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/lp/springer_journal/clinical-and-molecular-report-of-c-1331-1g-a-mutation-of-the-aaas-gene-CR93miLEh0
- Publisher
- Springer Journals
- Copyright
- Copyright © 2018 by The Author(s).
- Subject
- Medicine & Public Health; Pediatrics; Internal Medicine
- eISSN
- 1471-2431
- DOI
- 10.1186/s12887-018-1161-4
- Publisher site
- See Article on Publisher Site
Abstract
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. Keywords: Allgrove syndrome, C.1331 + 1G > A mutation, AAAS gene Background ALADIN protein (alacrima, achalasia, adrenal insuffi- The triple association of achalasia, alacrimia and adrenal ciency and neurological disorder) [7]. The pathogenic insufficiency characterizes the Allgrove syndrome (AS, gene has a ubiquitous expression in the human tissues OMIM 231550), also known as the triple A syndrome with a particularly high expression in the adrenal gland, [1–3]. The more recent recognition of a fourth compo- gastrointestinal tract and brain [8]. AS has been reported nent - autonomic dysfunction, in association with motor from different parts of the world. The c.1331 + 1G > A neuropathy, sensory disorder, mental retardation and mutation is one of the most common mutations de- similar neurologic diseases, has given rise to the term “4 scribed in the literature particularly in North Africa, A syndrome” [4, 5]. AS is a progressive disorder with having been identified in Tunisian, Algerian and Libyan various clinical manifestations The syndrome usually populations recently [9]. According to an extensive occurs in the first decade of life but cases of late onset literature review and to the best of our knowledge, we in adulthood have been reported [6]. The AAAS gene is describe here the first case of an AAAS gene mutation, located on chromosome 12q13 and encodes the namely the c.1331 + 1G > A genotype, to be reported in Morocco. * Correspondence: hajar.berrani@um5s.net.ma Pediatrics III, Children’s Hospital of Rabat, University Mohammed V, Belarbi El Alaoui Avenue, 6203 Rabat, PB, Morocco Case presentation Nutrition and Food Science Departments, Faculty of Medicine and Case 1: A five-year-old Moroccan girl was diagnosed Pharmacy, Mohammed V University-Rabat, Belarbi El Alaoui Avenue, 6203 clinically as having AS at 12 months. Her apparently Rabat, Morocco Full list of author information is available at the end of the article healthy parents were third cousins. She was born by © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Berrani et al. BMC Pediatrics (2018) 18:184 Page 2 of 4 normal vaginal delivery after a full-term pregnancy with while crying from birth. From 9 months there was a his- a normal birth weight of 3800 g. From the age of tory of generalized weakness, asthenia and anorexia, 5 months she had a history of asthenia, anorexia and with progressive hyperpigmentation of the skin for vomiting. From 12 months, she had generalized hyper- 3 months. On admission at the age of 15 months, height pigmentation of the skin and failure to thrive. She had was 75 cm (− 2 SD), weight 9 kg (− 2 SD) and blood not been able to produce tears since infancy. Physical pressure was 83/50 mmHg. A long philtrum and narrow examination at this time showed height 67 cm (− 2.84 upper lip were observed (Fig. 1). Hyperpigmentation was SD), weight 8.300 g (− 1.27 SD), blood pressure 84/ noted over most of the body. Examination of the ner- 43 mmHg. No abnormality was found in the heart, vous system and external genitalia was normal. Baseline lungs, abdomen, nervous system and external genitalia. investigations revealed normal complete blood count, Baseline investigations revealed normal full blood count, serum creatinine and electrolytes with serum sodium serum creatinine and electrolytes. Basal serum cortisol 139 mmol/L potassium 4.3 mmol/L and urine sodium at 8 AM was unrecordable at < 0.3 nmol/L while plasma 20 mmol/24 h. Basal serum cortisol at 8 am was unre- adrenocorticotropic hormone (ACTH) was markedly ele- cordable at < 0.3 nmol/L with markedly elevated ACTH vated at 228.8 pmol/L. The results of a bilateral Schirmer at 416 pmol/L. The results of a bilateral Schirmer test test confirmed the diagnosis of alacrima. Hydrocortisone were 4 mm, confirming the diagnosis of severe hypola- therapy replacement was started at 10 