Triple-A Syndrome (TAS): An In-Depth Overview on Genetic and Phenotype Heterogeneity

Pogliaghi, Gabriele; Cangiano, Biagio; Duminuco, Paolo; Vezzoli, Valeria; Bonomi, Marco

doi:10.2174/0929866527666200613215449

Cited by 7 publications

(2 citation statements)

References 131 publications

(138 reference statements)

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“…Interestingly, despite having the same variant (AAAS: c.1331+1G>A), North African Triple-A patients manifested phenotypic variability of the disease, suggesting a lack of genotype-phenotype correlation [Kallabi et al 2016a[Kallabi et al , 2016bBenabdallah et al, 2014;Berrani et al, 2018;Alakeel et al, 2015]. In fact, in the current literature, the high phenotypic heterogeneity even among members of the same family is rather well known for Triple-A [Barat et al, 2004;Brooks et al, 2005;Singh et al, 2018;Pogliaghi et al, 2020].…”

Section: Discussionmentioning

confidence: 91%

Triple-A Syndrome in Morocco: Founder Effect, Age Estimation of the AAAS c.1331+1G>A Variant, and Implications for Genetic Diagnosis

Belmokhtar,

Cherkaoui,

Lhousni

et al. 2023

Mol Syndromol

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Introduction: Triple-A syndrome (Triple-A) is an autosomal recessive disorder characterized by alacrimia, achalasia, and adrenal insufficiency. Several variants on the AAAS gene have been described, and some variants are clustered in particular geographical areas, such as the c.1331+1G>A variant which is very frequent in North Africa. Here, we describe the genetic features of Triple-A in a series of unrelated families from Morocco. Methods: Screening for the AAAS c.1331+1G>A variant was performed by direct sequencing or by PCR-RFLP. Haplotype analysis using Single Tandem Repeat (STR) markers flanking AAAS gene was performed in order to evaluate the founder effect and estimate the age of the c.1331+1G>A variant. Results: Seven unrelated families with ten individuals clinically diagnosed with Triple-A were evaluated for sequence variations in the AAAS gene. The median age at diagnosis was 3 years, with a range between 2 and 11 years. Molecular analysis revealed that all patients were homozygous for the c.1331+1G>A variant. This variant was not found in 200 healthy controls, indicating that carriers are very rare in the general Moroccan population. Subsequently, STR marker analysis revealed a founder effect and that the most recent common ancestor of Triple-A patients in Morocco would have lived 125 years ago. Conclusion: This is the largest series of Triple-A in Morocco. The same AAAS c.1331+1G>A variant was found in all patients, suggesting a founder effect in Morocco which was subsequently confirmed by microsatellite marker analysis. Therefore, this variant should be systematically investigated to diagnose Triple-A in Morocco.

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Section: Discussionmentioning

confidence: 91%

Triple-A Syndrome in Morocco: Founder Effect, Age Estimation of the AAAS c.1331+1G>A Variant, and Implications for Genetic Diagnosis

Belmokhtar,

Cherkaoui,

Lhousni

et al. 2023

Mol Syndromol

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“…Triple-A syndrome (also named Allgrove syndrome), another autosomal recessive disorder involving primary adrenal insufficiency (due to an ACTH resistant status), is a very rare condition with underlying mutations of the AAA (or AAAS) gene on chromosome 12q13 in 90% of cases; it also includes alacrimia (defects of tear formation) and (esophageal) achalasia, which induces difficulties of swelling, dry mouth, and vomiting due to esophagitis with potential dental damage [ 157 , 158 , 159 , 160 ]. Tadini et al reported a case of triple-A syndrome associated with peculiar dental anomalies [ 161 ].…”

Section: Methodsmentioning

confidence: 99%

New Approach to Addison Disease: Oral Manifestations Due to Endocrine Dysfunction and Comorbidity Burden

