Toward a deeper and more comprehensive understanding of neurological symptoms related to Allgrove syndrome: a case report

Abstract

Introduction and importance:

Allgrove syndrome (AS) is a rare autosomal recessive disorder caused by triple A syndrome gene mutations, characterized by alacrima, achalasia, and adrenocorticotropic hormone (ACTH)-resistant adrenal insufficiency, with potential neurological complications. Early signs include absent tears, feeding difficulties, vomiting, and growth issues, while adrenal crises and neurological symptoms may appear later. Diagnosis is often delayed when only one feature is present.

Case presentation:

We report a 13-year-old boy with AS on oral hydrocortisone who presented with recurrent vomiting for 1 month. Neurological examination revealed below-average intellectual function, decreased muscle bulk, mild weakness, bilateral hyperreflexia, wide-based ataxic gait, intention tremor, dysarthria, and positive finger–nose test. Cranial nerves and sensation were intact. Laboratory investigations showed elevated ACTH due to poor hydrocortisone absorption, and endoscopy confirmed achalasia. He was switched to intravenous hydrocortisone and underwent Heller myotomy with Nissen fundoplication, resulting in resolution of vomiting and normalization of ACTH, though neurological symptoms persisted.

Clinical discussion:

AS often presents first with alacrima, followed by achalasia, causing dysphagia and vomiting, and adrenal insufficiency developing in childhood, which can be life-threatening. Neurological manifestations may include ataxia, tremor, hyperreflexia, and cognitive impairment. Our case highlights the impact of achalasia on hydrocortisone absorption and the need for early multidisciplinary intervention.

Conclusion:

Early recognition, long-term follow-up, and proper care are crucial to prevent adrenal crises and manage neurological complications, improving outcomes and quality of life in affected patients.

Introduction

Triple A syndrome (AAAS), also known as Allgrove syndrome (AS), is a rare autosomal recessive disorder characterized by the triad of alacrima, achalasia, and adrenocorticotropic hormone (ACTH)-resistant adrenal insufficiency[1]. It has an estimated prevalence of 10 patients per 100 000 population, which makes it rare[2]. The underlying genetic cause is a mutation on chromosome 12q13, affecting the AAAS gene, which encodes the ALADIN protein – named for its association with Alacrima, Achalasia, Adrenal Insufficiency, and Neurologic abnormalities[3].

HIGHLIGHTS

• Allgrove syndrome sometimes exhibits a mixture of peripheral, central, and autonomic neurological manifestations.

• In line with other findings emphasizing the progressive and multisystemic nature of this condition, neurological signs such as ataxia, dysarthria, tremor, hyperreflexia, and cognitive delay were also noted.

• It is crucial to identify gastrointestinal involvement in patients with unexplained adrenal insufficiency, as demonstrated in our instance, where chronic vomiting initially made adrenal replacement therapy more difficult.

• Early diagnosis, close long-term follow-up, and proper management are critical to prevent complications and monitoring late-onset neurological deficits to improve patients’ quality of life.

The clinical presentation of AS varies depending on the patient’s age. Common early signs include alacrima, often noted as absent or reduced tear production during crying in infancy, as well as feeding difficulties, recurrent vomiting, and weight loss due to achalasia. In some cases, seizures caused by hypoglycemia during an adrenal crisis, delayed developmental milestones, and growth retardation may also occur. Neurological complications are frequently reported as the disease progresses[4]. Early diagnosis can be challenging, particularly when only one symptom is present, leading to consideration of other differential diagnoses. However, the presence of two hallmark features should raise a strong suspicion of the syndrome.

Here, we present an interesting case of this rare disorder in a 13-year-old boy who was previously diagnosed with AS and was admitted for recurrent vomiting and neurological disorders.

This work has been reported in line with the SCARE criteria[5].

Case presentation

A 13-year-old boy with a known history of AS, on daily oral hydrocortisone replacement for adrenal insufficiency, presented with recurrent vomiting for 1 month, occurring three to four times per day and involving large volumes of all food types. The vomiting was not associated with fever.

Cardiac, pulmonary, and abdominal examinations were unremarkable. However, on neurological examination, the patient had below-average intellectual function, with no evidence of meningeal irritation. Cranial nerves were intact. Motor examination revealed decreased muscle bulk with normal tone and a muscle strength of 4/5. Sensory evaluation was normal. Deep tendon reflexes were brisk, with bilateral hyperreflexia (+3) in both the upper and lower limbs. Plantar reflexes were flexor bilaterally. Cerebellar testing demonstrated a wide-based ataxic gait (Supplemental Digital Content Video 1, available at: http://links.lww.com/MS9/B123), a positive finger–nose test, intention tremor, and dysarthria. In addition to that, the child had mild tongue enlargement with clear fissures on it (Fig. 1).

