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Angela Huebner - One of the best experts on this subject based on the ideXlab platform.
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“Crying without tears” as an early diagnostic sign-post of triple A (Allgrove) Syndrome: two case reports
BMC Pediatrics, 2018Co-Authors: Daniel Tibussek, Angela Huebner, Sujal Ghosh, Joerg Schaper, Ertan Mayatepek, Katrin KoehlerAbstract:Background Triple A Syndrome (or Allgrove Syndrome) is a rare autosomal recessive disorder characterized by alacrima, achalasia, adrenal insufficiency and autonomic/neurological abnormalities. The majority of cases are caused by mutations in the AAAS gene located on chromosome 12q13. However, the clinical picture as well as genetic testing may be complex since symptomatology is variable and mutations cannot be identified in all clinically diagnosed patients. We present two unrelated patients with triple-A Syndrome illustrating the importance of alacrima as an early clinical sign. Case presentation A 3.5 year old girl presented with repeated hypoglycaemic myoclonic events. Adrenal insufficiency was diagnosed. In addition, alacrima, obvious since early infancy, was incidentally reported by the mother and finally lead to the clinical diagnosis of triple A Syndrome. This was confirmed by positive mutation analysis of the AAAS gene. The second patient, an 8 months old boy was presented because of anisocoria and unilateral optic atrophy. MRI revealed cerebellar vermis hypotrophy. Psychomotor retardation, failure to thrive, and frequent vomiting lead to further diagnostic work-up. Achalasia was diagnosed radiologically. In addition, the mother mentioned absence of tears since birth leading to the clinical diagnosis of triple A Syndrome. In contrast to the first cases genetic testing was negative. Conclusion These two patients illustrate the heterogeneity of triple A Syndrome in both terms, clinical expression and genetic testing. We particularly aim to stress the importance of alacrima, which should be considered as a red flag symptom. Further differential diagnosis is required in every child affected by alacrima.
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"Crying without tears" as an early diagnostic sign-post of triple A (Allgrove) Syndrome: two case reports.
BMC pediatrics, 2018Co-Authors: Daniel Tibussek, Angela Huebner, Sujal Ghosh, Joerg Schaper, Ertan Mayatepek, Katrin KoehlerAbstract:Triple A Syndrome (or Allgrove Syndrome) is a rare autosomal recessive disorder characterized by alacrima, achalasia, adrenal insufficiency and autonomic/neurological abnormalities. The majority of cases are caused by mutations in the AAAS gene located on chromosome 12q13. However, the clinical picture as well as genetic testing may be complex since symptomatology is variable and mutations cannot be identified in all clinically diagnosed patients. We present two unrelated patients with triple-A Syndrome illustrating the importance of alacrima as an early clinical sign. A 3.5 year old girl presented with repeated hypoglycaemic myoclonic events. Adrenal insufficiency was diagnosed. In addition, alacrima, obvious since early infancy, was incidentally reported by the mother and finally lead to the clinical diagnosis of triple A Syndrome. This was confirmed by positive mutation analysis of the AAAS gene. The second patient, an 8 months old boy was presented because of anisocoria and unilateral optic atrophy. MRI revealed cerebellar vermis hypotrophy. Psychomotor retardation, failure to thrive, and frequent vomiting lead to further diagnostic work-up. Achalasia was diagnosed radiologically. In addition, the mother mentioned absence of tears since birth leading to the clinical diagnosis of triple A Syndrome. In contrast to the first cases genetic testing was negative. These two patients illustrate the heterogeneity of triple A Syndrome in both terms, clinical expression and genetic testing. We particularly aim to stress the importance of alacrima, which should be considered as a red flag symptom. Further differential diagnosis is required in every child affected by alacrima.
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Novel Mutations in a Patient with Triple A Syndrome.
Indian pediatrics, 2015Co-Authors: Jyoti Sanghvi, Ajit Anand Asati, Ravindra Kumar, Angela HuebnerAbstract:Background Triple A Syndrome (Allgrove Syndrome), a rare autosomal recessive disorder, is characterized by adrenal insufficiency, achalasia cardia and alacrimia. It is caused by mutations in AAAS gene which encodes a protein called ALADIN.
