Triple A syndrome: two siblings with a novel mutation in the AAAS gene
Triple A syndrome is a rare autosomal recessive disorder caused by mutations in the AAAS gene on chromosome 12q13. Its main clinical features are alacrima, achalasia, and adrenal insufficiency, with most patients also having neurological symptoms and autonomic dysfunction. The neurologic manifestations are less well-understood, especially in children. Here, we examine two siblings who were found to have a novel mutation in the AAAS gene and who were found to have subtle, but important, neurologic findings.
This is a case report of two siblings.
We discuss two siblings exhibiting different signs of the disorder including neurologic dysfunction found at varying ages. Genetic analysis revealed that both patients have the same compound heterozygous mutations in the AAAS gene consisting of one novel mutation (c.500 C>A, A167E) and one previously described mutation (c.1331+1G> A/IVS14+1 G>A). A diagnosis of triple A syndrome was reached based on their clinical and genetic findings.
The unique characteristic of these two cases is the novel mutation in the AAAS gene, which is likely pathogenic. In addition, they showcase the genotype-phenotype variability of the disease, as well as the importance of early identification of the neurologic abnormalities, which can result in early intervention and possibly improved outcomes.
KeywordsTriple A syndrome AAAS Allgrove syndrome Novel variant
Triple A syndrome (Allgrove syndrome) is an autosomal recessive disorder that was first described in 1978 by Allgrove and his colleagues . It is a syndrome with significant phenotypic and genotypic heterogeneity; its main clinical features are alacrima, achalasia, and adrenal insufficiency [2, 3, 4]. The denomination 4A syndrome has recently been proposed, as most of the patients present with additional neurological symptoms, including autonomic dysfunction.
Alacrima is the most common and consistent symptom of the syndrome, with up to a 99% prevalence . It has been suggested as an early diagnostic sign since it is present at birth in almost all cases [6, 7]. The pathophysiology of alacrima is thought to be due to autonomic denervation of the lacrimal gland and therefore may be due to autonomic dysfunction and not a separate clinical feature .
Achalasia usually develops during childhood, in the first decade of life, but may also occur later. It has an up to a 93% prevalence and often presents with vomiting, dysphagia, failure to thrive, and chronic cough .
Adrenal insufficiency (AI) is the third clinical feature of triple A syndrome that typically develops later in the course of the disease; in the first decade of life, in adolescence, or even in adulthood . It is caused by resistance of the adrenals to ACTH function, which results in very high serum levels of ACTH and low serum cortisol levels. It presents with the classic symptoms of AI (fatigue, weakness, abdominal pain), progressive hyperpigmentation in many patients, and significant hypoglycemic episodes . Cases of mineralocorticoid insufficiency have also been reported, although it is not commonly seen in triple A syndrome .
The fourth and most phenotypically heterogenic clinical manifestation of Allgrove syndrome is the neurological dysfunction, which can be central, peripheral, or autonomic. It usually occurs later in life and is progressive in nature, while it is the main clinical feature in adult triple A syndrome [10, 11, 12]. Less is known about the neurologic manifestations presenting in childhood. Other features of the syndrome that have been described are microcephaly, nasal speech, plantar and palmar hyperkeratosis, low bone mineral density and osteoporosis, short stature, and xerostomia [6, 13, 14].
Though cases of triple A syndrome have been reported in pediatric patients, there continues to be significant phenotypic heterogeneity among affected individuals. In this article, we present two siblings with the same compound heterozygous mutations consisting of one novel mutation and one previously described mutation in the AAAS gene. Although they have the same genotype, they exhibit different signs and symptoms presenting at varying times. These cases also highlight the possible subtlety of the neurologic phenotype and the importance of a detailed neurologic exam to identify signs early, as neurologic dysfunction in this condition is progressive.
Two months later, he presented with fatigue, somnolence, and abdominal pain. He underwent workup for adrenal insufficiency, including 8 am serum cortisol and ACTH levels and an ACTH stimulation test. His 8 am cortisol level was 6.8 μg/dL (reference range (RR) 4.8–19.5 μg/dL), and his ACTH level was significantly elevated at 881.7 pg/mL (RR 7–63 pg/mL). His cortisol levels after the ACTH stimulation were low, measuring 6 μg/dL and 8 μg/dL at 30 and 60 min respectively (normal > 18 μg/dL). The diagnosis of adrenal insufficiency was made, and he was started on hydrocortisone replacement.
His sibling was a developmentally appropriate 5-year-old girl, born full term after an uncomplicated pregnancy, but also found to have alacrima at birth. She began to develop severe post-prandial vomiting around 18 months of age that worsened over time leading to weight loss and failure to thrive despite multiple dietary manipulations. She was started on nasojejunal tube feeds around 3 years of age which she initially tolerated, but subsequently developed persistent post-prandial vomiting. An esophagogastroduodenoscopy was therefore performed, which revealed a severely dysfunctional esophagus and irregular contractions concerning for achalasia. Esophageal manometry was obtained which revealed aperistalsis and incomplete lower esophageal relaxation consistent with achalasia. She then underwent Heller esophagomyotomy and posterior Toupet fundoplication. Since the procedure, she has been able to tolerate food intake without emesis and is gaining weight well. She has not had any symptoms concerning for adrenal insufficiency at this point. She underwent genetic testing after her brother’s results were found, and she was identified to have the same two biallelic pathogenic variants (c. 1331+1G>A/IVS14+1 G>A and c.500C>A) in the AAAS gene.
