Triple A Syndrome Research Articles

Esophageal achalasia presenting as recurrent pneumonia in children: A case series.

Esophageal achalasia (EA) is a rare primary esophageal motility disorder that is considered a rare etiology of dysphagia among infants and children. The proposed primary pathophysiology is related to the loss of ganglion cells in the distal esophageal sphincters, particularly in the Auerbachian muscle layer, which then leads to the dysmotility and failure of lower esophageal sphincter relaxation. Dysphagia, vomiting, poor weight gain, cough, and recurrent aspiration pneumonia are the most common presenting complaints. Herein, we report 3 cases of EA who presented with chronic cough and recurrent aspiration pneumonia. This study reviewed 3 pediatric patients with typical symptoms of EA. All the patients were admitted and referred to the pediatric pulmonology service for evaluation of recurrent pneumonia and suspected aspiration syndrome. All patients underwent a barium esophagogram as a part of the aerodigestive workup of recurrent vomiting, dysphagia, and aspiration pneumonia. Additionally, all the patients underwent workup for other associated congenital anomalies, which included echocardiography, brain magnetic resonance imaging, and an abdominal ultrasound. All patients had EA and presented with recurrent pneumonia. All patients had isolated EA, and none had any evidence of Allgrove syndrome. Pneumatic balloon dilatation was performed for all patients at the same time as the upper gastrointestinal endoscopy. Later, all the patients underwent a laparoscopic Heller myotomy and had no postoperative complications, and their symptoms resolved. EA is a rare condition in children, yet it can be a serious and life-threatening condition if left untreated. Our cases emphasize the significance of considering achalasia in children who experience esophageal dysphagia and recurrent pneumonia. Several pediatric cases have been reported in which respiratory involvement was the primary manifestation of achalasia. These cases highlight the importance of considering gastrointestinal disorders, particularly EA, in the differential diagnosis of children who experience recurrent pneumonia. Early diagnosis and treatment with laparoscopic Heller myotomy can lead to good outcomes for children with achalasia.

7333 Does Allgrove Syndrome Have Endocrine Manifestations Beyond Adrenal Insufficiency?

7333 Does Allgrove Syndrome Have Endocrine Manifestations Beyond Adrenal Insufficiency?

483P Comprehensive investigation of neuromuscular manifestations in Triple-A syndrome: A combined clinical, molecular genetic and proteomic study

483P Comprehensive investigation of neuromuscular manifestations in Triple-A syndrome: A combined clinical, molecular genetic and proteomic study

Decoding allgrove syndrome: a clinical odyssey through diagnosis and management challenges

Decoding allgrove syndrome: a clinical odyssey through diagnosis and management challenges

Biallelic NDC1 variants that interfere with ALADIN binding are associated with neuropathy and triple A-like syndrome

Nuclear pore complexes (NPC) regulate nucleocytoplasmic transport and are anchored in the nuclear envelope by the transmembrane nucleoporin NDC1. NDC1 is essential for post-mitotic NPC assembly and the recruitment of ALADIN to the nuclear envelope. While no human disorder has been associated to one of the three transmembrane nucleoporins, biallelic variants in AAAS, encoding ALADIN, cause Triple-A syndrome (Allgrove syndrome). Triple A syndrome, characterized by alacrima, achalasia and adrenal insufficiency, often includes progressive demyelinating polyneuropathy and other neurological complaints. In this report, diagnostic exome and/or RNA-sequencing was performed in 7 individuals from 4 unrelated consanguineous families with AAAS negative triple A syndrome. Molecular and clinical studies followed to elucidate the pathogenic mechanism. The affected individuals presented with intellectual disability, motor impairment, severe demyelinating with secondary axonal polyneuropathy, alacrima and achalasia.. None of the affected individuals has adrenal insufficiency. All individuals presented with biallelic NDC1 in-frame deletions or missense variants, that affect amino acids and protein domains required for ALADIN binding. No other significant variants associated with the phenotypic features were reported. Skin fibroblasts derived from affected individuals show decreased recruitment of ALADIN to the NE and decreased post-mitotic NPC insertion, confirming pathogenicity of the variants. Taken together, our results implicate biallelic NDC1 variants in the pathogenesis of polyneuropathy and a Triple-A-like disorder without adrenal insufficiency, by interfering with physiological NDC1 functions, including the recruitment of ALADIN to the NPC.

