Triple A syndrome (Allgrove syndrome) is a rare, autosomal recessive disorder characterized by Adrenocorticotropic hormone resistant adrenal insuffi ciency, Alacrmia, Achalasia of the oesophageal cardia, progressive neurological degeneration and occasionally autonomic instability (making it 4A syndrome). Reported neurological abnormalities included developmental delay, ataxia and polyneuropathy with sensory, motor and autonomic components, long-tract degeneration, parkinsonism and mild dementia.In this paper we report a 13 year old boy with Allgrove syndrome presentingwith muscular weakness that was confi rmed by EMG studies. To our knowledge, muscle disease in Allogrove syndrome was not reported before.Keywords: Allgrove syndrome, triple A syndrome, alacrmia, cardiac achalasia, adrenal insufficiency

Elsayed, SM

Elsedfy, HH

Shawky, RM

English

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CASE REPORT                  Egypt. J. Med. Hum. Genet. Vol. 10, No. 1, May, 2009Copyright: All rights reserved for The Egyptian Journal of Medical Human Genetics105 ABSTRACT                                                                                                                                            Triple A syndrome presenting with myopathy: An Egyptian patientRabah M. Shawky1, Solaf M. Elsayed1 and  Heba H. Elsedfy21Genetics and 2Endocrinology clinics, Children’s Hospital, Ain Shams UniversityTriple A syndrome (Allgrove syndrome) is a rare, autosomal recessive disorder characterized by Adrenocorticotropic hormone resistant adrenal insuffi ciency, Alacrmia, Achalasia of the oesophageal cardia, progressive neurological degeneration and occasionally autonomic instability (making it 4A syndrome). Reported neurological abnormalities included developmental delay, ataxia and polyneuropathy with sensory, motor and autonomic components, long-tract degeneration, parkinsonism and mild dementia.In this paper we report a 13 year old boy with Allgrove syndrome presenting with muscular weakness that was confi rmed by EMG studies. To our knowledge, muscle disease in Allogrove syndrome was not reported before. Corresponding Author:  Rabah M. ShawkyE-mail: shawkyrabah@yahoo.comKey Words:Allgrove syndrome, triple A syndrome, alacrmia, cardiac achalasia, adrenal in-suffi ciency.INTRODUCTION                              Triple A syndrome (Allgrove syndrome) is a rare, autosomal recessive disorder character-ized by adrenocorticotrophic hormone (ACTH) resistant ad-renal insuffi ciency, alacrima, achalasia of the esophageal cardia, progressive neurologi-cal degeneration and occasion-ally autonomic instability1. The syndrome was fi rst reported by Allgrove in 1978 when they de-scribed two pairs of sibs (3 boys and 1 girl) with glucocorticoid defi ciency and achalasia of the stomach cardia. Three had de-fective tear formation (alacri-ma) and one showed other signs of autonomic dysfunction.2The condition is associated with impair-ment of the central, peripheral and auto-nomic nervous systems. Progression of neurological symptoms has been report-ed with worsening of peripheral neurop-athy, dementia, long tract degeneration, dysarthria and ataxia3. In this paper we report a 13 year old boy with Allgrove syndrome presenting with muscular weakness that was confi rmed by EMG studies. To our knowledge, muscle dis-ease in Allogrove syndrome was not re-ported before.CASE REPORT                                           A 13 year old boy, seventh in order of birth of one and half cousin marriage presented to the genetics clinic with a 106Triple A syndrome presenting with myopathyfour year history of headache, excessive fatigue, diffi culty in walking and climb-ing the stairs and recurrent fainting at-tacks. This was accompanied by contin-uous pain and recurrent ulcers in both eyes. One year ago, the patient started to have recurrent attacks of vomiting.On examination, his height was 140 cm (-3SD), weight was 28 kg (< - 4 SD). He had long thin face, long philtrum, deep seated eyes and darker skin than the rest of family members especially around the lips and knuckles. Chest, heart and abdominal examination showed no ab-normalities (Figures. 