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Novel mutations in a patient with triple a Syndrome
Indian Pediatrics, 2015Co-Authors: Jyoti Sanghvi, Ajit Anand Asati, Ravindra Kumar, Angela HuebnerAbstract:Background Triple A Syndrome (Allgrove Syndrome), a rare autosomal recessive disorder, is characterized by adrenal insufficiency, achalasia cardia and alacrimia. It is caused by mutations in AAAS gene which encodes a protein called ALADIN. Case characteristics 8-year-old boy who presented with hypoglycemic seizures, dysphagia, dry eyes and hyperpigmentation. Investigations confirmed achalasia cardia and adrenal insufficiency. Sequencing of AAAS gene revealed two novel mutations in compound heterozygous state (c.1101delG/ c.1310_1311delCT). Outcome Patient was managed with hydrocortisone and artificial tears. Message Sequencing analysis should be done to confirm the diagnosis of clinically suspected Triple A Syndrome.
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Triple A (Allgrove) Syndrome: an unusual association with syringomyelia
Italian journal of pediatrics, 2013Co-Authors: Carla Bizzarri, Danila Benevento, Cesare Terzi, Angela Huebner, Marco CappaAbstract:Triple A (Allgrove) Syndrome was first described by Allgrove in 1978 in two pairs of siblings. Since then, about 100 cases have been reported, all of them displaying an autosomal recessive pattern of inheritance. Clinical picture is characterized by achalasia, alacrimia and ACTH-resistant adrenal failure. A progressive neurological Syndrome including central, peripheral and autonomic nervous system impairment, and mild mental retardation is often associated. The triple A Syndrome gene, designated AAAS, is localized on chromosome 12q13. It consists of 16 exons, encoding for a 546 aminoacid protein called ALADIN (Alacrimia-Achalasia-aDrenal Insufficiency Neurologic disorder).
Fakhri Kallabi - One of the best experts on this subject based on the ideXlab platform.
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Splicing Defects in the AAAS Gene Leading to both Exon Skipping and Partial Intron Retention in a Tunisian Patient with Allgrove Syndrome
Hormone research in paediatrics, 2016Co-Authors: Fakhri Kallabi, Rahma Felhi, Leila Keskes, Bochra Ben Rhouma, Siwar Gargouri Baklouti, Rania Ghorbel, Hassen KamounAbstract:Background/Aims: Allgrove Syndrome is a rare autosomal recessive disorder characterized by the triad of adrenal insufficiency, achalasia, and alacrima. This Syndrome is caused by mutations in the AAAS gene. A major splice site mutation c.1331+1G>A was found previously in North African families affected by Allgrove Syndrome. In this study, we analyzed in vivo and in silico the effect of this mutation on the splicing process. Methods: Using reverse transcriptase-polymerase chain reaction, sequencing and bioinformatics tools, we analyzed all transcripts produced by the AAAS gene containing this splice site mutation. Results: The altered splicing of mRNA produces two aberrant transcripts: one with exon 14 skipping, the other with concurrent exon 14 skipping and retention of 99 bp of intron 14, both outcomes resulting in frameshifts with a new stop codon generation in the untranslated region of the last exon. Using in silico bioinformatics tools, we demonstrated that this mutation abolishes the splice donor site of exon 14 and activates a new intronic cryptic splice site in intron 14. Conclusion: This study demonstrated that a single splicing mutation affects the AAAS transcripts and consequently the ALADIN protein structure and function.
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Clinical and Genetic Characterization of 26 Tunisian Patients with Allgrove Syndrome.
Archives of medical research, 2016Co-Authors: Fakhri Kallabi, Neila Belghuith, Hajer Aloulou, Thouraya Kammoun, Soufiane Ghorbel, Mouna Hajji, Syrine Gallas, Jaleleddine Chemli, Imen Chabchoub, Hatem AzzouzAbstract:Background and Aims Allgrove Syndrome is characterized by achalasia, alacrima, and adrenal insufficiency as well as being associated with progressive neurological signs. This is an autosomal recessive disorder due to mutations in the AAAS gene located on chromosome 12q13. The AAAS gene encodes a protein of 546 amino acids, ALADIN. Mutations in this genwere reported in families from North Africa and Europe. Our objective is to conduct a clinical, molecular and genetic study of 26 Tunisian patients with Allgrove Syndrome. Methods We report 26 Tunisian patients with between two and four clinical features associated with Allgrove Syndrome. Blood samples were collected and isolated DNA derived from subjects was amplified. The entire sequence of the AAAS gene was analyzed by PCR and sequencing. PCR-RFLP method was performed to identify the frequent mutations found. Results Sequencing of the AAAS gene revealed a major homozygous mutation (c.1331+1G>A) in 25 patients and R286X mutation in one patient. The presence of a major mutation in several unrelated affected individuals suggests the presence of a founder effect in Tunisia and allows for a fast and targeted molecular diagnosis. Conclusions We created an easy and rapid molecular enzymatic protocol based on PCR-RFLP using MvaI restriction enzyme that directly targets this major mutation and can be used for prenatal diagnosis and genetic counseling for Tunisian families at risk. To the best of our knowledge, this is the first major series report of Allgrove Syndrome in Tunisia.