Anesthesia Management of a Patient Having Allgrove Syndrome

Abstract Background: Allgrove syndrome is an autosomal recessive disorder characterized by achalasia cardia, alacrimia and adrenocorticotropic hormone resistant adrenal insufficiency with progressive neurological impairment with or without mental retardation. Materials and Methods: Patient had undergone Heller’s myomectomy under GA. PAC was done, all routine investigations, oesophageal motility tests, ACTH level, Schirmer test was done. She was pre-medicated with glycopyrrolate, midazolam and induced with fentanyl, propofol, vecuronium, intubated with cuffed ET tube 6.5 and reversed with Neostigmine and glycopyrrolate. Result and Conclusion: Careful pre-operative evaluation, choice of sedatives, induction agents, muscle relaxant to avoid hyperventilation, hypokalemia, close monitoring of ABG and electrolytes, careful glycaemic control, eye protection, care to avoid aspiration and regurgitation are imperative for optimal management with Allgrove syndrome. The co-ordination of care for these patients require a multidisciplinary team of endocrinologist, neurologist, gasteroenterologist, ophthalmologist, surgeons and anaesthesiologists. We successfully conducted this case of 22 yrs old female with ALLGROVE SYNDROME.

Adrenal insufficiency in allgrove syndrome:a case report

Adrenal insufficiency in allgrove syndrome:a case report

Allgrove syndrome: a case report

Allgrove syndrome: a case report

Allgrove Syndrome: A Case Report and Review of the Literature

Allgrove syndrome, or Triple A syndrome, is a very rare autosomal recessive disorder with three key clinical features: achalasia, alacrima, and adrenal insufficiency. Around a third of patients present with additional features, such as neurological and autonomic manifestations (making it syndrome 4A). Alacrima usually appears in early childhood, while achalasia and adrenal insufficiency manifest later. In adulthood, the presentation is predominantly neurological, with autonomic impairment and polyneuropathy. We report the case of a 7-year-old female patient who consulted us with delayed weight gain and nutritional issues, alacrimia, and chronic vomiting since the age of 6 months. Clinical examination revealed malnutrition, with weight and BMI less than 3 standard deviations. Alacrima was confirmed by a positive Schirmer's test. Oesogastroduodenal transit, gastric fibroscopy, and manometry confirmed achalasia. In our case, there was no neurological involvement nor adrenal insufficiency. Treatment consisted of optimal managing of the manifestations of the disease.

Child Neurology: Allgrove Syndrome: An Intriguing Etiology of Motor Neuron Disease in Children

Motor neuron diseases are a rare group of neurodegenerative disorders with considerable phenotypic heterogeneity and a multitude of etiologies in the pediatric population. In this study, we report 2 unrelated adolescents (a boy and a girl) who presented with 4-6 years of progressive difficulty in walking, thinning of limbs, and gradually progressive darkening of the skin. Examination revealed generalized hyperpigmentation of skin and features suggestive of motor neuron involvement such as tongue atrophy, wasting of distal extremities, and brisk deep tendon reflexes. On detailed exploration for systemic involvement, history of dysphagia, inability to produce tears, and Addisonian crises were evident. An etiologic diagnosis of Allgrove syndrome, which is characterized by a triad of achalasia, alacrimia, and adrenal insufficiency was considered. Next-generation sequencing revealed pathogenic variants in the AAAS gene, confirming the diagnosis. Steroid replacement therapy was initiated along with relevant multidisciplinary referrals. The disease stabilized in the boy and a significant improvement was noted in the girl. These cases highlight the value of non-neurologic cues in navigating the etiologic complexities of motor neuron diseases in children and adolescents. It is imperative for neurologists to develop awareness of the diverse neurologic manifestations associated with Allgrove syndrome because they are often the first to be approached. A multidisciplinary team of experts including neurologists, endocrinologists, gastroenterologists, ophthalmologists, and dermatologists is essential for planning comprehensive care for these patients.