She presented to the NIH with her brother for both neurologic evaluation and evaluation of adrenal insufficiency. Her 8 am serum cortisol was 11.7 μg/dL and within the normal range, but her ACTH level was elevated at 162 pg/mL (RR 5.0–46.0 pg/mL). After the ACTH stimulation test, her cortisol levels were found to be suboptimal, measuring 16.8 and 16.8 μg/dL at 30 and 60 min respectively. She was then diagnosed with subclinical adrenal insufficiency and started on low-dose hydrocortisone replacement therapy. Her neurological exam was grossly normal except that she was slightly hyperreflexic. Her ophthalmologic exam also showed mild thinning of the nerve fiber rim of the optic nerves bilaterally. She also had a delayed at bone age, with an estimated age of 4 years and 2 months at a chronological age of 5 years and 7 months. Her height was at the second percentile and her weight was at the first percentile for age.
The family history is significant for a paternal first cousin once removed who is wheelchair-bound and has a history of alacrima and GERD suspicious for triple A syndrome but has never had genetic testing. No one else in the family has similar symptoms.
The classic features of triple A syndrome (alacrima, achalasia, adrenal insufficiency, and neurologic dysfunction) were found in varying degrees in these siblings who were found to have the same compound heterozygous mutations. One of the mutations in the AAAS gene (IVS14+I G>A) has been previously reported as a pathogenic mutation [15, 16]. However, these patients also carried a novel mutation in the second allele, not previously described in the literature (c.500 C>A, A167E). We believe this variant to also be pathogenic, as they both exhibit the constellation of clinical findings present in triple A syndrome. Although both patients carry the same genotype, the severity of each of their presentations differs with the younger sister having much more severe achalasia and no evident neurologic symptoms at this time compared to the brother.
The AAAS mutation is inherited in an autosomal recessive pattern in triple A syndrome; thus, the syndrome is rarely found in the family history. This disorder is caused by mutations in the AAAS gene on chromosome 12q13 . It encodes the 547 amino acid–containing protein called ALADIN, which stands for “alacrima - achalasia- adrenal insufficiency neurologic disorder”. ALADIN belongs to WD-repeat family of regulatory proteins and was identified as a component of nuclear pore complex (NPC), which mainly mediates nucleocytoplasmic transport in multiple cellular processes [16, 18]. In triple A syndrome, the altered ALADIN protein mislocalizes mainly in cytoplasm leading to defects in NPC function , but the specific molecular basis of this protein still remains unknown. A variety of disease-associated mutations have been found scattered throughout the AAAS gene, including missense, nonsense, frameshift, and splice-site mutations. The disease can manifest from homozygous or compound heterozygous mutations [16, 20, 21, 22]. The gene is ubiquitously expressed, but it is reported to have higher expression signals in endocrine and neuroendocrine derivatives, indicating its role in endocrine and neurological development [16, 20].
These siblings were both found to be compound heterozygotes and harbor the same mutations. One of the mutations they carry (c.1331+1G> A/IVS14+1 G>A) affects a conserved splice site and is considered pathogenic and has been previously described [15, 16]. A second mutation in the AAAS gene was found in both siblings (c.500C>A, pAla167Glu). This missense mutation leads to a substitution of alanine to glutamate at position 167 in the protein. This variant of A167E in the AAAS gene results in a nonconservative amino acid substitution, which likely impacts secondary protein structure. This position is conserved across species. A mutation affecting the same codon (A167V) has been reported in another patient with triple A syndrome .
Another interesting aspect of their presentation is their mild neurologic abnormalities. The older sibling exhibited mild muscle wasting, decreased vibratory sensation, anisocoria, bilateral thinning bilateral of the optic nerves, hyperreflexic deep tendon reflexes, and a history of significant sweating. The neurologic exam was reportedly normal for the second subject except for mild hyperreflexia and ophthalmologic finding of optic nerve thinning. A spectrum of neurologic dysfunction has been described in patients with triple A syndrome including intellectual disability, global developmental delay, a myriad of motor abnormalities, peripheral sensorimotor polyneuropathies, and autonomic dysfunction [6, 10, 24, 25]. Because neurologic dysfunction can present in numerous ways in triple A syndrome, it is particularly important to pay close attention to any neurologic dysfunction in early age. Although many of the neurologic symptoms associated with triple A disease may be mild or subtle initially, they can be progressive. Therefore, it is extremely important to actively screen for neurologic abnormalities when the other classic findings of triple A syndrome are present, in order to identify them and intervene early. Further investigation into whether or not intervention at the first signs of neurologic abnormalities can improve neurologic and developmental outcomes is warranted in this unique population.
In conclusion, we hope that this report can promote more awareness of this rare disorder and contribute to the growing body of knowledge regarding this syndrome, particularly in the field of pediatrics.
All authors have accepted the responsibility for the entire content of this submitted manuscript and approved the submission.
This research was supported in part by the Intramural Research Program of the National Institutes of Health (NIH), Eunice Kennedy Shriver National Institute of Child Health and Human Development.
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Conflict of interest
The authors declare that there are no conflicts of interest.
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