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Triple A syndrome with ophthalmic manifestations in two siblings

Babu, Kalpana MRCOphth; Murthy, Krishna R MRCOphth; Babu, Narendra MS; Ramesh, S MS

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Indian Journal of Ophthalmology: Jul–Aug 2007 - Volume 55 - Issue 4 - p 304-306
doi: 10.4103/0301-4738.33048
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Triple A syndrome (Allgrove syndrome) is a rare, autosomal recessive disorder characterized by adrenocorticotrophic hormone (ACTH) resistant adrenal insufficiency, alacrima, achalasia of the esophageal cardia, progressive neurological degeneration and occasionally autonomic instability.12 There are a few case reports in literature describing triple A syndrome with some ocular features.1234567 We report interesting cases of 2 siblings from consanguineous family with triple A syndrome who had notable ophthalmic manifestations.

Case 1

A 7-year-old girl, with diagnosis of triple A syndrome, was referred to the pediatric ophthalmology department, for ophthalmic evaluation. She had a history of frequent vomiting after intake of food, loss of weight and failure to thrive. She cried without tears since birth. Her antenatal and perinatal history was unremarkable. Her seven months old brother had similar complaints. The laboratory investigations showed renal function, liver function, serum electrolytes, ACTH and serum cortisol levels were in normal range. She did not have any adrenocortical insufficiency. The diagnosis of achalasia cardia of the esophagus was made on the basis of barium swallow X-ray. Neurological examination was normal.

Ocular examination showed a best corrected visual acuity of 20/20 in both eyes. The palpebral portion of the lacrimal gland was not visible in both eyes [Fig. 1]. Extraocular movements were full. There was anisocoria with sluggish pupillary reflexes in both eyes (direct, consensual and accommodation). Clinically her pupils were 5mm and 4mm in the right and left eyes respectively. Both pupils constricted to 2.5 mm with 0.125% topical pilocarpine in approximately 15 minutes indicating hypersensitivity to dilute pilocarpine. Slit lamp examination showed mild conjunctival congestion. Additionally, a decreased tear meniscus in both eyes along with a mild superficial punctate keratopathy in the right eye was seen. Schirmer's test I (Whatman filterpaper 41) showed 2 mm and 8 mm wetting in the right and left eyes respectively. Fundus examination was normal in both eyes. A cycloplegic refraction did not reveal any abnormality.

Figure 1
Figure 1:
Clinical photograph showing absence of the palpebral portion of the lacrimal gland on double eversion

Case 2

The girl's 7 months old brother also had a history of crying without tears since birth. His antenatal and natal history were normal. He also had a history of frequent vomiting after intake of milk, loss of weight and failure to thrive. The laboratory investigations showed renal function, liver function, serum electrolytes and ACTH levels in the normal range. However his initial serum cortisol levels were marginally elevated consistent with a stress response to the needle prick. The diagnosis of achalasia cardia of the esophagus was made on the basis of barium swallow X-ray [Fig. 2]. Neurological examination was normal.

Figure 2
Figure 2:
Barium swallow X ray showing achalasia of the esophageal cardia

His pupils measured 4 mm in both eyes with sluggish pupillary reactions to light. Both pupils constricted to 2.5 mm with 0.125% pilocarpine in approximately 15 minutes indicating hypersensitivity to dilute pilocarpine. Slitlamp examination showed superficial punctate keratopathy in both eyes. Schirmer's test I (Whatman filterpaper 41) showed 1 mm wetting in both eyes.

Frequent ocular lubrication with topical tear substitutes, four times a day was given to both the cases. For the esophageal achalasia, both of them underwent Hellers cardiomyotomy with fundus plication. Postoperatively, both are stable and doing well systemically, with no further ocular problems.


Triple A syndrome may also be remembered as 4A syndrome.45 Alacrima is the first and most consistent feature of this syndrome.6 Other features, such as achalasia cardia or insensitivity to ACTH may present over a variable time course.7 This syndrome is likely due to mutations in the AAAS gene whose predicted product is ALADIN (alacrima-achalasia-adrenal insufficiency neurologic disorder); located on chromosome 12q13.12 The findings associated with this condition are listed in table 1. There has also been an isolated report of association of triple A syndrome with chronic asymptomatic neutropenia.8

Table 1
Table 1:
Systemic features of Allgrove syndrome

The ophthalmic manifestations include alacrima, keratoconjunctivitis sicca, corneal melts, lacrimal gland atrophy, pupillary abnormalities including sluggish pupils, tonic pupils with hypersensitivity to dilute miotics, accommodative dysregulation, amblyopia and optic atrophy.12

Lacrimation (both reflex and basal), pupillary miosis and the process of accommodation are under parasympathetic control. Autonomic dysfunction at the level of the lacrimal gland and the pupil explains the abnormalities seen in this condition. Mullaneyet al.1 noted small lacrimal glands on orbital imaging and a reduced number of serous secreting cells on lacrimal gland biopsy of three patients with triple A syndrome. The hypersensitivity to dilute pilocarpine (0.125%) noted in this case is likely due to upregulation of postsynaptic muscarinic receptors on the iris sphincter due to autonomic instability. Refractive difficulties may occur in these patients as a result of accommodative dysregulation due to autonomic dysfunction or due to a neurodegenerative process affecting the cranial nerves. The varied clinical presentations described in the literature probably reflect a combination of both slow disease progression and clinical variability.1

Two cases with triple A syndrome with ocular features has been described. These case reports would make us aware of such disease associations. The ophthalmologists should look for other systemic features in children with ophthalmic manifestations of dry eyes.

1. Mullaney PB, Weatherhead R, Millar L, Ayyash II, Ayberk H, Cai F, et al Keratoconjunctivitis sicca associated with achalasia of the cardia, adrenalcortical insufficiency and lacrimal gland degeneration: Keratoconjunctivitis sicca secondary to lacrimal gland degeneration may parallel degenerative changes in esophageal and adrenocortical function Ophthalmology. 1998;105:643–50
2. Brooks BP, Kleta R, Caruso RC, Stuart C, Ludlow J, Stratakis CA. Triple A syndrome with prominent ophthalmic features and a novel mutation in the AAAS gene: A case report BMC Ophthalmol. 2004;4:7
3. Singh A, Shah A. Esophageal achalasia and alacrimia in siblings Indian Paediatr. 2006;43:161–3
4. Kimber J, McLean BN, Prevett M, Hammans SR. Allgrove or 4 "A" syndrome: An autosomal recessive syndrome causing multisystem neurological disease J Neurol Neurosurg Psychiatry. 2003;74:654–7
5. Gazarian M, Cowell CT, Bonney M, Grigor WG. The "4A" syndrome: Adrenocortical insufficiency associated with achalasia, alacrima, autonomic and other neurological abnormalities Eur J Pediatr. 1995;154:18–23
6. Moore PS, Couch RM, Perry YS, Shuckett EP, Winter JS. Allgrove syndrome: An autosomal recessive syndrome of ACTH insensitivity, achalasia and alacrima Clin Endocrinol (Oxf). 1991;34:107–14
7. Pedreira CC, Zacharin MR. Allgrove syndrome: When a recognizable paediatric disorder occurs in adulthood MJA. 2004;180:74–5
8. Spiegel R, Shaley S, Huebner A, Horovitz Y. Association of chronic symptomatic neutropenia with the Triple A syndrome J Paediatr Haematol Oncol. 2005;27:53–5

Alacrima; autonomic dysregulation; triple A syndrome.

© 2007 Indian Journal of Ophthalmology | Published by Wolters Kluwer – Medknow