness of the diagnosis, we now examined blood lymphocytes of this patient by single-strand conformation analysis and genomic sequencing. We identified a novel missense mutation in NSDHL that potentially may impair protein function. We conclude that a diagnosis of CHILD syndrome can be based on clinical features such as the highly characteristic morphology of the CHILD nevus. A symmetric distribution of this nevus can exceptionally be seen in patients with CHILD syndrome, and this bilateral involvement should not mislead the clinician to any other diagnosis. Apparently, the effect of random X-inactivation is responsible for different patterns of cutaneous involvement in female carriers of NSDHL mutations.
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PMID:A novel missense mutation of NSDHL in an unusual case of CHILD syndrome showing bilateral, almost symmetric involvement. 1190 15

Mammalian enzymes in late cholesterol biosynthesis have been localized uniformly over the endoplasmic reticulum by enzymatic methods. We report here the first mammalian cholesterol biosynthetic enzyme unequivocally localized at the surface of intracellular lipid storage droplets. NAD(P)H steroid dehydrogenase-like protein (Nsdhl), a mammalian C-3 sterol dehydrogenase involved in the conversion of lanosterol into cholesterol, was localized on lipid droplets by immunofluorescence microscopy and subcellular fractionation. Nsdhl was localized on lipid droplets even when cell growth exclusively depended on cholesterol biosynthesis mediated by this enzyme. Depletion of fatty acids in culture medium reduced the development of lipid droplets and caused Nsdhl redistribution to the endoplasmic reticulum. Elevating oleic acid in medium induced well developed, Nsdhl-positive lipid droplets, and simultaneously caused a reduction in cellular conversion of lanosterol into cholesterol. Manipulated human NSDHL with a missense mutation (G205S) causing a human embryonic developmental disorder, congenital hemidysplasia with ichthyosiform nevus and limb defects (CHILD) syndrome, could no longer be localized on lipid droplets. Although the expression of wild-type NSDHL could restore the defective growth of a CHO cholesterol auxotroph, LEX2 in cholesterol-deficient medium, the expression of NSDHL(G205S) failed to do so. These results point to functional significance of the localization of Nsdhl on lipid droplets. Functional significance was also suggested by the colocalization of Nsdhl on lipid droplets with TIP47, a cargo selection protein for mannose 6-phosphate receptors from late endosomes to the trans-Golgi network. These results add to the growing notion that the lipid droplet is an organelle endowed with more complex roles in various biological phenomena.
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PMID:Localization of mammalian NAD(P)H steroid dehydrogenase-like protein on lipid droplets. 1283 64

Congenital hemidysplasia with ichthyosiform nevus and limb defects (CHILD) syndrome is a rare X-linked dominant malformation syndrome characterized by unilaterally distributed ichthyosiform nevi, often sharply delimited at the midline, and ipsilateral limb defects. At least two-thirds of cases demonstrate involvement of the right side. Mutations in an essential enzyme of cholesterol biosynthesis, NAD(P)H steroid dehydrogenase-like [NSDHL], have been reported in five unrelated patients with right-sided CHILD syndrome and in a sixth patient with bilaterally, symmetric nevi and mild skeletal anomalies, but not with CHILD syndrome as originally defined. Although all of the molecularly diagnosed cases with the CHILD phenotype to date have had right-sided disease, we report here a novel nonsense mutation (E151X) of NSDHL in an infant with left-sided CHILD syndrome. This result demonstrates that both right- and left-sided CHILD syndrome can be caused by mutations in the same gene.
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PMID:Left-sided CHILD syndrome caused by a nonsense mutation in the NSDHL gene. 1296 26

NSDHL, for NAD(P)H steroid dehydrogenase-like, encodes a sterol dehydrogenase or decarboxylase involved in the sequential removal of two C-4 methyl groups in post-squalene cholesterol biosynthesis. Mutations in this gene are associated with human CHILD syndrome (congenital hemidysplasia with ichthyosiform nevus and limb defects), an X-linked, male lethal disorder, as well as the mouse mutations bare patches and striated. In the present study, we have investigated the subcellular localization of tagged proteins encoded by wild-type and selected mutant murine Nsdhl alleles using confocal microscopy. In addition to an ER localization commonly found for enzymes of post-squalene cholesterol biosynthesis, we have identified a novel association of NSDHL with lipid droplets, which are endoplasmic reticulum (ER)-derived cytoplasmic structures that contain a neutral lipid core. We further demonstrate that trafficking through the Golgi is necessary for ER membrane localization of the protein and propose a model for the association of NSDHL with lipid droplets. The dual localization of NSDHL within ER membranes and on the surface of lipid droplets may provide another mechanism for regulation of the levels and sites of accumulation of intracellular cholesterol.
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PMID:NSDHL, an enzyme involved in cholesterol biosynthesis, traffics through the Golgi and accumulates on ER membranes and on the surface of lipid droplets. 1450 30