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molecular analysis of libyan families with Allgrove Syndrome geographic expansion of the ancestral mutation c 1331 1g a in north africa
Hormone Research in Paediatrics, 2016Co-Authors: Fakhri Kallabi, Imen Ben Rebeh, Rahma Felhi, Dorra Sellami, Saber Masmoudi, Leila Keskes, Hassen KamounAbstract:Background/Aims: Allgrove Syndrome is a rare autosomal recessive disorder characterized by alacrima, achalasia, and adrenal insufficiency. It is caused by mutatio
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Molecular Analysis of Libyan Families with Allgrove Syndrome: Geographic Expansion of the Ancestral Mutation c.1331+1G>A in North Africa.
Hormone research in paediatrics, 2015Co-Authors: Fakhri Kallabi, Imen Ben Rebeh, Rahma Felhi, Dorra Sellami, Saber Masmoudi, Leila Keskes, Hassen KamounAbstract:Background/Aims: Allgrove Syndrome is a rare autosomal recessive disorder characterized by alacrima, achalasia, and adrenal insufficiency. It is caused by mutatio
N. Mouane - One of the best experts on this subject based on the ideXlab platform.
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Clinical and molecular report of c.1331 + 1G > A mutation of the AAAS gene in a Moroccan family with Allgrove Syndrome: a case report
BMC Pediatrics, 2018Co-Authors: H. Berrani, T. Meskini, M. Zerkaoui, H. Merhni, S. Ettair, A. Sefiani, N. MouaneAbstract:Background Allgrove Syndrome is a rare autosomal recessive disorder characterized by the triad of achalasia, alacrimia and adrenal insufficiency. It is caused by the mutations of the AAAS gene located on chromosome 12q13. The c.1331 + 1G > A mutation is one of the most common described in North Africa including Tunisia, Algeria and Libya. We report here the clinical and genetic profile of a Moroccan family with Allgrove Syndrome. Case presentation A Moroccan sister and brother born to consanguineous parents were found, at the ages of twelve and fifteen months old respectively, to have alacrimia and isolated glucocorticoid deficiency. Later, they developed achalasia whereupon Allgrove Syndrome was diagnosed clinically and confirmed by DNA sequencing which revealed a c.1331 + 1G > A mutation in the AAAS gene. Conclusion This finding reinforces previous studies in demonstrating the geographic expansion of the ancestral mutation c.1331 + 1G > A in North African patients and thus enabling targeted genetic counseling. To the best of our knowledge, this is the first report of the AAAS gene mutation in Moroccan patients.
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Clinical and molecular report of c.1331 + 1G > A mutation of the AAAS gene in a Moroccan family with Allgrove Syndrome: a case report
BMC pediatrics, 2018Co-Authors: H. Berrani, T. Meskini, M. Zerkaoui, H. Merhni, S. Ettair, A. Sefiani, N. MouaneAbstract:Allgrove Syndrome is a rare autosomal recessive disorder characterized by the triad of achalasia, alacrimia and adrenal insufficiency. It is caused by the mutations of the AAAS gene located on chromosome 12q13. The c.1331 + 1G > A mutation is one of the most common described in North Africa including Tunisia, Algeria and Libya. We report here the clinical and genetic profile of a Moroccan family with Allgrove Syndrome. A Moroccan sister and brother born to consanguineous parents were found, at the ages of twelve and fifteen months old respectively, to have alacrimia and isolated glucocorticoid deficiency. Later, they developed achalasia whereupon Allgrove Syndrome was diagnosed clinically and confirmed by DNA sequencing which revealed a c.1331 + 1G > A mutation in the AAAS gene. This finding reinforces previous studies in demonstrating the geographic expansion of the ancestral mutation c.1331 + 1G > A in North African patients and thus enabling targeted genetic counseling. To the best of our knowledge, this is the first report of the AAAS gene mutation in Moroccan patients.
