Triple A Syndrome with prominent ophthalmic features: a rare case report

1. Triple A Syndrome withprominent ophthalmic features: a rare case report Alacrima Adrenocorticotropic hormone–resistant adrenal insufficiency Achalasia cardia Dr. Ashish Doshi Dr. Priya Patil Dept. of Pediatric Ophthalmology K. B. Haji Bachooali Ophthalmic Hospital, Mumbai

2. Triple A (3A) syndrome • First described by Allgrove et al -1978 • Rare, autosomal recessive Characterized by • Childhood onset • Adrenocorticotropic hormone–resistant adrenal insufficiency • Achalasia cardia • Alacrima, • Autonomous neuropathy • Also called 4A syndrome* * Yasawy M. Allgrove’s syndrome: case report and literature review.J Fam Community Med 2009;16(1):37-40. • Parental consanguinity • previously affected siblings primary risk factors

3. CASE REPORT • 11 year-old girl • product of 2nd degree consanguineous marriage HISTORY: • H/O crying without tears since birth • long-standing dysphagia that started at age two, with frequent regurgitation • family noticed the progressive nasal speech by 4yrs of age • H/O hyperpigmentation by 4-5yrs • H/O anorexia and lack of weight gain by 9yrs • strong family history her brother who suffered from similar complaints as hers, died of acute adrenal insufficiency

4. OCULAR EXAMINATION • Vision BE 6/6 N6 • conjunctivalxerosis • Slit lamp: trace injection, ↓ed tear lake & marked bilateral superficial punctate keratopathy • Schirmer test:1mm RE 3mm LE • BE fundi: pale optic disc • Hypersensitivity to dilute miotics + (signs of autonomic dysfunction, such as pupillary abnormalities)

5. INVESTIGATIOS • Barium swallow: cricopharynx- cervical esophagus junction narrowing with anterior indentation/ filling defect • Diagnosed with adrenocortical insufficiency at age 4 and was subsequently pharmacologically supplemented with glucocorticoids. After ACTH was within normal limits, mineralocorticoid supplementation was initially instituted, but was subsequently discontinued.

6. DISCUSSION • Triple A syndrome is a multisystemic disorder due to a progressive loss of cholinergic function throughout the body. • This disorder may represent a dysfunction of melanocortin receptor signaling, as melanocortin receptors are known to regulate adrenal function and skin exocrine gland function.

7. Pathophysiology • No unifying pathologic features common to the 3 primary sites affected in this syndrome (esophagus, lacrimal glands, adrenal glands) are known. • In 2000, Huebner et al. mapped the syndrome to a 6 cM interval on human chromosome 12q13 near the type II keratin gene cluster.* * Huebner A, Yoon SJ, Ozkinay F, et al. (November 2000). "Triple Asyndrome--clinical aspects and molecular genetics". 26 (4): 751–9. • The triple A syndrome is caused by mutations in the AAAS gene, which encodes a protein known as ALADIN (ALacrima Achalasia aDrenalInsuffiency Neurologic disorder).* * Huebner, Angela; Kaindl, A.M.; Knobeloch, K.P.; Petzold, H.; Mann, P.; Koehler, K. “The Triple A Syndrome Is Due to Mutations in Aladin, a Novel Member of the Nuclear Pore Complex.” Endocrine Research 30 (2004): 891-899 • Since inheritance and gene for the association is known, early diagnosis can allow genetic counseling.* * Bharadia, Lalit; Kalla, Mukesh; Sharma, S K; Charan, Rohit; Gupta, J B; Khan, Firoz. “Triple A Syndrome.” Indian Journal of Gastroenterology 24 (2005): 218 .

8. General manifestations of triple A includes:* Isolated glucocorticoid failure: hypoglycemia, weakness, fatigue, anorexia, nausea, vomiting, constipation, abdominal pain, diarrhea, salt carving, Postural dizziness, hypotension, weight loss, hyperpigmentation, vitiligo, auricular calcification, electrolyte disturbances, anemia, eosinophilia, Hypothyroidism Alacrima, Achalasia. * Allgrove J, Clayden GS, Grant DB, Macaulay JC. Familial glucocorticoid deficiency with achalasia of the cardia and deficient tear production. Lancet. 1978; 1: 1284 – 1286.

9. Other manifestations: • Palmoplantar hyperkeratosis, • short stature, • gonadal failure, • microcephaly, • osteoporosis, • pes cavus. • Neurological abnormalities comprise autonomic, • sensory, and motor neuropathies, • progressive • spastic tetraparesis, dysarthria, • prolonged nerve conduction times, • Muscle weakness, distal limb atrophy, • deafness, • Mild mental retardation, • periventricular brain heterotopias, • mild dementia, • cerebellar ataxia Allgrove J, Clayden GS, Grant DB, Macaulay JC. Familial glucocorticoid deficiency with achalasia of the cardia and deficient tear production. Lancet. 1978; 1: 1284 – 1286.

10. Ophthalmic manifestations of Triple A includes: • Alacrima • keratoconjunctivalsicca, sometimes result in corneal melting • lacrimal gland atrophy • pupillary abnormalities includes sluggish pupils, tonic pupils & hypersensitivity to dilute miotics • Optic atrophy • El-RayyesKalid, HegabSamiha, Besisso Mohammed: A syndrome of alacrima, achlasia, and neuroloogic anomalies without adremocortical insufficiency. J PediatrOphthalmol Strabismus 1991, 28:35-37. • Mullaney PB, Weatherhead R, Millar L, Ayyash II, Ayberk H, Cai F, Risco JM: Keratoconjunctivitissicca associated with achalasia of the cardia, adrenocorticalinsufficiency, and lacrimal gland degeneration. Ophthalmology 1998, 105:643-650. • Tsilou E, Stratakis CA, Rubin BI, Hay BN, Patronas N, Kaiser-Kupfer MI: Ophthalmic manifestations of Allgrovesyndrome:report of a case.Clin Dysmorphol2001,10:231-233. • Brooks B, Kleta R , Rafael C,Stuart C, Ludlow J, Constantine A. Triple-A syndrome with prominent ophthalmic features and a novel mutation in the AAAS gene: a case report. BMC Ophthalmology 2004, 4:7doi:10.1186/1471-2415-4-7

11. CONCLUSION • This is an evolving condition and patients may develop multiple features over time. • Even in the presence of only one of the main symptoms a high index of suspicion should be maintained. • There is marked clinical variability even in one family and all siblings should be thoroughly investigated. • Early diagnosis helps in screening for the subsequent development of associated features and reduces the risk of presentation with potentially life-threatening adrenal failure. • Effective management can result in near normal life span.