Rothmund–Thomson Syndrome with Myelodysplasia

Narayan, Shyam; Fleming, Colin; Trainer, Alison H.; Craig, John A.

doi:10.1046/j.1525-1470.2001.018003210.x

Cited by 33 publications

(23 citation statements)

References 16 publications

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“…Dental defects are common in our cases, in agreement with the literature [4,13,26,33]. Hypogonadism was identified in male patients #17a and #26 and previously reported [3,34].…”

Section: Discussionsupporting

confidence: 92%

“…Indeed, apart from our patients #17a and the infant #25, all herein described PN patients display overt skeletal signs including zygodactyly between the second and third digit (#26), multiple bone fractures (#11), intermediate osteopetrosis (#21) or X-ray detectable skeletal findings (#16) (Table 1). A relationship may be envisaged between zygodactyly and the swan neck hand hyperflexibility noticed in a few described patients [3,5,33]. More generally delayed bone maturation has been recorded [32] in the girl subsequently confirmed to carry two distinct C16orf57 mutations [6], and diffuse osteosclerosis has been underlined by Porter [26] in the patient found to harbour C16orf57 mutations [10].…”

Section: Discussionmentioning

confidence: 99%

“…When considering bone marrow hypocellularity, increased myeloid precursors and delayed neutrophils maturation, a higher percentage of C16orf57 -positive cases displays this feature [4,5,10,11] highlighting the sensitivity of the myeloid lineage to C16orf57 mutations. Evolution to acute myeloid leukemia has been reported in a few PN patients [10,26] and in other untested cases [25,33-35]. This evidence features PN as a cancer predisposing syndrome affecting the myeloid compartment and connects PN to RTS, a syndrome with an increased risk for osteosarcoma and skin cancer [7], and DC which predisposes to a wide variety of haematological and solid tumors [36].…”

Section: Discussionmentioning

confidence: 99%

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Novel C16orf57 mutations in patients with Poikiloderma with Neutropenia: bioinformatic analysis of the protein and predicted effects of all reported mutations

Colombo

Bazán

Negri

et al. 2012

Orphanet J Rare Dis

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BackgroundPoikiloderma with Neutropenia (PN) is a rare autosomal recessive genodermatosis caused by C16orf57 mutations. To date 17 mutations have been identified in 31 PN patients.ResultsWe characterize six PN patients expanding the clinical phenotype of the syndrome and the mutational repertoire of the gene. We detect the two novel C16orf57 mutations, c.232C>T and c.265+2T>G, as well as the already reported c.179delC, c.531delA and c.693+1G>T mutations. cDNA analysis evidences the presence of aberrant transcripts, and bioinformatic prediction of C16orf57 protein structure gauges the mutations effects on the folded protein chain.Computational analysis of the C16orf57 protein shows two conserved H-X-S/T-X tetrapeptide motifs marking the active site of a two-fold pseudosymmetric structure recalling the 2H phosphoesterase superfamily. Based on this model C16orf57 is likely a 2H-active site enzyme functioning in RNA processing, as a presumptive RNA ligase.According to bioinformatic prediction, all known C16orf57 mutations, including the novel mutations herein described, impair the protein structure by either removing one or both tetrapeptide motifs or by destroying the symmetry of the native folding.Finally, we analyse the geographical distribution of the recurrent mutations that depicts clusters featuring a founder effect.ConclusionsIn cohorts of patients clinically affected by genodermatoses with overlapping symptoms, the molecular screening of C16orf57 gene seems the proper way to address the correct diagnosis of PN, enabling the syndrome-specific oncosurveillance.The bioinformatic prediction of the C16orf57 protein structure denotes a very basic enzymatic function consistent with a housekeeping function. Detection of aberrant transcripts, also in cells from PN patients carrying early truncated mutations, suggests they might be translatable. Tissue-specific sensitivity to the lack of functionally correct protein accounts for the main cutaneous and haematological clinical signs of PN patients.

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“…Dental defects are common in our cases, in agreement with the literature [4,13,26,33]. Hypogonadism was identified in male patients #17a and #26 and previously reported [3,34].…”

Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Novel C16orf57 mutations in patients with Poikiloderma with Neutropenia: bioinformatic analysis of the protein and predicted effects of all reported mutations

Colombo

Bazán

Negri

et al. 2012

Orphanet J Rare Dis

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“…Squamous cell carcinoma (SCC) is the most common epithelial tumour. As far as haematological tumours are concerned, myelodysplasia has been reported in three cases [36,38,39]. Tumours that have been described only once are also included in Fig.…”

