Rothmund–Thomson syndrome type 1 caused by biallelic ANAPC1 gene mutations

ObjectiveAutoimmune polyglandular syndrome type 1 (APS-1) is characterised by multiple autoimmune diseases. Detection of autoimmune regulator (AIRE) gene mutations facilitates timely and precise diagnosis.DesignAIRE mutation detection was performed in a cohort of 11 patients. Two did not meet clinical APS-1 criteria and several started with atypical presentation.MethodsSequencing and TaqMan genotyping were used to identify AIRE mutations. Complete AIRE deletion was confirmed and framed by real-time PCR, long-range amplification and analysis of the microsatellite markers.ResultsSeven different mutations were detected, three were novel: c.892G>A in exon 8, silent mutation c.462A>T in exon 3 most likely affecting splicing, and a complete deletion of a single AIRE allele ((?_68)_(1567-14_?)del). Novel (chronic otitis) and rare (systemic juvenile rheumatoid arthritis, autoimmune bronchiolitis, epilepsy) clinical presentations were observed.ConclusionsAIRE mutation detection was valuable in the diagnostics of APS-1 in patients with atypical presentation. Chronic otitis media possibly broadened the cluster of APS-1 manifestations.

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Autoimmune polyendocrine syndrome type 1: an Italian survey on 158 patients

Journal of Endocrinological Investigation ◽

10.1007/s40618-021-01585-6 ◽

2021 ◽

Author(s):

S. Garelli ◽

M. Dalla Costa ◽

C. Sabbadin ◽

S. Barollo ◽

B. Rubin ◽

...

Keyword(s):

Gene Mutations ◽

Premature Menopause ◽

Chronic Mucocutaneous Candidiasis ◽

Syndrome Type ◽

Inherited Disease ◽

Autoimmune Thyroid Diseases ◽

Autoimmune Polyendocrine Syndrome ◽

Autoimmune Conditions

Abstract Background Autoimmune Polyglandular Syndrome type 1 (APS-1) is a rare recessive inherited disease, caused by AutoImmune Regulator (AIRE) gene mutations and characterized by three major manifestations: chronic mucocutaneous candidiasis (CMC), chronic hypoparathyroidism (CH) and Addison’s disease (AD). Methods Autoimmune conditions and associated autoantibodies (Abs) were analyzed in 158 Italian patients (103 females and 55 males; F/M 1.9/1) at the onset and during a follow-up of 23.7 ± 15.1 years. AIRE mutations were determined. Results The prevalence of APS-1 was 2.6 cases/million (range 0.5–17 in different regions). At the onset 93% of patients presented with one or more components of the classical triad and 7% with other components. At the end of follow-up, 86.1% had CH, 77.2% AD, 74.7% CMC, 49.5% premature menopause, 29.7% autoimmune intestinal dysfunction, 27.8% autoimmune thyroid diseases, 25.9% autoimmune gastritis/pernicious anemia, 25.3% ectodermal dystrophy, 24% alopecia, 21.5% autoimmune hepatitis, 17% vitiligo, 13.3% cholelithiasis, 5.7% connective diseases, 4.4% asplenia, 2.5% celiac disease and 13.9% cancer. Overall, 991 diseases (6.3 diseases/patient) were found. Interferon-ω Abs (IFNωAbs) were positive in 91.1% of patients. Overall mortality was 14.6%. The AIRE mutation R139X was found in 21.3% of tested alleles, R257X in 11.8%, W78R in 11.4%, C322fsX372 in 8.8%, T16M in 6.2%, R203X in 4%, and A21V in 2.9%. Less frequent mutations were present in 12.9%, very rare in 9.6% while no mutations in 11% of the cases. Conclusions In Italy, APS-1 is a rare disorder presenting with the three major manifestations and associated with different AIRE gene mutations. IFNωAbs are markers of APS-1 and other organ-specific autoantibodies are markers of clinical, subclinical or potential autoimmune conditions.

