Double ‘A’ phenotypes with mineralocorticoid deficiency: A rare presentation of Allgrove syndrome

Abstract

Allgrove syndrome (AS), an uncommon multisystem disorder, is characterized by the classic clinical triad of alacrimia, achalasia, and adrenal insufficiency, and is typically limited to glucocorticoid deficiency with preserved mineralocorticoid (MC) function. Here, we present the case of a 5-yr-old girl with alacrimia since birth, failure to thrive, and generalized hyperpigmentation for the past two years, who presented to the emergency department with an altered sensorium. Upon admission, the patient was found to have hypoglycemia and hyponatremia. After subsequent evaluation, the patient was diagnosed with phenotypically incomplete AS with mineralocorticoid insufficiency and harbored a novel homozygous mutation in exon 7 of the AAAS gene (c.618del; p.Ser207LeufsTer84). Treatment with hydrocortisone and fludrocortisone yielded remarkable outcomes. Given the variable presentations of this condition, a high index of clinical suspicion and awareness of atypical features are essential for early diagnosis and initiation of coordinated care to prevent unnecessary morbidity and mortality. When AS is suspected, molecular genetic testing should be performed to confirm the diagnosis, plan management, and provide genetic counseling.

Highlights

● AS usually presents with glucocorticoid-limited adrenal insufficiency with preserved MC function.

● A novel AAAS exon 7 mutation (c.618del; p.Ser207LeufsTer84) resulted in incomplete AS with MC deficiency.

Introduction

Triple A syndrome, also known as Allgrove syndrome (AS; OMIM: #231550), is an uncommon autosomal recessive multisystem disorder characterized by the cardinal triad of alacrimia, achalasia, and adrenal insufficiency (AI) which is resistant to ACTH stimulation. The disease spectrum varies widely and is sometimes associated with autonomic manifestations called the ‘4A’ syndrome (1, 2). Nearly two-thirds of patients present with all three primary symptoms, whereas approximately one-third present with only two. Fewer than 10% of patients present with only a single symptom (3). The presence of two cardinal clinical entities strongly suggests a diagnosis. Since its first description by Allgrove et al. (4), knowledge about its phenotypic and genotypic characteristics has continued to expand; however, the literature on this condition is primarily composed of case reports and case series. Given its rarity, high phenotypic heterogeneity even among members of the same kin, and atypical presentations, early recognition of the syndrome is challenging. A high index of clinical suspicion and awareness of atypical features are paramount for establishing a diagnosis and initiating early coordinated care for better outcomes.

We report a rare case of phenotypically incomplete AS in a 5-yr-old girl who presented with mineralocorticoid insufficiency.

Case Report

A 5-yr-old girl was referred to our hospital for evaluation of an altered sensorium and hyperpigmentation of the skin. She was the offspring of healthy nonconsanguineous parents and had two healthy older sisters. The patient had an uneventful perinatal period, age-appropriate developmental milestones, and unremarkable medical history. However, her parents reported that the child had experienced failure to thrive over the past two years and had lacked tears while crying since early infancy, for which no medical consultation had been sought during that period.

On initial assessment, she was drowsy and tachycardic (heart rate: 130 beats/min), had a blood pressure below the 5^th centile (82/52 mmHg), had a respiratory rate of 29 cycles/min, and maintained 98% oxygen saturation in room air. Her height (112 cm) was between the 50^th and 97^th centiles, and her weight (13.5 kg) was below the 3^rd centile on the WHO charts. Initial investigations revealed hypoglycemia (blood glucose: 35 mg/dL) and hyponatremia (Na: 121 mmol/L). The patient was transferred to the pediatric intensive care unit (PICU). Critical blood and urine samples were collected. Initial resuscitation was performed with normal saline and a 10% dextrose bolus as per the institutional PICU protocol. Gradual correction of hyponatremia was performed over 48 h with 3% normal saline, and no rebound hyponatremia was noted thereafter.