P-10 A rare case of Triple A Syndrome with familial involvement

Abstract Introduction Alacrimia, achalasia cardia, and adrenocorticotrophic hormone (ACTH)-resistant adrenal insufficiency make up the triple-A syndrome. It is an uncommon disease with an autosomal recessive inheritance pattern. The AAAS gene, which codes for the ALADIN protein and is located on chromosome 12q13, is the cause of Allgrove syndrome. The initial and typical symptoms are achalasia cardia and adrenal insufficiency. The majority of neurological disorders have autonomic signs, and they typically show in later life. The other typical neurological conditions are polyneuropathy, amyotrophy, and optic atrophy. Clinical Case A 25-year-old female patient presented to our clinic with complaints of weakness, dizziness, and hyperpigmentation of the skin. Her medical history revealed a recent intensive care unit (ICU) stay due to hypotension, during which her condition was managed with steroid therapy. However, she did not continue the steroid treatment after discharge. Notably, the patient had a family history of achalasia with operative intervention in all three siblings. The patient and her family members were also under the care of a gastroenterology specialist. Additionally, the patient reported experiencing dry eyes, for which she was using artificial tears. Physical examination revealed hyperpigmentation of tongue, gums and buccal mucosa. Upon examination, her baseline investigations revealed a hemoglobin of 11.4 g/dL, sodium 137 mmol/L and potassium 4.0 mmol/L. The patient's adrenocorticotropic hormone (ACTH) level was measured at 1250 pg/ml, with a basal cortisol level of 0.5 ug/dL, leading to the diagnosis of adrenal insufficiency. Hydrocortisone treatment was initiated at a dosage of 2×10mg, resulting in a decline of the ACTH level to 31. Given the combination of symptoms including achalasia, alacrima, and adrenal insufficiency, genetic testing was conducted. Both alleles revealed a homozygous c.1432C>T (p.Arg478*) mutation, confirming the diagnosis of Triple A Syndrome. Following the genetic diagnosis, a familial investigation was initiated. This investigation revealed the presence of the homozygous positive mutation in two siblings and two cousins. The constellation of symptoms and the genetic findings confirmed the occurrence of Triple A Syndrome within this family. Conclusion This case highlights the significance of recognizing Triple A Syndrome as an underlying cause of adrenal insufficiency in the presence of achalasia, alacrima, and a suggestive clinical history. In order to confirm the diagnosis and identify any affected family members, genetic testing is crucial. To avoid potential complications brought on by adrenal insufficiency and other systemic Triple A Syndrome manifestations, early identification and treatment are crucial.

Familial achalasia isolated or syndromic: about 18 families

Aim: Familial achalasia (FA) is a very rare condition. This work aims to evaluate its prevalence, characterize its clinical profile in a large series, and assess the efficacy and safety of pneumatic dilation (PD) in this context. Methods: A total of 817 patients with achalasia were collected over a period of 20 years (1990–2010). All cases of FA: isolated or associated to Allgrove syndrome, were looked for in both parents and siblings. Results: In this study, 18 families with FA were identified n = 41 patients (5%). Two members were affected in each family, in 14 families, three members per family in three others, and for the remaining family 04 members. All cases of achalasia were observed in siblings and parent to child transmission was unfound. Achalasia was associated to Allgrove syndrome in 15 families. It was isolated in 3 families. Consanguinity was found in 89% of patients, and death at a young age in the siblings was recorded in 27% of cases. Achalasia was present before the age of 5 years in 75% of cases. There was no difference between the two groups for age, age at onset, sex and the presence of the cardinal signs of achalasia. A total of 102 dilations were performed. Only one session in 31% of cases, two in 38%, three in 17% and more than three sessions in 14%. The long-term success rate of PD was low. Conclusions: FA manifests almost exclusively in childhood. It is rarely isolated; most often falls under Allgrove syndrome. Alacrima is the earliest sign that should lead to the diagnosis. The long-term success rate of PD is rather low. This requires recourse to multiple sessions of PD or Heller’s cardiomyotomy which may be the best initial approach.

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

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.

Hypogonadotropic hypogonadism in a patient with Allgrove syndrome: A case report

Hypogonadotropic hypogonadism in a patient with Allgrove syndrome: A case report

SCARB1 downregulation in adrenal insufficiency with Allgrove syndrome

BackgroundAllgrove disease is a rare genetic syndrome characterized by adrenal insufficiency, alacrimia, achalasia and complex neurological involvement. Allgrove disease is due to recessive mutations in the AAAS gene, which encodes for the nucleoporin Aladin, implicated in the nucleocytoplasmic transport. The adrenal insufficiency has been suggested to rely on adrenal gland-ACTH resistance. However, the link between the molecular pathology affecting the nucleoporin Aladin and the glucocorticoid deficiency is still unknown.ResultsBy analyzing postmortem patient’s adrenal gland, we identified a downregulation of Aladin transcript and protein. We found a downregulation of Scavenger receptor class B-1 (SCARB1), a key component of the steroidogenic pathway, and SCARB1 regulatory miRNAs (mir125a, mir455) in patient’s tissues. With the hypothesis of an impairment in the nucleocytoplasmic transport of the SCARB1 transcription enhancer cyclic AMP-dependent protein kinase (PKA), we detected a reduction of nuclear Phospho-PKA and a cytoplasmic mislocalization in patient’s samples.ConclusionsThese results shed a light on the possible mechanisms linking ACTH resistance, SCARB1 impairment, and defective nucleocytoplasmic transport.