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clinical and molecular report of c 1331 1g a mutation of the aaas gene in a moroccan family with Allgrove Syndrome a case report
BMC Pediatrics, 2018Co-Authors: H. Berrani, T. Meskini, M. Zerkaoui, H. Merhni, S. Ettair, A. Sefiani, N. MouaneAbstract:Allgrove Syndrome is a rare autosomal recessive disorder characterized by the triad of achalasia, alacrimia and adrenal insufficiency. It is caused by the mutations of the AAAS gene located on chromosome 12q13. The c.1331 + 1G > A mutation is one of the most common described in North Africa including Tunisia, Algeria and Libya. We report here the clinical and genetic profile of a Moroccan family with Allgrove Syndrome. A Moroccan sister and brother born to consanguineous parents were found, at the ages of twelve and fifteen months old respectively, to have alacrimia and isolated glucocorticoid deficiency. Later, they developed achalasia whereupon Allgrove Syndrome was diagnosed clinically and confirmed by DNA sequencing which revealed a c.1331 + 1G > A mutation in the AAAS gene. This finding reinforces previous studies in demonstrating the geographic expansion of the ancestral mutation c.1331 + 1G > A in North African patients and thus enabling targeted genetic counseling. To the best of our knowledge, this is the first report of the AAAS gene mutation in Moroccan patients.
H. Berrani - One of the best experts on this subject based on the ideXlab platform.
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Clinical and molecular report of c.1331 + 1G > A mutation of the AAAS gene in a Moroccan family with Allgrove Syndrome: a case report
BMC Pediatrics, 2018Co-Authors: H. Berrani, T. Meskini, M. Zerkaoui, H. Merhni, S. Ettair, A. Sefiani, N. MouaneAbstract:Background Allgrove Syndrome is a rare autosomal recessive disorder characterized by the triad of achalasia, alacrimia and adrenal insufficiency. It is caused by the mutations of the AAAS gene located on chromosome 12q13. The c.1331 + 1G > A mutation is one of the most common described in North Africa including Tunisia, Algeria and Libya. We report here the clinical and genetic profile of a Moroccan family with Allgrove Syndrome. Case presentation A Moroccan sister and brother born to consanguineous parents were found, at the ages of twelve and fifteen months old respectively, to have alacrimia and isolated glucocorticoid deficiency. Later, they developed achalasia whereupon Allgrove Syndrome was diagnosed clinically and confirmed by DNA sequencing which revealed a c.1331 + 1G > A mutation in the AAAS gene. Conclusion This finding reinforces previous studies in demonstrating the geographic expansion of the ancestral mutation c.1331 + 1G > A in North African patients and thus enabling targeted genetic counseling. To the best of our knowledge, this is the first report of the AAAS gene mutation in Moroccan patients.
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Clinical and molecular report of c.1331 + 1G > A mutation of the AAAS gene in a Moroccan family with Allgrove Syndrome: a case report
BMC pediatrics, 2018Co-Authors: H. Berrani, T. Meskini, M. Zerkaoui, H. Merhni, S. Ettair, A. Sefiani, N. MouaneAbstract:Allgrove Syndrome is a rare autosomal recessive disorder characterized by the triad of achalasia, alacrimia and adrenal insufficiency. It is caused by the mutations of the AAAS gene located on chromosome 12q13. The c.1331 + 1G > A mutation is one of the most common described in North Africa including Tunisia, Algeria and Libya. We report here the clinical and genetic profile of a Moroccan family with Allgrove Syndrome. A Moroccan sister and brother born to consanguineous parents were found, at the ages of twelve and fifteen months old respectively, to have alacrimia and isolated glucocorticoid deficiency. Later, they developed achalasia whereupon Allgrove Syndrome was diagnosed clinically and confirmed by DNA sequencing which revealed a c.1331 + 1G > A mutation in the AAAS gene. This finding reinforces previous studies in demonstrating the geographic expansion of the ancestral mutation c.1331 + 1G > A in North African patients and thus enabling targeted genetic counseling. To the best of our knowledge, this is the first report of the AAAS gene mutation in Moroccan patients.