A detailed physical examination revealed palmoplantar hyperkeratosis with generalized hyperpigmentation of the skin, knuckles, lips, gums, buccal mucosa, palmar creases, and elbows, which had gradually increased over the past 2 yr (Fig. 1). Results of other general and systemic examinations, including those of the nervous system, were normal. There were no signs of autonomic instability.

Fig. 1.

Clinical image of the patient showing hyperpigmentation of the (A) eyelids, (B) lips, (C) oral mucosa with dental caries, (D) palms, and (E) soles.

An ophthalmological consultation was performed to evaluate the presence of alacrimia. The corrected visual acuity was 20/20 in both eyes. Upon double eversion of the upper eyelids, the palpebral portion of the lacrimal gland was not visible in either eye. Extraocular movements were normal, although the pupillary reflexes (direct, indirect, and accommodation) were sluggish in both eyes. The pupils measured 4 mm in diameter and were constricted to 2 mm after application of 0.125% topical pilocarpine for 15 min, indicating hypersensitivity to dilute pilocarpine. Slit-lamp examination revealed a decreased tear meniscus in both eyes and mild superficial punctate keratopathy in the left eye. The Schirmer test (using Whatman filter paper 41) revealed 3 mm of wetting in the right eye and 5 mm in the left eye, confirming a dry eye (normal wetting was greater than 10 mm). Cycloplegic refraction revealed no abnormalities. Fundus examination results were normal for both eyes.

AI was suspected based on the patient’s clinical presentation. Hormonal evaluation revealed markedly low morning serum cortisol levels (< 0.4 µg/dL) with elevated ACTH levels (361 pg/mL), consistent with primary AI. Thyroid function testing showed elevated thyroid stimulating hormone (TSH) levels with borderline low free thyroxine (T4) levels and negative anti-thyroid antibodies, suggestive of subclinical hypothyroidism without evidence of autoimmune thyroid disease. The patient also had hyponatremia, normokalemia, and increased plasma renin activity (PRA) (Table 1).

Table 1. Laboratory profile of the patient.

The patient received an initial intravenous bolus of hydrocortisone (50 mg/m²), followed by 50 mg/m² per day in four divided doses. Following clinical stabilization, she was transitioned to oral hydrocortisone for ongoing glucocorticoid replacement, along with fludrocortisone to address mineralocorticoid deficiency. Magnetic resonance imaging (MRI) of the abdomen revealed little to no adrenal gland tissue (Fig. 2A). Brain MRI normal; MRI orbits revealed bilateral hypoplastic lacrimal glands (Fig. 2B). The interictal EEG was normal. Nerve conduction study revealed no abnormalities. Infectious etiologies of AI were ruled out by relevant investigations. A barium meal swallowing study revealed no abnormalities. Mutation analysis identified a homozygous deletion in exon 7 of the AAAS gene (c.618del; p.Ser207LeufsTer84), resulting in a truncated nonfunctional protein, which confirmed the diagnosis of triple A syndrome in our patient.

Fig. 2.

Fat-suppressed MR sequences showing (A) an atrophied streak-like left adrenal gland (red arrow) with no visualization of the right adrenal gland and (B) bilateral hypoplastic lacrimal glands (yellow arrowheads).

Subsequently, oral maintenance therapy was started with hydrocortisone (dosed at 15 mg/m²/d) and 50 μg/d of fludrocortisone. Artificial tears containing topical vitamin A were prescribed for the treatment of alacrimia. This treatment resulted in the maintenance of normal electrolytes, blood glucose, and blood pressure, with normalization of the thyroid function status within 3 mo. On regular follow-up for 12 mo, a remarkable improvement was noted in the patient’s auxological parameters, and pigmentation also decreased significantly.

Ethical consideration

This study complied with all the relevant national regulations, institutional policies, and the Declaration of Helsinki. Written informed consent was obtained from the patient’s parents for genetic testing and publication of clinical images and investigative findings.