1, 2). Neurologi-cal examination showed wasting, slight hypotonia, diminished deep tendon re-fl exes and weakness of proximal mus-cles of upper and lower limbs.Morning cortisol level was 2.7 μg/dl (normal level: 4.3- 22.4), ACTH was more than 1250 pg/ml (normal level: 10-60), sodium level was 132 mmol/L (normal: 138-145), potassium level was 5.9 mmol/L (normal:3-5). TSH: 3.94 μIU /ml (normal: 0. 33-5.5), free T4; 1.1 ng/dl (0.8-1.9).Digital computed radiography of bari-um swallow of the oesophagus showed mild gastro-oesophageal refl ux. Oph-thalmological examination showed bilateral alacrmia. EMG studies for abductor policies brevis, right biceps, and right extensor hallucis brevis muscles showed no spontaneous activ-ity at rest. On mild contraction, motor unit action potentials were of small amplitude, prolonged duration and oc-casional polyphasia and early recruit-ment, with full interference pattern on maximum. Nerve conduction velocity of both median and right tibial nerves revealed normal distal latencies with nerve conduction velocity and average amplitude for CMAPs. These fi ndings were suggestive of a myogenic pattern. Audiometry, CT brain and EEG were all normal. Figs. 1,2: Anteroposterior view of the patient showing the darkness around the lip and the knuckles.DISCUSSION                                                   Neurological abnormalities in Allo-grove syndrome was fi rst reported by Ehrich et al.4 in 1987 in two brothers with severe developmental delay, short stature, microcephaly, ataxia and op-tic atrophy4. Furthermore, follow-up of the patients originally described by Allgrove et al.2 showed that they had developed neurologic manifestations, including polyneuropathy with senso-ry, motor and autonomic components, long-tract degeneration, parkinsonism, and mild dementia3. Although our pa-tient did not have any of the previous 107Shawky et al.neurological manifestations, he had typical symptoms and signs suggestive of muscle disease. This was confi rmed by electromyogram and nerve conduc-tion studies.Muscle weakness could be explained by the long-term undiagnosed adrenal insuffi ciency which makes a major con-tribution to reduced motor function and quality of life. But unlike other neuro-logical disorders associated with adre-nal insuffi ciency, neurological change with Allgrove syndrome was reported to be extremely slow5. Our patient had the onset of muscle weakness very ear-ly (at the age of nine years) which is against the theory of long-term adrenal insuffi ciency.Distinct facial appearance of Allgrove syndrome includes long thin face with a long philtrum, narrow upper lip, down-turned mouth and microcephaly6. Except for microcephaly, these features were typical to our patient.Alacrima is the most consistent fea-ture of this syndrome and is usually the earliest manifestation7. This was evident in our patient who had persis-tent complaint of eye pain and redness and was not diagnosed with alacramia till his presentation to our clinic. Other reported ophthalmic manifestations include keratoconjunctivitis sicca, corneal melts, lacrimal gland atrophy, pupillary abnormalities including slug-gish pupils, tonic pupils with hypersen-sitivity to dilute miotics, accommoda-tive dysregulation, amblyopia and optic atrophy.1,8Our patient had both glucocorticoid and mineralcorticoid defi ciency. Most patients in the literature reported had glucocorticoid defi ciency with normal mineralocorticoid function, but defi -ciency has been reported in only 15% of patients.9The orthostatic hypotension that was re-ported by our patient could be explained by abnormal cardiovascular refl exes (progressive loss of cholinergic func-tion) due to autonomic dysfunction.10Although our patient did not develop cardiac achlasia yet, it is known that other authors reported Allogrove pa-tients who had only 2 of the 3 features, with variable neurological defects11. This was further confi rmed by Prpic et al.12 who demonstrated marked pheno-typic variability in 3 patients with ge-netically confi rmed triple-A syndrome. Two patients had achalasia, alacrima, and adrenocortical defi ciency as well as neurologic and autonomic dysfunction. The third patient had only achalasia and neurologic dysfunction. All patients were homozygous for mutations in the AAAS gene. In the patient with isolated achalasia, the diagnosis of triple-A syn-drome could only be