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clinical and molecular report of c 1331 1g a mutation of the aaas gene in a moroccan family with Allgrove Syndrome a case report
BMC Pediatrics, 2018Co-Authors: H. Berrani, T. Meskini, M. Zerkaoui, H. Merhni, S. Ettair, A. Sefiani, N. MouaneAbstract:Allgrove Syndrome is a rare autosomal recessive disorder characterized by the triad of achalasia, alacrimia and adrenal insufficiency. It is caused by the mutations of the AAAS gene located on chromosome 12q13. The c.1331 + 1G > A mutation is one of the most common described in North Africa including Tunisia, Algeria and Libya. We report here the clinical and genetic profile of a Moroccan family with Allgrove Syndrome. A Moroccan sister and brother born to consanguineous parents were found, at the ages of twelve and fifteen months old respectively, to have alacrimia and isolated glucocorticoid deficiency. Later, they developed achalasia whereupon Allgrove Syndrome was diagnosed clinically and confirmed by DNA sequencing which revealed a c.1331 + 1G > A mutation in the AAAS gene. This finding reinforces previous studies in demonstrating the geographic expansion of the ancestral mutation c.1331 + 1G > A in North African patients and thus enabling targeted genetic counseling. To the best of our knowledge, this is the first report of the AAAS gene mutation in Moroccan patients.
C. Pirro - One of the best experts on this subject based on the ideXlab platform.
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Triple A Syndrome: a novel compound heterozygous mutation in the AAAS gene in an Italian patient without adrenal insufficiency.
Journal of the Neurological Sciences, 2010Co-Authors: M Luigetti, Henry Houlden, A. Pizzuti, C. Pirro, S Bartoletti, I Bottillo, F Madia, P A Tonali, Amelia Conte, M SabatelliAbstract:Allgrove Syndrome (or triple A Syndrome) is a rare autosomal recessive disorder characterized by alacrima, achalasia, ACTH-resistant adrenal insufficiency and autonomic/neurological abnormalities. It is caused by mutations in the AAAS gene. located on chromosome 12q13. We describe a 42-year-old patient who presented with neuropathy and was found to have alacrima, achalasia, mild autonomic dysfunction with significant central and peripheral nervous system involvement. She was later diagnosed with oligosymptomatic triple A Syndrome. Sequencing of the AAAS gene identified two heterozygous mutations within exon 14 and its donor splice site (p.L430F - c.1288C>T and c.1331 + 1G>T), one of which is novel. Allgrove Syndrome should be suspected in patients with neurological impairment associated with two or more of the main symptoms (alacrima, achalasia or adrenal insufficiency). (C) 2009 Elsevier B.V. All rights reserved.
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Triple A Syndrome: a novel compound heterozygous mutation in the AAAS gene in an Italian patient without adrenal insufficiency.
Journal of the neurological sciences, 2010Co-Authors: M Luigetti, A. Conte, A. Pizzuti, C. Pirro, S Bartoletti, H Houlden, I Bottillo, F Madia, P A Tonali, M SabatelliAbstract:Allgrove Syndrome (or triple A Syndrome) is a rare autosomal recessive disorder characterized by alacrima, achalasia, ACTH-resistant adrenal insufficiency and autonomic/neurological abnormalities. It is caused by mutations in the AAAS gene, located on chromosome 12q13. We describe a 42-year-old patient who presented with neuropathy and was found to have alacrima, achalasia, mild autonomic dysfunction with significant central and peripheral nervous system involvement. She was later diagnosed with oligosymptomatic triple A Syndrome. Sequencing of the AAAS gene identified two heterozygous mutations within exon 14 and its donor splice site (p.L430F-c.1288C>T and c.1331+1G>T), one of which is novel. Allgrove Syndrome should be suspected in patients with neurological impairment associated with two or more of the main symptoms (alacrima, achalasia or adrenal insufficiency).
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Case report of adult-onset Allgrove Syndrome
Neurological Sciences, 2007Co-Authors: F. Gilio, S. Rezze, A. Conte, V. Frasca, E. Iacovelli, C. Marini Bettolo, M. Gabriele, E. Giacomelli, A. Pizzuti, C. PirroAbstract:Allgrove Syndrome is a rare autosomal recessive disorder characterised by childhood onset, alacrima, oesophageal achalasia, adrenocortical insufficiency, neurological and occasionally autonomic involvement. Although the disease has been associated with mutations in the ALADIN gene on chromosome 12q13, it is genetically heterogeneous. The case we report is interesting because of its onset in adulthood, long duration of disease and prominent neurological dysfunctions. After the onset of neurological abnormalities the diagnosis went unrecognised for years until the patient presented for evaluation of dysphagia. The presence of achalasia with dysphagia, adrenal insufficiency, reduced tear production, optic atrophy and peripheral motor-sensory neuropathy with axonal loss led us to clinically diagnose Allgrove Syndrome even though a genetic study showed no mutations in the ALADIN gene exons. The case we report shares many clinical features with Allgrove Syndrome and, even with the limitations of a single case, underlines the variability in this Syndrome and the need for appropriate investigations along with a multidisciplinary approach.