mg/m /day with crima. Esophagography was normal at this time. AS was artificial tears and topical vitamin A. At this time, esopha- diagnosed and treatment with hydrocortisone, artificial gography showed no abnormality. At follow up, aged tears and topical vitamin A was started. At 2 and a half 2 years, the patient presented with high blood pressure - years the boy developed dysphagia and vomiting. Eso- 120/70 mmHg. Plasma aldosterone was 170 pmol/l (refer- phagography now showed achalasia of the lower esopha- ence range 22–477) and plasma renin activity was gus at the cardia. He also had partial loss of primary 359.7mUI/l with a normal aldosterone to renin ratio. dentition (Fig. 2). Genetic testing confirmed a c.1331 + Echocardiography was normal. Autonomic dysfunction 1G > A homozygote mutation of the AAAS gene (Fig. 3). and hence the 4 A syndrome was therefore diagnosed. After 10 months of the treatment with captopril, the blood Discussion and conclusion pressure normalized at 90/50 mmHg and antihypertensive Allgrove syndrome can be considered as a multisystem treatment was stopped. At this time, the patient presented disorder, which can be life-threatening when diagnosis is with perioral cyanosis and cold extremities and was found delayed. The features of AS are ACTH resistant adrenal to have hyponatraemia (plasma sodium 126 mmol/L) with insufficiency, achalasia and alacrimia. Review of litera- high urine sodium (35 mmol/24 h). Mineralocorticoid de- ture reveals alacrima as the earliest and most consistent ficiency was diagnosed and treated with fludrocortisone clinical sign of AS and was indeed the initial symptom 50 μg per day. Partial loss of primary teeth was noted from reported in our patients. Thus, when a child presents 2 years of age at which time esophagography showed a di- with alacrima Allgrove syndrome should be suspected, lated esophagus with distal narrowing. Manometry was even if the other typical clinical features are absent, and not performed in view of the patient’s age. Following the particularly when the patient is of North African origin. diagnosis of achalasia, the patient underwent surgery with Adrenal insufficiency is also an early manifestation of esophago-cardiomyotomy and fundoplication. She became AS, and may present with severe hypoglycemia or symptom free for about 19 months, but the dysphagia re- curred and was treated with balloon dilatation of the esophagus. A year later the symptoms recurred and bal- loon dilatation was again performed but without relief of symptoms on this occasion. High resolution manometry showed normal lower esophageal sphincter (LES) rest- ing pressure (29 mmHg) with incomplete relaxation, prolonged integrated relaxation pressure (IRP) (27 mmHg) and aperistalsis. By the age of 3 years and six months, her weight had become static at 10 kg (− 2.5 SD) and a gastrostomy tube was inserted. Currently the patient is aged five years, weight 15 kg (− 1.5 SD) and height 97 cm (−2SD). Case 2: The brother of Case 1 is aged 2.6 years and Fig. 1 Patient 2 with Allgrove Syndrome showing partial loss of was born by normal vaginal delivery at term, birth primary dentition weight normal at 3400 g. His parents noted no tears Berrani et al. BMC Pediatrics (2018) 18:184 Page 3 of 4 gastro-esophageal sphincter and secondary dilatation in the proximal esophagus. A severe form of achalasia was noted in our first patient, managed by repeated balloon dilatation after surgery hadprovedtobeofonlytemporary benefit only, followed by insertion of gastrostomy tube when dilata- tion was no longer effective. Neurological symptoms may manifest in certain subgroups of patients with AS who show alesssevereand more chronic courseofthedisease [12]. Currently our first patient has presented with auto- nomic dysfunction and was thus diagnosed as having 4 A syndrome, however the second patient has not exhibited yet any neurological symptoms. Our patients also presented Fig. 2 Patient 2 with Allgrove Syndrome showing long philtrum and with partial loss of their primary dentition which occurried narrow upper lip at the same age as gastro-esophageal disease was diagnosed. We have excluded other possiblecauses of this dental loss, hypotension, which may lead to sudden death during such as trauma, local infection or dental caries. Two cases childhood [10]. Less