made on the ba-sis of the molecular genetic analysis of the AAAS gene. The authors proposed that the diagnosis of triple-A syndrome should be made on the basis of molecu-lar analysis of the AAAS gene and may therefore include patients with 1 or 2 of the 3 main symptoms.12Achalasia was also reported to have a variable, often insidious presentation. Dysphagia may be present for years be-fore the diagnosis of achalasia is made and may be present as gastroesophageal refl ux.13Unlike ACTH resistance syndromes (fa-milial glucocorticoid defi ciency), triple A syndrome is not due to mutations in the ACTH receptor, but it has some fea-108Triple A syndrome presenting with myopathytures of a contiguous gene syndrome10. The triple A syndrome is due to muta-tions in the AAAS gene whose product is ALADIN (alacrima-achalasia-adre-nal insuffi ciency neurologic disorder); located on chromosome 12q13.1,8In conclusion, patients with triple A syndrome often reports to a specialist with one complaint and the association may remain unsuspected, leaving the patient prone to complications like Ad-disonian crisis, recurrent aspiration and failure to thrive. All children presenting with one of the three symptoms should be screened for triple A syndrome. Neu-rological manifestations of Allogrove syndrome may include muscle disease. REFERENCES                                          Mullaney PB, Weatherhead R, Mil-1. lar L, Ayyash II, Ayberk H, Cai F, et al. Keratoconjunctivitis sicca associ-ated with achalasia of the cardia, ad-renocortical insuffi ciency and lacrimal gland degeneration: Keratoconjuncti-vitis sicca secondary to lacrimal gland degeneration may parallel degenera-tive changes in esophageal and adre-nocortical function. Ophthalmology 1998;105 (4): 643-50.Allgrove J, Clayden GS, Grant DB, 2. Macaulay JC. Familial glucocorticoid defi ciency with achalasia of the cardia and defi cient tear production. Lancet 1978 17; 1 (8077): 1284-6.Grant DB, Dunger DB, Smith I, Hy-3. land K. Familial glucocorticoid defi -ciency with achalasia of the cardia as-sociated with mixed neuropathy, long-tract degeneration and mild dementia. Eur. J. Pediatr. 1992; 151 (2): 85-9.Ehrich E, Aranoff G, Johnson WG. 4. Familial achalasia associated with ad-renocortical insuffi ciency, alacrima and neurological abnormalities. Am. J. Med. Genet. 1987; 26 (3): 637-44.Pedreira CC, Zacharin MR. Allgrove 5. syndrome: When a recognisable pae-diatric disorder occurs in adulthood. Med. J. Aust. 2004 19;180 (2):74-5.Heinrichs C, Tsigos C, Deschepper J, 6. Drews R, Collu R, Dugardeyn C, et al. Familial adrenocorticotropin un-responsiveness associated with alac-rima and achalasia: Biochemical and molecular studies in two siblings with clinical heterogeneity. Eur. J. Pediatr. 1995; 154 (3): 191-6.Moore PS, Couch RM, Perry YS, 7. Shuckett EP, Winter JS. Allgrove syn-drome: An autosomal recessive syn-drome of ACTH insensitivity, acha-lasia and alacrima. Clin. Endocrinol. (Oxf) 1991; 34 (2): 107-14.Brooks BP, Kleta R, Caruso RC, Stu-8. art C, Ludlow J, Stratakis CA. Triple-A syndrome with prominent ophthalmic features and a novel mutation in the AAAS gene: A case report. BMC Oph-thalmol. 2004 24; 4:7.Lanes R, Plotnick LP, Bynum TE, 9. Lee PA, Casella JF, Fox CE, et al. Glucocorticoid and partial mineralo-corticoid defi ciency associated with achalasia. J. Clin. Endocrinol. Metab. 1980; 50 (2): 268-70.Chu ML, Berlin D, Axelrod FB. All-10. grove syndrome: Documenting cholin-ergic dysfunction by autonomic tests. J. Pediatr. 1996; 129 (1): 156-9.Clark AJ, Weber A. Molecular insights 11. into inherited ACTH resistance syn-109Shawky et al.dromes. Trends Endocrinol. Metab. 1994; 5 (5): 209-14.Prpic I, Huebner A, Persic M, 12. Handschug K, Pavletic M. Tri-ple  A syndrome: Genotype-phe-notype assessment. Clin. Genet. 2003; 63 (5): 415-7.Brooks BP, Kleta R, Stuart C, Tuch-13. man M, Jeong A, Stergiopoulos SG, et al. Genotypic heterogeneity and clinical phenotype in triple A syn-drome: A review of the NIH ex-perience 2000-2005. Clin. Genet. 2005; 68 (3): 215-21.

Triple A syndrome presenting with myopathy: An Egyptian patient

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Triple A syndrome presenting with myopathy: An Egyptian patient

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