Discussion

AS is increasingly considered a multisystem disease; its phenotype is complex and all clinical features are progressive, suggesting a degenerative process. The exact disease burden in children remains unknown because it has been frequently misdiagnosed and underreported (5). The median age at presentation is 5 yr. The lifetime prevalence of alacrimia, achalasia, and AI is reported to be 99%, 90.1%, and 79.4%, respectively (1, 3).

The onset of the clinical features of this syndrome does not follow a specific order. However, alacrimia is usually the earliest symptom that may present from birth or early infancy, as in our case, but it is often overlooked by parents, possibly owing to its negligible clinical relevance and morbidity (6). Other ocular manifestations of AS include keratoconjunctivitis sicca and pupillary abnormalities such as sluggish or tonic pupils with heightened sensitivity to dilute miotics, accommodative dysregulation, amblyopia, and optic atrophy (7, 8).

In addition to AS, alacrimia, an early clinical diagnostic signpost, is observed only in a limited number of congenital disorders such as familial dysautonomia (OMIM #223900), lacrimoauriculodentodigital syndrome (OMIM #149730), anhidrotic ectodermal dysplasia (OMIM #224900), Sjogren’s syndrome (OMIM #270150), congenital disorders of glycosylation (OMIM #615273), and triple A-like syndrome without AI (7). Children presenting with alacrimia with or without other systemic features should be thoroughly investigated for these underlying conditions.

Lacrimation (both basal and reflex), pupillary, and accommodation reflexes are controlled by the parasympathetic nervous system. Autonomic dysfunction affecting the lacrimal gland and pupils results in AS abnormalities, as observed in the present case (8, 9). A biopsy of the lacrimal gland revealed evidence of neuronal degeneration and a reduction in the number of secretory granules within the acinar cells (10). The upregulation of postsynaptic muscarinic receptors in the iris sphincter, likely due to autonomic instability, is thought to be responsible for the hypersensitivity to pilocarpine (0.125%) observed in this case. Furthermore, refractive issues may arise from accommodative dysregulation, which can result from autonomic dysfunction or neurodegenerative changes affecting the cranial nerves (11). Other autonomic manifestations may include orthostatic hypotension, decreased sweating, sexual impotence, heart rate and rhythm disturbances, and abnormal reactions to intradermal histamine (1, 3, 12).

Almost two-thirds of patients receive clinical attention owing to AI, as in our case. It is usually the 2^nd most common triad component after alacrimia. Hypofunction of the adrenal glands is not present at birth but develops gradually over time, with a median age of presentation of 6 yr, and is usually progressive (13). Adrenal impairment is generally restricted to patients with glucocorticoid deficiency, whereas mineralocorticoid deficiency has only been reported in 15% of the patients (1, 13, 14). A possible hypothesis for the relative preservation of the zona glomerulosa is that aldosterone biosynthesis involves lower oxidative stress than cortisol biosynthesis, potentially due to differences in steroid output. However, this hypothesis remains speculative. Mutations in the AAAS gene lead to ALADIN dysfunction, which disrupts nuclear import of DNA repair and antioxidant proteins. This increases cellular susceptibility to oxidative stress, which may impair steroidogenesis by promoting electron leakage in the steroidogenic pathway and enhancing reactive oxygen species (ROS) production (13, 15, 16).

Adrenal function can be deficient, insufficient, or compensated. Depending on the adrenal function status, the child can present with near-fatal hypoglycemic seizures, as observed in our patient, hypotensive attacks, or no symptoms due to compensatory adrenal function (13). Therefore, timely diagnosis of triple A syndrome is essential to prevent an unrecognized adrenal crisis. The corticotropin stimulation test is the ‘gold standard’; morning cortisol < 5 μg/dL in combination with plasma ACTH > 2-fold the upper limit of the reference range is virtually consistent with the diagnosis of primary AI, as found in our patient (17).