et al. 2022

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This review highlights oral anomalies with major clinical impact in Addison disease (AD), including dental health and dermatologic features, through a dual perspective: pigmentation issues and AD comorbidities with oral manifestations. Affecting 92% of AD patients, cutaneomucosal hyperpigmentation is synchronous with or precedes general manifestations by up to a decade, underlying melanocytic infiltration of the basal epidermal layer; melanophages in the superficial dermis; and, rarely, acanthosis, perivascular lymphocytic infiltrate, and hyperkeratosis. Intraoral pigmentation might be the only sign of AD; thus, early recognition is mandatory, and biopsy is helpful in selected cases. The buccal area is the most affected location; other sites are palatine arches, lips, gums, and tongue. Pigmented oral lesions are patchy or diffuse; mostly asymptomatic; and occasionally accompanied by pain, itchiness, and burn-like lesions. Pigmented lingual patches are isolated or multiple, located on dorsal and lateral areas; fungiform pigmented papillae are also reported in AD individuals. Dermoscopy examination is particularly indicated for fungal etiology; yet, it is not routinely performed. AD’s comorbidity burden includes the cluster of autoimmune polyglandular syndrome (APS) type 1 underlying AIRE gene malfunction. Chronic cutaneomucosal candidiasis (CMC), including oral CMC, represents the first sign of APS1 in 70–80% of cases, displaying autoantibodies against interleukin (IL)-17A, IL-17F ± IL-22, and probably a high mucosal concentration of interferon (IFN)-γ. CMC is prone to systemic candidiasis, representing a procarcinogenic status due to Th17 cell anomalies. In APS1, the first cause of mortality is infections (24%), followed by oral and esophageal cancers (15%). Autoimmune hypoparathyroidism (HyP) is the earliest endocrine element in APS1; a combination of CMC by the age of 5 years and dental enamel hypoplasia (the most frequent dental complication of pediatric HyP) by the age of 15 is an indication for HyP assessment. Children with HyP might experience short dental roots, enamel opacities, hypodontia, and eruption dysfunctions. Copresence of APS-related type 1 diabetes mellitus (DM) enhances the risk of CMC, as well as periodontal disease (PD). Anemia-related mucosal pallor is related to DM, hypothyroidism, hypogonadism, corresponding gastroenterological diseases (Crohn’s disease also presents oral ulceration (OU), mucogingivitis, and a 2-3 times higher risk of PD; Biermer anemia might cause hyperpigmentation by itself), and rheumatologic diseases (lupus induces OU, honeycomb plaques, keratotic plaques, angular cheilitis, buccal petechial lesions, and PD). In more than half of the patients, associated vitiligo involves depigmentation of oral mucosa at different levels (palatal, gingival, alveolar, buccal mucosa, and lips). Celiac disease may manifest xerostomia, dry lips, OU, sialadenitis, recurrent aphthous stomatitis and dental enamel defects in children, a higher prevalence of caries and dentin sensitivity, and gingival bleeding. Oral pigmented lesions might provide a useful index of suspicion for AD in apparently healthy individuals, and thus an adrenocorticotropic hormone (ACTH) stimulation is useful. The spectrum of autoimmune AD comorbidities massively complicates the overall picture of oral manifestations.

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Rare forms of genetic paediatric adrenal insufficiency: Excluding congenital adrenal hyperplasia

Hasenmajer

Ferrigno

Minnetti

et al. 2023

Rev Endocr Metab Disord

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Adrenal insufficiency (AI) is a severe endocrine disorder characterized by insufficient glucocorticoid (GC) and/or mineralocorticoid (MC) secretion by the adrenal glands, due to impaired adrenal function (primary adrenal insufficiency, PAI) or to insufficient adrenal stimulation by pituitary ACTH (secondary adrenal insufficiency, SAI) or tertiary adrenal insufficiency due to hypothalamic dysfunction. In this review, we describe rare genetic causes of PAI with isolated GC or combined GC and MC deficiencies and we also describe rare syndromes of isolated MC deficiency. In children, the most frequent cause of PAI is congenital adrenal hyperplasia (CAH), a group of adrenal disorders related to steroidogenic enzyme deficiencies, which will not be included in this review. Less frequently, several rare diseases can cause PAI, either affecting exclusively the adrenal glands or with systemic involvement. The diagnosis of these diseases is often challenging, due to the heterogeneity of their clinical presentation and to their rarity. Therefore, the current review aims to provide an overview on these rare genetic forms of paediatric PAI, offering a review of genetic and clinical features and a summary of diagnostic and therapeutic approaches, promoting awareness among practitioners, and favoring early diagnosis and optimal clinical management in suspect cases.

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Triple-A Syndrome (TAS): An In-Depth Overview on Genetic and Phenotype Heterogeneity

Cited by 7 publications

References 131 publications

Triple-A Syndrome in Morocco: Founder Effect, Age Estimation of the <i>AAAS</i> c.1331+1G>A Variant, and Implications for Genetic Diagnosis

Triple-A Syndrome in Morocco: Founder Effect, Age Estimation of the <i>AAAS</i> c.1331+1G>A Variant, and Implications for Genetic Diagnosis

New Approach to Addison Disease: Oral Manifestations Due to Endocrine Dysfunction and Comorbidity Burden

Rare forms of genetic paediatric adrenal insufficiency: Excluding congenital adrenal hyperplasia

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Triple-A Syndrome (TAS): An In-Depth Overview on Genetic and Phenotype Heterogeneity

Cited by 7 publications

References 131 publications

Triple-A Syndrome in Morocco: Founder Effect, Age Estimation of the <i>AAAS</i> c.1331+1G&gt;A Variant, and Implications for Genetic Diagnosis

Triple-A Syndrome in Morocco: Founder Effect, Age Estimation of the <i>AAAS</i> c.1331+1G&gt;A Variant, and Implications for Genetic Diagnosis

New Approach to Addison Disease: Oral Manifestations Due to Endocrine Dysfunction and Comorbidity Burden

Rare forms of genetic paediatric adrenal insufficiency: Excluding congenital adrenal hyperplasia

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Product

Resources

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Triple-A Syndrome in Morocco: Founder Effect, Age Estimation of the <i>AAAS</i> c.1331+1G>A Variant, and Implications for Genetic Diagnosis

Triple-A Syndrome in Morocco: Founder Effect, Age Estimation of the <i>AAAS</i> c.1331+1G>A Variant, and Implications for Genetic Diagnosis