The role of WD40 repeat-containing proteins in endocrine (dys)function.

WD40 repeat-containing proteins play a key role in many cellular functions including signal transduction, protein degradation, and apoptosis. The WD40 domain is highly conserved, and its typical structure is a β-propeller consisting of 4-8 blades which probably serves as a scaffold for protein-protein interaction. Some WD40 repeat-containing proteins form part of the corepressor complex of nuclear hormone receptors, a family of ligand-dependent transcription factors that play a central role in the regulation of gene transcription. This explains their involvement in endocrine physiology and pathology. In the present review, we first touch upon the structure of WD40 repeat-containing proteins. Next, we describe our current understanding of the role of WD40 domain-containing proteins in nuclear receptor signaling, e.g., as corepressor or coactivator. In the final part of this review, we focus on WD40 domain-containing proteins that are associated with endocrine pathologies. These pathologies vary from isolated dysfunction of one endocrine axis, e.g., congenital isolated central hypothyroidism, to more complex congenital syndromes comprising endocrine phenotypes, such as the Triple-A syndrome.

Allgrove Syndrome: Case Series on 4A and Triple A Syndrome in Children with Rare Presentation

Allgrove Syndrome: Case Series on 4A and Triple A Syndrome in Children with Rare Presentation

The evaluation of thiol-disulfide homeostasis in children with Triple-A syndrome.

Triple-A syndrome occurs due to the dysfunction of the ALADIN protein as a result of a mutation in the AAAS gene. ALADIN is involved in redox homeostasis in human adrenal cells and steroidogenesis. It has also been shown to have important roles in DNA repair and the protection of cells against oxidative stress. We planned to investigate serum thiol/disulfide homeostasis, which is a part of redox hemostasis in patients with Triple-A syndrome. The study included patients with the Triple-A syndrome (26 patients) and healthy children (26 patients). Thiol and disulfide levels of patients and healthy groups were compared. In addition, patients with the Triple-A syndrome were divided into 2 subgroups according to the mutation type, and their thiol and disulfide levels were compared. Triple-A syndrome patients had increased native thiol (SH), total thiol (SH+SS) concentrations, and native thiol/total thiol (SH/SH+SS) ratios than healthy controls. However, Triple-A syndrome patients had lowered disulfide (SS), disulfide/native thiol (SS/SH), and disulfide/total thiol (SS/SH+SS) ratios than the controls. When the group with the p.R478* mutation and the group with other mutation were compared, disulfide level, disulfide/native thiol ratio, and disulfide/total thiol ratio were statistically higher in the group with the p.R478* mutation, while native thiol/total thiol ratio was found to be lower. However, no statistical difference was found between native thiol and total thiol levels. This is the first study in the literature to evaluate thiol-disulfide homeostasis in patients with the Triple-A syndrome. Patients with Triple-A syndrome had an increased level of thiol compared with healthy controls. Comprehensive studies are needed to clarify these thiol levels, which are thought to be compensatory. Also, mutation type affects thiol-disulfide levels.

Quality-of-life Assessment among Children with Esophageal Achalasia.