Figure 1.

A photograph of the child showing his deep tongue fissures.

Laboratory investigations showed normal sodium, potassium, and calcium levels. His ACTH level was elevated at 231 pg/mL, which was attributed to poor absorption of oral hydrocortisone due to persistent vomiting. Brain magnetic resonance imaging (MRI) was normal. Upper endoscopy revealed a widened esophagus without inflammation and a constricted lower esophageal sphincter, consistent with achalasia (Supplemental Digital Content Video 2, available at: http://links.lww.com/MS9/B124).

In view of impaired oral absorption, hydrocortisone was switched to intravenous administration at 1 mg/kg/day. The patient underwent Heller myotomy for definitive management of achalasia, followed by a Nissen fundoplication to prevent postoperative gastroesophageal reflux.

Following this treatment, the patient’s vomiting resolved, and the ACTH level returned to a normal value.

Discussion

AS is a rare condition which was first identified by Allgrove et al in 1978[6], and since then more than 70 cases have been documented globally[3]. Alacrima, typically evident within the first year of life and observed as dry eyes while crying, is the earliest identifiable feature of the disease^[2,7^]. Alacrima is often diagnosed with Schirmer’s test, MRI, and lacrimal gland biopsy. Lacrimal gland biopsy may show neuronal loss accompanied by a reduction in secretory granules within the acinar cell[8], but Schirmer’s test often confirms the diagnosis[2].

Achalasia, which is the second hallmark of the disease, is characterized by the inability of the lower esophageal sphincter to relax with a loss of coordinated muscle contractions of the esophageal body and appears later in life[7]. The main symptoms of achalasia include dysphagia, reflux, weight loss, and failure to thrive^[2,7^]. Achalasia may also present with respiratory symptoms such as shortness of breath, coughing, throat discomfort, wheezing, voice hoarseness, and aspiration[2]. Esophageal manometry is the gold standard test to diagnose achalasia[7]. There are some additional tests to further evaluate achalasia, such as barium swallow, barium esophagogram, and gastroduodenoscopy[2]. The development of achalasia is found to be a mix of autoimmune targeting the enteric nervous system, nerve degeneration, and fibrotic processes[7]. In our case, upper endoscopy was performed and revealed failure of lower esophageal sphincter relaxation, which confirmed achalasia.

Adrenal insufficiency manifests in approximately 85% of patients with AAAS and often develops within the first 10 years of life[7]. Given that both adrenal insufficiency and achalasia are detected within the first decade of life points to the crucial role of endocrine and gastroenterological evaluation when AS is suspected^[7,8^]. The cause of adrenal insufficiency in AS is secondary to ACTH resistance[7]. Adrenal insufficiency is a leading cause of mortality in patients with AS due to the development of severe hypoglycemia and sudden death^[7,8^]. The diagnosis is established by assessing morning fasting cortisol level, ACTH level and corticotropin stimulation test[7]. Adrenal dysfunction is not confined to glucocorticoid deficiency, as it was reported that 15% of patients had mineralocorticoid deficiency and electrolyte disturbances^[7,8^]. Treatment is done through hydrocortisone and fludrocortisone if mineralocorticoid deficiency is observed[7].

Interestingly, our patient had a noticeably enlarged tongue with deep fissures. Although rare, oral findings – such as a large, deeply fissured tongue – have been reported in isolated cases of AS, highlighting the importance of careful oral examination even in atypical presentations[9]. In addition, AS sometimes exhibits a mixture of peripheral, central, and autonomic neurological manifestations[8]. These abnormalities include motor dysfunction, peripheral neuropathy, and corticospinal tracts abnormality[7]. Some other reported signs and symptoms are muscular weakness, muscular atrophy, intellectual disability, brisk reflexes, dysarthria, ataxia, and other sensory manifestations[8]. Ophthalmic signs were also identified in AS, such as abnormal reflexes of pupils and optic nerve atrophy[7].

Our patient had a number of AS hallmarks, such as neurological impairment, achalasia, and adrenal insufficiency. Because of his achalasia-related recurrent vomiting, he had trouble absorbing hydrocortisone orally, which led to increased ACTH levels. In line with other findings emphasizing the progressive and multisystemic nature of this condition, neurological signs such as ataxia, dysarthria, tremor, hyperreflexia, and cognitive delay were also noted^[10–12^].

Making an early diagnosis is frequently difficult. Although alacrima is often the first symptom, it can be unnoticed and mild, and neurological or gastrointestinal symptoms can be mistaken for other pediatric disorders. It is crucial to identify gastrointestinal involvement in patients with unexplained adrenal insufficiency, as demonstrated in our instance, where chronic vomiting initially made adrenal replacement therapy more difficult[13].