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Mutations in ANAPC1, Encoding a Scaffold Subunit of the Anaphase-Promoting Complex, Cause Rothmund-Thomson Syndrome Type 1

The American Journal of Human Genetics ◽

10.1016/j.ajhg.2019.06.011 ◽

2019 ◽

Vol 105 (3) ◽

pp. 625-630 ◽

Cited By ~ 5

Author(s):

Norbert F. Ajeawung ◽

Thi Tuyet Mai Nguyen ◽

Linchao Lu ◽

Thomas J. Kucharski ◽

Justine Rousseau ◽

...

Keyword(s):

Syndrome Type ◽

Anaphase Promoting Complex ◽

Rothmund Thomson Syndrome

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Autoimmune polyendocrine syndrome type 1 in an Indian cohort: a longitudinal study

Endocrine Connections ◽

10.1530/ec-17-0022 ◽

2017 ◽

Vol 6 (5) ◽

pp. 289-296 ◽

Cited By ~ 8

Author(s):

Ghazala Zaidi ◽

Vijayalakshmi Bhatia ◽

Saroj K Sahoo ◽

Aditya Narayan Sarangi ◽

Niharika Bharti ◽

...

Keyword(s):

Clinical Features ◽

Genetic Heterogeneity ◽

Clinical Manifestations ◽

Gene Mutations ◽

Young Age ◽

Clinical Aspects ◽

Syndrome Type ◽

Autoimmune Polyendocrine Syndrome ◽

Organ Specific

Objective Autoimmune polyendocrine syndrome type 1 (APS1) is a rare autosomal recessive disorder characterized by progressive organ-specific autoimmunity. There is scant information on APS1 in ethnic groups other than European Caucasians. We studied clinical aspects and autoimmune regulator (AIRE) gene mutations in a cohort of Indian APS1 patients. Design Twenty-three patients (19 families) from six referral centres in India, diagnosed between 1996 and 2016, were followed for [median (range)] 4 (0.2–19) years. Methods Clinical features, mortality, organ-specific autoantibodies and AIRE gene mutations were studied. Results Patients varied widely in their age of presentation [3.5 (0.1–17) years] and number of clinical manifestations [5 (2–11)]. Despite genetic heterogeneity, the frequencies of the major APS1 components (mucocutaneous candidiasis: 96%; hypoparathyroidism: 91%; primary adrenal insufficiency: 55%) were similar to reports in European series. In contrast, primary hypothyroidism (23%) occurred more frequently and at an early age, while kerato-conjunctivitis, urticarial rash and autoimmune hepatitis were uncommon (9% each). Six (26%) patients died at a young age [5.8 (3–23) years] due to septicaemia, hepatic failure and adrenal/hypocalcaemic crisis from non-compliance/unexplained cause. Interferon-α and/or interleukin-22 antibodies were elevated in all 19 patients tested, including an asymptomatic infant. Eleven AIRE mutations were detected, the most common being p.C322fsX372 (haplotype frequency 37%). Four mutations were novel, while six others were previously described in European Caucasians. Conclusions Indian APS1 patients exhibited considerable genetic heterogeneity and had highly variable clinical features. While the frequency of major manifestations was similar to that of European Caucasians, other features showed significant differences. A high mortality at a young age was observed.

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Distinct Clinical Phenotype and Immunoreactivity in Japanese Siblings with Autoimmune Polyglandular Syndrome Type 1 (APS-1) Associated with Compound Heterozygous Novel AIRE Gene Mutations

Clinical Immunology ◽

10.1006/clim.2002.5208 ◽

2002 ◽

Vol 103 (3) ◽

pp. 277-283 ◽

Cited By ~ 29

Author(s):

Kazuhiko Kogawa ◽

Jun Kudoh ◽

Seiho Nagafuchi ◽

Shouichi Ohga ◽

Hitoshi Katsuta ◽

...