Analyze the surgical management strategy and the current effects on Quality of Life of diagnosed Esophageal Achalasia (EA) patients in our department, with an assessment of the incidence, clinical course, and related disorders. Data was based on a retrospective review of all children who received achalasia treatment at our department between 2008 and 2022. Using the Pediatric Quality of Life Inventory Generic Core (PedsQL) Scales and the Pediatric-QL Gastrointestinal Symptoms Module (GI-PedsQL), we evaluated the long-term effects of this diagnosis on our patients' quality of life. Esophageal achalasia (EA) was identified in a total of 13 cases (F: 7; M: 6). The mean patient delay was 27.90 months, and the median age was 6.5 years at diagnosis (2 months to 15 years). Regurgitation was the most frequently observed symptom, and the median follow-up was 7.32 (3- 30.7) months. There were descriptions of associations with Allgrove syndrome (n=7) and Down syndrome (n=1). All patients were treated by Open Heller myotomy (OHM) with one patient (n=1) initially treated by pneumatic dilatation (PD). In all 13 laparotomy myotomies, simultaneous fundoplication was performed using the DOR (n=12) and THAL (n=1) techniques. At follow-up, 12 patients had complete symptom relief with 1 patient exhibiting a persistence of symptoms. All 13 patients were prospectively contacted with a median time from latest check-up to date of inclusion of 2.9 (0.3-8.8) years. In comparison to data from a control group of EA patients, the overall PedsQL score of our patients was 72/100 (±17), with higher established scores in physical and emotional functioning but lower scores in social and school settings. On the other hand, when compared to a control group presenting with a gastroesophageal reflux disease (GERD), the GI-PedsQL overall score in our patients was higher with a 76/100 (±14.9), but they scored significantly lower in the dimensions: Foods and drinks limitations, difficulty swallowing, heartburn and vomiting. Our study group's characteristics join most of the published literature with 54% of our patients presenting with Allgrove syndrome but it also joins the much rarer descriptions of Achalasia and Down's syndrome association with a singular case. The clinical course of our diagnosis process mainly consisted of timed esophagram and UGI endoscopy, lacking significantly in HREM evaluations but was efficient enough in guiding the surgical management. Our findings confirm the safety and effectiveness of Open Heller's myotomy with a success rate of 92.3% However, we concede that a laparoscopic approach should be further adopted if no contradiction is found. Moreover, we presented insight on long term QoL of patients posteriori to HM which was in concordance with other global experiences where patients reported dissatisfaction with their health and limited lifestyle. This significant negative impact was prominently present in comparison to healthy control groups as well as patients with inflammatory bowel diseases and compels a much needed discussion on the major chronic repercussions of Esophageal Achalasia in children. Even when managed by interdisciplinary teams of professionals, managing esophageal achalasia in specialized institutions is still a subject of debate. Early pediatric diagnosis is best achieved with routine physiological function tests and HREM. Moreover, more research is required to assess long-term Quality of Life. Standardized lifelong follow-up and qualified resources, both human and technological, are required to improve postoperative outcomes.

Abstract 134

Background: Glucocorticoid deficiency associated with achalasia of the cardia and absent tear production was described by Allgrove et al. The estimated prevalence is 1 per 10,00,000 individuals. Lanes et al. suggested that a progressive degenerative process may be responsible for the three components of the disease and coined the term ‘triple-A syndrome’ (AAAS). Gazarian et al. referred this syndrome as ‘4A syndrome’ associating various autonomic and neurologic abnormalities as components. It is an autosomal recessive disease with mutation usually in the AAAS gene on chromosome 12q13. The gene produces alacrima-achalasia-adrenal insufficiency neurologic disorder (ALADIN), which belongs to the WD-repeat family of proteins. Clark and Weber et al. pointed out that the AAAS has variable phenotypic expression. Case Report: A 9 years 9-month-old female child was referred from pediatrics for hypoglycemic seizures. Patient was apparently normal 5 years back. Parents observed blackening of the body with frequent fever, vomiting, abdominal pain and seizures for a year. She was diagnosed with hypothyroidism and seizure disorder and was prescribed levothyroxine and valproate. Addisons disease was diagnosed at another hospital and valproate was discontinued. Hydrocortisone was added. Later she discontinued the drugs. Now she has presented with similar complaints. Careful history revealed that she had “always cried without tears”, generalisedblackening of skin, recurrent vomiting and seizures. Her birth history was normal without delayed milestones. On examination she was irritable, had generalised hyperpigmentation, strabismus, pre-pubertal secondary sexual characters, and normal blood pressure. Investigations showed low serum cortisol, high ACTH, <1 mm Schirmer test score, bilateral partial optic atrophy, and bilateral thin and streaky adrenals on CT abdomen. Barium swallow did not show achalasia. In view of Alacrima, Adrenal insufficiency, and optic atrophy the diagnosis of Allgrove syndrome was considered and hydrocortisone was started. Patient has shown significant improvement. Levothyroxine was continued. Regular follow up is suggested. Discussion: Majority of the AAAS patients present with achalasia but homozygous nonsense mutation in Exon 9 (R312X) and homozygous substitution in Exon 8 (S263P) were reported by ErdalKurnaz et al. with Alacrima and adrenal insufficiency without associated achalasia at presentation. Conclusion: All children presenting with Alacrima in conjunction to Addisons disease should be suspected of Allgrove syndrome and periodically evaluated for achalasia and neurological defects as the onset can be variable.