frequently, adrenal insufficiency of two siblings with AS and premature loss of permanent may present with chronic vomiting, hyperpigmentation, teeth were reported by Palka et al. [13]. These authors spec- or developmental delay [11]. Mineralocorticoid produc- ulated that tooth loss could be an additional feature of the tion is generally preserved in AS but can be impaired in multisystemic disorder. Our patients also had some dys- 15% of patients [11]. Both of our patients showed morphic features such as long philtrum and thin upper lip isolated glucocorticoid deficiency initially but then which may be relevant to the genotype. developed mineralocorticoid deficiency. The esophageal AS is caused by a mutation in the AAAS gene, located dysfunction in AS features absence of peristalsis within on chromosome 12q13. More than 70 mutations have the body of the esophagus with a relaxation defect in the been described in patients from different parts of the world. The c.1331 + 1G > A mutation is one of the most frequent mutations of the AAAS gene in the world and the most frequent mutation in North Africa [9] being found Algerian and Tunisian families [14] and recently in Libyan families [9]. This frequent mutation seems to be inherited from a common ancestor and spread in North African populations [9] and it is of note that the c.1331 + 1G > A mutation was found in our family. To our knowledge, this is the report of a c.1331+1G>A mu- tation in a Moroccan family and it is this mutation which should be specifically looked for in future patients from Maghreb countries with a clinical diagnosis of AS. Abbreviations ACTH: Plasma adrenocorticotropic hormone; AS: Allgrove syndrome; IRP: Integrated relaxation prolonged; LES: Lower esophageal sphincter Acknowledgments We thank gratefully Doctor Malcolm Donaldson for revising the manuscript. We thank also the patient’s family for their understanding and cooperation. Availability of data and materials All data generated or analysed during this study are included in this published article. Authors’ contributions HB cared for the patient, drafted the manuscript and carried out the literature research. SE, TM, NM helped to draft and critically read the manuscript. MZ, HM, AS contributed to analyze the sequencing results and critically read the manuscript. All authors read and approved the final manuscript. Ethics approval and consent to participate Fig. 3 DNA sequencing showing a c.1331 + 1G > A mutation of the Written informed consent was obtained from the parents of the patient for AAAS gene the genetic analysis and publication of any accompanying images of this Berrani et al. BMC Pediatrics (2018) 18:184 Page 4 of 4 case report. This study was approved by the Human Research Ethic Committee at the Faculty of Medicine of Rabat, Mohammed V University, Morocco. Consent for publication Written informed consent was obtained from the patient’s parents for publication of this case report and any accompanying images. Competing interests The authors declare that they have no competing interests. Publisher’sNote Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Author details Pediatrics III, Children’s Hospital of Rabat, University Mohammed V, Belarbi El Alaoui Avenue, 6203 Rabat, PB, Morocco. Nutrition and Food Science Departments, Faculty of Medicine and Pharmacy, Mohammed V University-Rabat, Belarbi El Alaoui Avenue, 6203 Rabat, Morocco. Medical Genetics Institute, Institut National d’Hygiène, University Mohammed V, Rabat, Morocco. Received: 11 January 2018 Accepted: 29 May 2018 References 1. Online Mendelian Inheritance in Man (OMIM), Center for Medical Genetics, Johns Hopkins University, and National Center for Biotechnology Information, National Library of Medicine. Bethesda; 2015. http://omim.org/ entry/231550. 2. Allgrove J, Clayden GS, Grant DB, Macaulay JC. Familial glucocorticoid deficiency with achalasia of the cardia and deficient tear production. Lancet. 1978;1(8077):1284–6. 3. Li W, Gong C, Qi Z, Wu DI, Cao B. Identification of AAAS gene mutation in Allgrove syndrome: a report of three cases. Exp Ther Med. 2015;10(4):1277– 82. https://doi.org/10.3892/etm.2015.2677. 4. Gazarian M, Cowell CT, Bonney M, Grigor WG. 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Journal
BMC Pediatrics – Springer Journals
Published: Jun 4, 2018