Keyword(s):

Clinical Phenotype ◽

Gene Mutations ◽

Compound Heterozygous ◽

Syndrome Type ◽

Autoimmune Polyglandular Syndrome ◽

Aire Gene ◽

Autoimmune Polyglandular Syndrome Type

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Rothmund-Thomson syndrome type 1

10.32388/s2d3bq ◽

2020 ◽

Author(s):

Keyword(s):

Syndrome Type ◽

Rothmund Thomson Syndrome

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Malignant phenotype and two SDHD mutations in a family with paraganglioma syndrome type 1

Genetics Research ◽

10.1017/s0016672315000063 ◽

2015 ◽

Vol 97 ◽

Cited By ~ 3

Author(s):

FRANCIELE B. LEIDENZ ◽

LUCIANA BASTOS-RODRIGUES ◽

MARCELO OLIVEIRA ◽

MARCELO MAMEDE ◽

MARTA SARQUIS ◽

...

Keyword(s):

Locally Advanced ◽

Gene Mutations ◽

Germline Mutations ◽

Allelic Loss ◽

Syndrome Type ◽

Malignant Phenotype ◽

Exon 2 ◽

Bilateral Carotid ◽

Paraganglioma Syndrome

SummaryBackground: Paraganglioma syndrome type 1 (PGL1) is a rare autosomal dominant syndrome associated with multiple, overwhelmingly benign, pheochromocytomas and paragangliomas, attributed to SDHD gene mutations. Objective: Clinically and molecularly characterize a family with uncommon malignant phenotype of paragangliomas attributed to two seemingly pathogenic SDHD germline mutations. Materials & methods: The proband presented with large bilateral carotid body tumours and family history of cervical masses in his five siblings. All family members underwent clinical examination, imaging studies (18F-FDG PET/CT) and genotyping of relevant genes. The proband was diagnosed with locally advanced paraganglioma; his hypertensive, otherwise asymptomatic father, had locally advanced pheochromocytoma and his three siblings showed multiple head and neck masses, confirmed to be paragangliomas with local metastasis. All affected patients carried two germline mutations in the SDHD gene; a previously reported nonsense mutation in exon 1 (p.Trp5X) and a novel missense mutation in exon 2 (p.Pro53Leu), highly deleterious by in silico analysis. Allelic loss at the SDHD locus was not shown for any of the analysed tumours. Conclusions: This is a rare case of malignant PGL1 with seemingly double pathogenic mutations in the SDHD gene, highlighting the possibility that the presence of both mutations is associated with the more aggressive phenotype.

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Challenges in the Diagnostic Conceptualization of CRPS-1 (Formerly Conceptualized as RSD)

Guides Newsletter ◽

10.1001/amaguidesnewsletters.2006.marapr01 ◽

2006 ◽

Vol 11 (2) ◽

pp. 1-3, 9-12

Author(s):

Robert J. Barth ◽

Tom W. Bohr

Keyword(s):

Clinical Practice ◽

Complex Regional Pain Syndrome ◽

Somatoform Disorders ◽

International Association ◽

Pain Syndrome ◽

Somatoform Disorder ◽

Syndrome Type ◽

Previous Issue

Abstract From the previous issue, this article continues a discussion of the potentially confusing aspects of the diagnostic formulation for complex regional pain syndrome type 1 (CRPS-1) proposed by the International Association for the Study of Pain (IASP), the relevance of these issues for a proposed future protocol, and recommendations for clinical practice. IASP is working to resolve the contradictions in its approach to CRPS-1 diagnosis, but it continues to include the following criterion: “[c]ontinuing pain, which is disproportionate to any inciting event.” This language only perpetuates existing issues with current definitions, specifically the overlap between the IASP criteria for CRPS-1 and somatoform disorders, overlap with the guidelines for malingering, and self-contradiction with respect to the suggestion of injury-relatedness. The authors propose to overcome the last of these by revising the criterion: “[c]omplaints of pain in the absence of any identifiable injury that could credibly account for the complaints.” Similarly, the overlap with somatoform disorders could be reworded: “The possibility of a somatoform disorder has been thoroughly assessed, with the results of that assessment failing to produce any consistencies with a somatoform scenario.” The overlap with malingering could be addressed in this manner: “The possibility of malingering has been thoroughly assessed, with the results of that assessment failing to produce any consistencies with a malingering scenario.” The article concludes with six recommendations, and a sidebar discusses rating impairment for CRPS-1 (with explicit instructions not to use the pain chapter for this purpose).

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