The clinical presentation of mineralocorticoid deficiency is characteristically associated with hypovolemia and electrolyte abnormalities, such as hyponatremia, hyperkalemia, and metabolic acidosis. Although the serum aldosterone concentration could not be measured in the index case, the presence of hyponatremia and elevated plasma renin activity (PRA) indicated mineralocorticoid deficiency (1). In the early stages of this deficiency, PRA may be elevated, even when aldosterone levels are normal (18). Hyperkalemia may also be absent during the evolving phase of zona glomerulosa dysfunction because the remaining functional cells can still produce aldosterone in response to severe hypovolemia, thereby preventing hyperkalemia (19). Thus, an elevated PRA serves as an early indicator of zona glomerulosa involvement. Early diagnosis of mineralocorticoid deficiency, even at the subclinical stage, is essential to initiate appropriate replacement therapy. Inadequate mineralocorticoid treatment in primary adrenal insufficiency often leads to persistent symptoms such as salt craving and postural dizziness. Furthermore, the replacement of mineralocorticoids is commonly compensated for by glucocorticoid overreplacement, which is linked to adverse long-term outcomes.

Esophageal achalasia in childhood is rare, with fewer than 5% of patients being diagnosed under 15 years of age and is often misdiagnosed and treated as a gastroesophageal reflux disorder (1). The exact mechanism is not fully understood; however, fibrosis of the intermuscular plane and absence of myenteric ganglia at the lower end of the esophagus are the most accepted hypotheses (20). Esophageal manometry is the gold standard for diagnosis. Owing to the lack of indicative signs and symptoms and a normal barium meal swallow study, we deferred this test for the time being with a plan to prompt the elucidation of any suggestive symptoms during follow-up.

Most cases are caused by a mutation in the AAAS gene located on chromosome 12q13, which encodes a nucleoprotein named ALADIN that is involved in the transduction of intracellular signaling pathways in the context of nuclear defense against oxidative stress. Some of the remaining cases may be attributed to mutations in GMPPA or TRAPPC11, which produce features resembling triple-A syndrome without AI (21, 22). This protein is primarily found in the brain, pituitary gland, cerebellum, adrenal glands, and gastrointestinal tract, which are the key organs affected by this condition.

Genotype-phenotype correlations in AS remain variable (3). The c.618del (p.Ser207LeufsTer84) truncating mutation in the AAAS gene has previously been reported in two unrelated Swiss patients with early onset glucocorticoid deficiency and alacrimia, but preserved mineralocorticoid function (23). By contrast, our patient exhibited both glucocorticoid and mineralocorticoid deficiencies. This phenotypic divergence suggests variable expressivity of the same mutation, potentially influenced by population-specific genetic modifiers or environmental factors affecting the zona glomerulosa function. To our knowledge, this novel frameshift variant has not been previously reported in Indian patients, highlighting its rarity in the local population (24, 25). These findings support the need for routine evaluation of both the glucocorticoid and mineralocorticoid axes in patients with AAAS mutations. Furthermore, as an autosomal recessive disorder, AS carries a 25% recurrence risk in future pregnancies, highlighting the importance of identifying the causative mutations and monitoring at-risk asymptomatic siblings for timely interventions.

In conclusion, AS is a multisystem disorder characterized by various phenotypic presentations that can manifest at any age. Given the variable presentation, a high index of clinical suspicion and awareness of atypical features are paramount for an early diagnosis and the initiation of coordinated care to avert undue morbidity and mortality. Occasionally, direct questioning to elucidate alacrimia in a patient presenting with AI or achalasia may aid in diagnosis. When suspected, molecular genetic testing should be performed to confirm the diagnosis, plan management, and provide genetic counseling. However, more research is urgently needed to expand the knowledge on clinical and genetic patterns to define the phenotype more precisely and permit the identification of patients with incomplete AS manifestations.

Conflict of interests

The authors declare no conflicts of interest.