Section: Clinical Descriptionmentioning

confidence: 99%

Rothmund-Thomson syndrome

Larizza

Roversi

Volpi

2010

Orphanet J Rare Dis

247

276

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Rothmund-Thomson syndrome (RTS) is a genodermatosis presenting with a characteristic facial rash (poikiloderma) associated with short stature, sparse scalp hair, sparse or absent eyelashes and/or eyebrows, juvenile cataracts, skeletal abnormalities, radial ray defects, premature aging and a predisposition to cancer. The prevalence is unknown but around 300 cases have been reported in the literature so far. The diagnostic hallmark is facial erythema, which spreads to the extremities but spares the trunk, and which manifests itself within the first year and then develops into poikiloderma. Two clinical subforms of RTS have been defined: RTSI characterised by poikiloderma, ectodermal dysplasia and juvenile cataracts, and RTSII characterised by poikiloderma, congenital bone defects and an increased risk of osteosarcoma in childhood and skin cancer later in life. The skeletal abnormalities may be overt (frontal bossing, saddle nose and congenital radial ray defects), and/or subtle (visible only by radiographic analysis). Gastrointestinal, respiratory and haematological signs have been reported in a few patients. RTS is transmitted in an autosomal recessive manner and is genetically heterogeneous: RTSII is caused by homozygous or compound heterozygous mutations in the RECQL4 helicase gene (detected in 60-65% of RTS patients), whereas the aetiology in RTSI remains unknown. Diagnosis is based on clinical findings (primarily on the age of onset, spreading and appearance of the poikiloderma) and molecular analysis for RECQL4 mutations. Missense mutations are rare, while frameshift, nonsense mutations and splice-site mutations prevail. A fully informative test requires transcript analysis not to overlook intronic deletions causing missplicing. The diagnosis of RTS should be considered in all patients with osteosarcoma, particularly if associated with skin changes. The differential diagnosis should include other causes of childhood poikiloderma (including dyskeratosis congenita, Kindler syndrome and Poikiloderma with Neutropaenia), other rare genodermatoses with prominent telangiectasias (including Bloom syndrome, Werner syndrome and Ataxia-telangiectasia) and the allelic disorders, RAPADILINO syndrome and Baller-Gerold syndrome, which also share some clinical features. A few mutations recur in all three RECQL4 diseases. Genetic counselling should be provided for RTS patients and their families, together with a recommendation for cancer surveillance for all patients with RTSII. Patients should be managed by a multidisciplinary team and offered long term follow-up. Treatment includes the use of pulsed dye laser photocoagulation to improve the telangiectatic component of the rash, surgical removal of the cataracts and standard treatment for individuals who develop cancer. Although some clinical signs suggest precocious aging, life expectancy is not impaired in RTS patients if they do not develop cancer. Outcomes in patients with osteosarcoma are similar in RTS and non-RTS patients, with a five-year survival rate of 60-70%. The...

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“…Hematopoietic abnormalities such as aplastic anemia and myelodysplastic syndrome have been described in RTS [Narayan et al, 2001; Rizzari et al, 1996; Knoell et al, 1999]. However, unlike RTS, patients with PN have significant neutropenia that is non-cyclical in pattern and leads to recurrent sinopulmonary infections.…”

Section: Introductionmentioning

confidence: 99%

Identification of a novel C16orf57 mutation in Athabaskan patients with Poikiloderma with Neutropenia

Clericuzio

Harutyunyan

Jin

et al. 2010

American J of Med Genetics Pt A

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Poikiloderma with Neutropenia (PN), Clericuzio‐Type (OMIM #604173) is characterized by poikiloderma, chronic neutropenia, recurrent sinopulmonary infections, bronchiectasis, and nail dystrophy. First described by Clericuzio in 1991 in 14 patients of Navajo descent, it has since also been described in non‐Navajo patients. C16orf57 has recently been identified as a causative gene in PN. The purpose of our study was to describe a spectrum of C16orf57 mutations in a cohort of PN patients including five patients of Athabaskan (Navajo and Apache) ancestry. Eleven patients from eight kindreds were enrolled in an IRB‐approved study at Baylor College of Medicine. Five patients were of Athabaskan ancestry. PCR amplification and sequencing of the entire coding region of the C16orf57 gene was performed on genomic DNA. We identified biallelic C16orf57 mutations in all 11 PN patients in our cohort. The seven new deleterious mutations consisted of deletion (2), nonsense (3), and splice site (2) mutations. The patients of Athabaskan ancestry all had a common deletion mutation (c.496delA) which was not found in the six non‐Athabaskan patients. Mutations in the C16orf57 gene have been identified thus far in all patients studied with a clinical diagnosis of PN. We have identified seven new mutations in C16orf57 in PN patients. One of these is present in all patients of Athabaskan descent, suggesting that c.496delA represents the PN‐causative mutation in this subpopulation. © 2010 Wiley‐Liss, Inc.

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Rothmund–Thomson Syndrome with Myelodysplasia

Cited by 33 publications

References 16 publications

Novel C16orf57 mutations in patients with Poikiloderma with Neutropenia: bioinformatic analysis of the protein and predicted effects of all reported mutations

Novel C16orf57 mutations in patients with Poikiloderma with Neutropenia: bioinformatic analysis of the protein and predicted effects of all reported mutations

Rothmund-Thomson syndrome

Identification of a novel C16orf57 mutation in Athabaskan patients with Poikiloderma with Neutropenia

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