AS is increasingly acknowledged as a progressive and independent disease component, with neurological involvement playing a vital role^[13,14^]. In our patient, prominent central and peripheral neurological features were remarked in the absence of autonomic neuropathy. This pattern aids the concept that neurological dysfunction in AS may reflect selective neuronal vulnerability affecting cerebellar and corticospinal pathways, rather than uniform autonomic involvement^[1,15^]. The dissociation between autonomic and non-autonomic neurological features in our case underlines the marked phenotypic heterogeneity of the disorder and states that neurological progression may follow a distinct trajectory^[1,13^]. These findings emphasize the need for early neurological surveillance and long-term follow-up, even in patients without autonomic symptoms, as neurological deficits may evolve independently and contribute significantly to long-term morbidity^[13,15^].

In comparison with previously published cases, our patient demonstrated both overlapping and unique clinical features^[8,11,16–18^]. Cognitive impairment in our case, manifesting as below-average intellectual function, contrasts with the predominantly normal cognition seen in most reports, with the exception of the case of Tibussek et al, which demonstrated marked global developmental delay[11]. Distal muscle wasting and weakness were consistent findings across cases, often following a distal-predominant pattern, although the generalized mild weakness observed in our patient was milder than multiple reported cases, where distal hand and foot muscles were prominently affected. Hyperreflexia was a shared characteristic, present in our patient and in most cases, yet the preservation of flexor plantar responses in our patient differs from the frequent occurrence of extensor plantar responses. Cerebellar signs were notably prominent in our patient, including wide-based ataxic gait, intention tremor, dysarthria, and impaired coordination, whereas several reports described absent or mild cerebellar findings, highlighting phenotypic heterogeneity. Cranial nerve involvement, including optic atrophy, pupillary abnormalities, palatal weakness, and tongue wasting, was reported by Tibussek et al and Kimber et al but was absent in our patient, making our presentation more special^[11,18^]. Sensory examination was normal in our patient and across most cases, with distal sensory loss observed only by Kimber et al[18]. Autonomic features were also reported, varying from labile hypertension to postural hypotension, and pain was a rare manifestation. Overall, these observations indicate that while distal wasting, hyperreflexia, and gait disturbances represent common features, the combination of preserved plantar responses, absence of cranial nerve deficits, and prominent cerebellar involvement may represent a distinct clinical variant within this condition. AS is still mostly managed with supportive care. Glucocorticoid replacement is used to treat adrenal insufficiency, but mineralocorticoid secretion is usually maintained^[6,19^]. The best way to treat achalasia is surgically, and in order to avoid postoperative gastroesophageal reflux, Heller myotomy is sometimes paired with fundoplication[11]. After receiving intravenous hydrocortisone and definitive surgical care, our patient responded favorably to this method, with the vomiting cessation and the ACTH levels returning to normal. The current state of neurological characteristics, which frequently worsen with age, lacks disease-modifying treatments and is instead treated with supportive measures, including speech and physical therapy.

Special difficulties for pediatric patients include decreased oral steroid absorption during vomiting episodes, which, if not identified in time, can cause adrenal crises. As our patient showed, intravenous glucocorticoids should be started as soon as possible in these situations[20]. For children with AS, this example thus highlights the importance of a high index of suspicion, prompt multidisciplinary management, and long-term monitoring for neurological, gastrointestinal, and endocrine issues.

Conclusion

This case shows that AS is a heterogeneous multisystem disorder that may extend beyond the classical triad to include significant neurological symptoms such as cerebellar signs, increased reflexes, and decreased mental functions. Hence, even in the absence of autonomic involvement, any neurological features in the context of such a triad should raise suspicion for diagnosing AS. Early diagnosis, close long-term follow-up, and proper management are critical to prevent complications and monitoring late-onset neurological deficits to improve patients’ quality of life.

Ethical approval

Ethical approval was not required for this study as it is a single case report describing clinical observations without any experimental intervention.

Consent

Written informed consent was obtained from the patient’s parents for publication of this case report and accompanying image and videos. A copy of the written consent is available for review by the Editor-in-Chief of this journal upon request.

Sources of funding

None.

Author contributions

FA, HD, SH, HS, RA, HA, and AS: writing, editing, and reviewing the manuscript. LK: supervised and performed the final review.

Conflicts of interest disclosure

The authors declare that they have no conflicts of interest.

Research registration unique identifying number (UIN)

Registration is not applicable for this type of study.

Guarantor

Lina Khouri.

Provenance and peer review

Not commissioned, externally peer-reviewed.

Data availability statement

Not applicable.