Initial Cutaneous Manifestations of Hutchinson‐Gilford Progeria Syndrome

Rork, Jillian F.; Huang, Jennifer T.; Gordon, Leslie B.; Kleinman, Monica E.; Kieran, Mark W.; Liang, Marilyn G.

doi:10.1111/pde.12284

Cited by 37 publications

(27 citation statements)

References 23 publications

(35 reference statements)

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“…Compared with classic HGPS, she experienced hair loss but not the total alopecia pathognomonic of classic HGPS,11 mandibular recession that is less pronounced than classic HGPS12 and milder than expected joint contractures. Proband birth weight and length patterns were similar to classic HGPS 13.…”

Section: Resultsmentioning

confidence: 85%

A novel somatic mutation achieves partial rescue in a child with Hutchinson-Gilford progeria syndrome

et al. 2016

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BackgroundHutchinson-Gilford progeria syndrome (HGPS) is a fatal sporadic autosomal dominant premature ageing disease caused by single base mutations that optimise a cryptic splice site within exon 11 of the LMNA gene. The resultant disease-causing protein, progerin, acts as a dominant negative. Disease severity relies partly on progerin levels.Methods and resultsWe report a novel form of somatic mosaicism, where a child possessed two cell populations with different HGPS disease-producing mutations of the same nucleotide—one producing severe HGPS and one mild HGPS. The proband possessed an intermediate phenotype. The mosaicism was initially discovered when Sanger sequencing showed a c.1968+2T>A mutation in blood DNA and a c.1968+2T>C in DNA from cultured fibroblasts. Deep sequencing of DNA from the proband's blood revealed 4.7% c.1968+2T>C mutation, and 41.3% c.1968+2T>A mutation.ConclusionsWe hypothesise that the germline mutation was c.1968+2T>A, but a rescue event occurred during early development, where the somatic mutation from A to C at 1968+2 provided a selective advantage. This type of mosaicism where a partial phenotypic rescue event results from a second but milder disease-causing mutation in the same nucleotide has not been previously characterised for any disease.

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Section: Resultsmentioning

confidence: 85%

A novel somatic mutation achieves partial rescue in a child with Hutchinson-Gilford progeria syndrome

et al. 2016

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“…Patients begin to lose cranial hair around 10 months of age. However, with time, patients lose body hair and eyebrows and progress to almost complete alopecia (Rork, Huang et al 2014). HGPS patients also have distinctive craniofacial characteristics, developing micrognathia, prominent eyes, and a beaked nose (Kieran, Gordon et al 2007, Domingo, Trujillo et al 2009).…”

Section: Pathophysiology Of Hgpsmentioning

confidence: 99%

“…HGPS patients also have distinctive craniofacial characteristics, developing micrognathia, prominent eyes, and a beaked nose (Kieran, Gordon et al 2007, Domingo, Trujillo et al 2009). Prominent forehead scalp veins and perioral cyanosis become evident, both likely the result of decreased subcutaneous fat (Rork, Huang et al 2014). Patients also have multiple dental abnormalities, including both lack of teeth as well as dental crowding, which can manifest as double rows of teeth (Gordon, McCarten et al 2007, Domingo, Trujillo et al 2009).…”

Section: Pathophysiology Of Hgpsmentioning

confidence: 99%

“…Though manifestations can present with differing degrees of severity, typical alterations include areas of discoloration, stippled pigmentation, and tightened areas that restrict movement. Sclerodermoid changes, which give the skin a dimpled appearance with varying pigmentation, frequently appear over the abdomen and lower extremities (Rork, Huang et al 2014). …”

Section: Pathophysiology Of Hgpsmentioning

confidence: 99%

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Hutchinson-Gilford Progeria Syndrome: A premature aging disease caused by LMNA gene mutations

Gonzalo

Kreienkamp

Askjaer

2017

Ageing Research Reviews

217

210

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Products of the LMNA gene, primarily lamin A and C, are key components of the nuclear lamina, a proteinaceous meshwork that underlies the inner nuclear membrane and is essential for proper nuclear architecture. Alterations in lamin A and C that disrupt the integrity of the nuclear lamina affect a whole repertoire of nuclear functions, causing cellular decline. In humans, hundreds of mutations in the LMNA gene have been identified and correlated with over a dozen degenerative disorders, referred to as laminopathies. These diseases include neuropathies, muscular dystrophies, lipodystrophies, and premature aging diseases. This review focuses on one of the most severe laminopathies, Hutchinson-Gilford Progeria Syndrome (HGPS), which is caused by aberrant splicing of the LMNA gene and expression of a mutant product called progerin. Here, we discuss current views about the molecular mechanisms that contribute to the pathophysiology of this devastating disease, as well as the strategies being tested in vitro and in vivo to counteract progerin toxicity. In particular, progerin accumulation elicits nuclear morphological abnormalities, misregulated gene expression, defects in DNA repair, telomere shortening, and genomic instability, all of which limit cellular proliferative capacity. In patients harboring this mutation, a severe premature aging disease develops during childhood. Interestingly, progerin is also produced in senescent cells and cells from old individuals, suggesting that progerin accumulation might be a factor in physiological aging. Deciphering the molecular mechanisms whereby progerin expression leads to HGPS is an emergent area of research, which could bring us closer to understanding the pathology of aging.

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“…Diffuse tightness of the skin rather than nodular or pearly papular lesions, lack of gingival hypertrophy, and histopathologic absence of dermal eosinophilic hyaline deposits excluded juvenile hyaline fibromatosis in our patient. Progeria is a uniformly fatal premature aging disease with dermatologic features including sclerodermoid change, prominent superficial veins, circumoral cyanosis, dyspigmentation, and alopecia . Sclerodermoid lesions are commonly located over the abdomen and bilateral lower extremities and described as tight, indurated outpouchings or dimpling of the skin.…”

Section: Discussionmentioning

confidence: 99%