Clin Genet 2010: 77: 298–301 Printed in Singapore. All rights reserved
© 2010 John Wiley & Sons A/S CLINICAL GENETICS doi: 10.1111/j.1399-0004.2009.01348.x
Letter to the Editor
Two Italian patients with novel AAAS gene mutation expand allelic and phenotypic spectrum of triple A (Allgrove) syndrome To the Editor: Triple A or Allgrove syndrome (AS) (MIM 231550) is a rare autosomal recessive disorder of adreno cortico tropic hormone (ACTH) resistant adrenal insufficiency, achalasia and alacrimia (1). While alacrimia is often present at birth, and if untreated may lead to acute keratopathy and corneal ulcerations (2), achalasia manifests with age with dysphagia and feeding difficulties together with adrenal insufficiency (3, 4). This core phenotype may evolve with progressive neurological degeneration, cutaneous alterations (palmoplantar hyperkeratosis), short stature and osteoporosis (5–7), the first cause of death being an undiagnosed ‘adrenal crisis’. AS is caused by mutations in the AAAS gene (8–10), encoding Aladin, a member of the nucleoporin family at the nuclear pore complex (NPC), composed of a central 170-aa domain with four WD repeats (11). Nucleoporins play a crucial role in transport processes between nucleus and cytoplasm, while Aladin interaction with the NPC suggests a role as a structural scaffold (12, 13). No clear genotype–phenotype correlations have been established in AS (14), and lack of AAAS gene mutations in some AS patients suggested genetic heterogeneity (5, 15). We have ascertained two unrelated Italian patients affected by AS who shared in common a novel AAAS mutation together with discrete clinical manifestations. Patient 1 is a 29-year-old woman, the fourth child of healthy, non-consanguineous parents, born at term after an uneventful pregnancy with weight, length and head circumference values within normal parameters. At age 2, feeding difficulties with recurrent vomit occurred. A barium esophagogram showed dilated and hypotonic proximal esophagus with a column of barium visible above the lower esophageal sphincter (LES), while achalasia was confirmed by manometry revealing esophageal aperistalsis and a poor relaxing LES. Gait disturbances manifested at age 12 with inability to walk 298
on her heel. Lower-limb distal muscle atrophy was recorded and electromyography disclosed axonal motor and sensory polyneuropathy. Evoked visual potentials performed at age 22 showed reduced amplitude and elongated latency in the right eye, while brain magnetic resonance did not reveal any abnormality. At age 29, she had a suffering appearance (Fig. 1a) with generalized weakness, nasal speech, and scrotal tongue with fasciculation (Fig. 1b). Edentulism was noticed secondary to teeth decays, recurrent caries and multiple abscesses occurring by the age of 12. Generalized muscular hypotrophy associated with atrophic intrinsic hand muscles and bilateral pes cavus with thin legs were observed (Fig. 1c–f). She used to cry without tears, and Schirmer test confirmed alacrimia ( C heterozygous, the father being wild type in the presence of a biologically proven nonpaternity condition. Both mutations were absent in a panel of 300 control chromosomes from healthy individuals. The herein described AS patients represent the first Italian mutated cases (15). So far, more than 30 different AAAS mutations are reported (www.hgmd.cf.ac.uk/), causing in most cases the truncation of the C-terminal portion of Aladin (16, 17). Conversely, only five missense alterations are described (four within the WD-repeat domain and one close to the N-terminal 299
Letter to the Editor Table 1. Clinical and laboratory findings in two patients with Allgrove syndrome (AS) compared to previously reported features Clinical characteristics Gender Age at diagnosis Achalasia Alacrimia Glucocorticoid deficiency Neurological dysfunction Nasal speech Mineralcorticoid deficiency Osteoporosis Scrotal tongue Palmoplantar hyperkeratosis Short stature Edentulism
Patient 1
Patient 2
Previously reported patients
F 30 + + +
M 18 + + +
F–M Variable + + +
+
+
+
+ −
+ +
+ ±
− + −
− − −
± ± ±
− +
− +
± −
F, female; M, male; +, constant feature; ±, feature present in some AS patients; −, feature not reported.