The CHILD syndrome is an acronymic designation for congenital hemidysplasia with ichthyosiform nevus and limb defects. This X-linked dominant, male-lethal trait is caused by mutations in the gene NSDHL that is localized at Xq28 and involved in cholesterol metabolism. The CHILD nevus that constitutes a hallmark of this multisystem birth defect usually shows a striking lateralization pattern. Until now, a report of Zellweger and Uehlinger from 1948 was believed to represent the first published case of CHILD syndrome. However, we have now found an earlier report published in 1903 by Otto Sachs. An 8-year-old girl had a "xanthoma-like nevus" involving the right axillary region and a congenital muscular weakness of the right upper arm. Sachs described the clinical and histopathological features of CHILD nevus comprehensively, including the characteristic changes of verruciform xanthoma that can be taken within the group of epidermal nevi as a pathognomonic feature of CHILD nevus. This report is the earliest description of CHILD syndrome known so far. Moreover, Sachs presented in this article a comprehensive description of verruciform xanthoma, thus anticipating Shafer's "first report" of this histopathological phenomenon (1971) by almost 70 years.
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PMID:CHILD syndrome avant la lettre. 1472 63

The X-linked dominant CHILD syndrome (congenital hemidysplasia with ichthyosiform nevus and limb defects) is a rare developmental defect characterized by a strictly lateralized inflammatory nevus. In the majority of cases, the right side of the body is affected. Ipsilateral hypoplastic lesions may involve the brain, skeletal structures, lungs, heart or kidneys. We describe a case of CHILD syndrome involving the left side of the body. Absence of metacarpal, metatarsal and phalangeal bones of the left hand and foot resulted in oligodactyly, with only 3 fingers and 1 toe. An ipsilateral inflammatory epidermal nevus with hyperkeratosis, parakeratosis, acanthosis and perivascular lymphohistiocytic infiltrate was strictly confined to the left half of the patient's body. The phenotype was shown to be associated with a deletion of exons 6-8 of the X-linked NSDHL gene, confirming that CHILD syndrome is due to loss of function of an enzyme involved in cholesterol biosynthesis.
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PMID:CHILD syndrome caused by a deletion of exons 6-8 of the NSDHL gene. 1608 65

CHILD syndrome is an acronym for Congenital Hemidysplasia with Ichthyosiform nevus and Limb Defects. This is an X-linked dominant disorder affecting females with early lethality in hemizygous males. The clinical features are congenital hemidysplasia with ichthyosiform erythroderma and ipsilateral hypoplasia of limbs and other parts of the skeleton as well as defects of the brain, heart, kidney and lung. CHILD syndrome is caused by mutations in the NSDHL (steroid dehydrogenase-like protein) gene at Xq28, which affects cholesterol biosynthesis. A female premature newborn with left side body hemidysplasia and ipsilateral defects of the skin, visceral organs and brain is reported. Analysis of child DNA isolated from skin fibroblasts showed missense mutation c.1046A>G;PpY349C in the NSDHL gene that could cause the phenotype.
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PMID:Brain and cerebellar hemidysplasia in a case with ipsilateral body dysplasia and suspicion of CHILD syndrome. 1882 99

CHILD syndrome is an acronym signifying congenital hemidysplasia with ichthyosiform nevus and limb defects. A 27-year-old woman presented with chronic verrucous and hyperkeratotic skin lesions involving the left genital area, left hand and left foot since childhood. The histopathologic findings were consistent with verruciform xanthoma. In correlation with the clinical picture of a linear lesion, the diagnosis of CHILD nevus was made. Subsequent genetic analysis identified a germline c.324C>T (p.A105V) NSDHL mutation and confirmed a diagnosis of CHILD syndrome. This syndrome can be associated with only minimal clinical symptoms. The anatomical distribution of the lesions, a static clinical course and the typical histopathologic features of a CHILD nevus can serve as the clue to a diagnosis of CHILD syndrome in such cases.
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PMID:CHILD syndrome with mild skin lesions: histopathologic clues for the diagnosis. 2509 65

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.
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PMID:Male CDPX2 patient with EBP mosaicism and asymmetrically lateralized skin lesions with strict midline demarcation. 3103 46


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