portion), suggesting these domains are mandatory for its correct targeting to NPC (16, 17). The novel Leu469Pro mutation we report alters a highly conserved residue of the Aladin protein (Fig. 1h) and represents the first missense mutation located in the C-terminal domain. Its recurrence in two unrelated patients is surprising, taking into consideration the different geographic origins (Central and North-Eastern Italy). Seeking for possible genotype–phenotype correlates, we looked for discrete clinical manifestations in our patients and, indeed, both exhibiting edentulism, a sign not previously described in AS (Table 1). Although this observation points to a possible correlation with the newly reported Leu469Pro mutation, further studies are needed to support this hypothesis. In conclusion, we have broadened the allelic and phenotypic spectrum of AS due to AAAS mutations. The recurrence of the Leu469Pro mutation highlights a possible major role for this alteration in the Italian population with relevant implications for genetic testing and counseling. C Palkaa R Giuliania F Brancatia – c A Mohnd A Di Muzioc O Calabresee A Huebner f 300
D De Grandise F Chiarellid A Ferlinie L Stuppiaa,c,g a Department of Biomedical Sciences, “G. d’Annunzio” University, Chieti-Pescara, Italy, b IRCCS-CSS, San Giovanni Rotondo and CSS-Mendel, Rome, Italy, c Ageing Research Centre, CESI, “G. d’Annunzio” University Foundation, Chieti-Pescara, Italy, d Department of Pediatrics “G. d’Annunzio” University, Chieti-Pescara, Italy, e Department of Experimental and Diagnostic Medicine, Section of Medical Genetics, University of Ferrara, Ferrara, Italy, f Children’s Hospital, Technical University Dresden, Dresden, Germany, and g IGM CNR, Bologna, Italy
References 1. Allgrove J, Clayden GS, Grant DB et al. Familial glucocorticoid deficiency with achalasia of the cardia and deficient tear production. Lancet 1978: 1 (8077): 1284–1286. 2. Moore PSJ, Couch RM, Perry YS et al. Allgrove syndrome: an autosomal recessive syndrome of ACTH insensitivity, achalasia and alacrima. Clin Endocrinol (Oxf) 1991: 34 (2): 107–114. 3. Bentes C, Santos-Bento M, de S´a J et al. Allgrove syndrome in adulthood. Muscle Nerve 2001: 24 (2): 292–296. 4. Grant DB, Barnes ND, Dumic M et al. Neurological and adrenal dysfunction in the adrenal insufficiency/alacrima/ achalasia (3A) syndrome. Arch Dis Child 1993: 68 (6): 779–782. 5. Houlden H, Smith S, De Carvalho M et al. Clinical and genetic characterization of families with triple A (Allgrove) syndrome. Brain 2002: 125 (Pt 12): 2681–2690. 6. Prpic I, Huebner A, Persic M et al. Triple A syndrome: genotype-phenotype assessment. Clin Genet 2003: 63 (5): 415–417. 7. Koehler K, Brockmann K, Krumbholz M et al. Axonal neuropathy with unusual pattern of amyotrophy and alacrima associated with a novel AAAS mutation p.Leu430Phe. Eur J Hum Genet 2008: 16 (12): 1499–1506. 8. Huebner A, Kaindl AM, Knobeloch KP et al. The triple A syndrome is due to mutations in ALADIN, a novel member of the nuclear pore complex. Endocr Res 2004: 30 (4): 891–899. 9. Hadj-Rabia S, Salomon R, Pelet A et al. Linkage disequilibrium in inbred North African families allows fine genetic and physical mapping of triple A syndrome. Eur J Hum Genet 2000: 8 (8): 613–620. 10. Tullio-Pelet A, Salomon R, Hadj-Rabia S et al. Mutant WDrepeat protein in triple-A syndrome. Nat Genet 2000: 26 (3): 332–335. 11. Cronshaw JM, Krutchinsky AN, Zhang W et al. Proteomic analysis of the mammalian nuclear pore complex. J Cell Biol 2002: 158 (5): 915–927. 12. Rabut G, Doye V, Ellenberg J. Mapping the dynamic organization of the nuclear pore complex inside single living cells. Nat Cell Biol 2004: 6 (11): 1114–1121.
Letter to the Editor 13. Rabut G, L´en´art P, Ellenberg J. Dynamics of nuclear pore complex organization through the cell cycle. Curr Opin Cell Biol 2004: 16 (3): 314–321. 14. Sandrini F, Farmakidis C, Kirschner LS et al. Spectrum of mutations of the AAAS gene in Allgrove syndrome: lack of mutations in six kindreds with isolated resistance to corticotropin. J Clin Endocrinol Metab 2001: 86 (11): 5433– 5437. 15. Brooks BP, Kleta R, Stuart C et al. Genotypic heterogeneity and clinical phenotype in triple A syndrome: a review of the NIH experience 2000–2005. Clin Genet 2005: 68 (3): 215–221. 16. Cronshaw JM, Matunis MJ. The nuclear pore complex protein ALADIN is mislocalized in triple A syndrome. Proc Natl Acad Sci U S A 2003: 100 (10): 5823–5827.
17. Cho AR, Yang KJ, Bae Y et al. Tissue-specific expression and subcellular localization of ALADIN, the absence of which causes human triple A syndrome. Exp Mol Med 2009: 41 (6): 381–386. Correspondence: Professor Liborio Stuppia Department of Biomedical Sciences University “G. D’Annunzio” Via dei Vestini 35 66013 Chieti Italy Tel.: +39 0871 3554137 Fax: +39 0871 3554133 e-mail:
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