Aortic annular ectasia: An unusual finding in an infant with Pompe disease

INTRODUCTION

Pompe disease (PD), also known as glycogen storage disease type II, is an autosomal recessively inherited storage disorder that results from the deficiency of lysosomal enzyme acid alpha-glucosidase (GAA). Failure of degradation of glycogen within lysosomes and its resultant accumulation leads to progressive tissue damage, mainly affecting skeletal and cardiac muscle. The disease exhibits a broad phenotypic spectrum, ranging from the rapidly progressive infantile-onset form infantile-onset PD (IOPD) to more slowly progressive late-onset forms.^[1]

IOPD typically presents within the first few months of life with hypertrophic cardiomyopathy, generalised hypotonia, feeding difficulties, failure to thrive, hepatomegaly and respiratory insufficiency. Dried blood spot testing for GAA activity is considered a first-tier test for PD, which is rapid and convenient. The diagnosis needs to be confirmed by molecular genetics by demonstrating GAA deficiency with pathogenic variants in the GAA gene.

Without early diagnosis and enzyme replacement therapy (ERT), the disease is uniformly fatal within the 1^st year of life in the classical presentation. ERT, in the form of alglucosidase alpha, improves cardiac and skeletal muscle function. Gene therapy, focusing on the restoration of GAA production, is under clinical development.^[2]

While cardiac involvement in the form of hypertrophic cardiomyopathy is a hallmark feature of IOPD, the association with aortopathy, particularly aortic annular ectasia, has not been previously described in this age group.^[3] Later, as cardiac function worsens, patients may develop features of dilated cardiomyopathy.

Here, we report a unique case of an infant with IOPD who presented with distinctive facial features, hypertrophic cardiomyopathy and an unusual finding of aortic annular dilatation. This case adds to the expanding clinical phenotype of PD and raises awareness of potential vascular involvement even in early-onset cases.

CASE REPORT

A 3-month-old male infant, firstborn out of a third-degree consanguineous marriage, presented with respiratory distress for 5 days to our centre. He was found to be failing to thrive – being severely underweight (weight 3.5 kg: −4.15Z) and stunted (length 56 cm: −2.15Z) with microcephaly (head circumference 36.4 cm: −3.59Z). There was no associated fever, cough, vomiting, jaundice, or persistent loose stools noted. He was born vaginally after a full-term, uneventful pregnancy with no obvious congenital anomalies noted at birth. There was a history of diaphoresis while breastfeeding and suck-rest-suck cycles since birth. Currently at the age of 3 months, he has attained partial head control with a social smile and coos actively.

On examination, he had a distinctive facial profile with prominent lips, macroglossia and a flat-bridged nose with a fleshy tip. He was also found to have generalised hypotonia and hepatosplenomegaly. Examination of joints, skin and spine was normal. There was no pallor, icterus or cyanosis. He was tachypnoeic without any cardiac murmur or signs of cardiac failure. His chest radiograph showed a right upper lobar consolidation with cardiomegaly (cardio-thoracic ratio of 64%). He was started on humidified oxygen and intravenous antibiotics.

Complete blood counts, serum electrolytes, and renal and liver function tests were within normal limits. Thyroid function tests, blood glucose levels, ophthalmological examination of the fundus and hearing assessment were normal. Suspecting mucopolysaccharidoses, urine for glycosaminoglycans was sent, which was negative. The electrocardiogram showed a short PR interval with high voltage QRS complex and biventricular hypertrophy. Echocardiography revealed evidence of severe hypertrophic cardiomyopathy with a dilated aortic annulus (+3.9 Z: As per the nomogram provided in the study published in 2017 by Cantinotti et al.)^[4] and preserved ejection fraction. There was no evidence of coarctation of the aorta or bicuspid aortic valves. No other anomalies were found on screening ultrasonography of the abdomen and cranium. Genetic studies were planned as the child had conflicting features of lysosomal and glycogen storage disorders. Next-generation sequencing showed a novel predicted to be pathogenic homozygous missense variant (c.1598G>A) in exon 11 of the GAA gene, confirming a diagnosis of PD. Both parents had a heterozygous mutation of the same variant detected in the child. As mutational analysis was performed in both parents and the child, we chose not to perform enzyme analysis for the diagnosis. The infant was referred to the paediatric geneticist at our nearby tertiary care centre for further treatment and consideration of early ERT.

DISCUSSION

PD is a known cause of hypertrophic cardiomyopathy, which results from pathological accumulation of glycogen in the cardiac musculature.^[1] Without ERT with alglucosidase alpha, infantile-onset classical PD is almost universally fatal.

Paediatric aortopathy refers to the dilatation, tortuosity and/or aneurysms of the thoracic aorta. The most common associated diagnoses include congenital heart disease (particularly bicuspid aortic valve), followed by connective tissue diseases.^[5] Aortopathy is a described complication of late-onset PD but is unusual for IOPD.^[6] There is increasing interest in the concept of metabolic storage aortopathies with the description of mild-to-moderate aortic enlargement in lysosomal storage disorders.^[7] Other metabolic conditions apart from PD which would fall into the differential diagnoses include other glycogenoses such as glycogen storage diseases III and IX, glycolipidoses (Fabry disease), L-carnitine deficiency, mannosidosis, mucopolysaccharidoses type I, II and V and mitochondrial disorders.^[8] While cardiac involvement in the form of hypertrophic cardiomyopathy is a hallmark feature of IOPD, the association with aortopathy, particularly aortic annular ectasia, was not found in the literature.^[3] Hence, we hope to expand the phenotypic spectrum of IOPD with this case.

CONCLUSION

We hereby highlight a rare finding of aortic annular dilatation in infantile-onset PD. Early recognition of IOPD, even in the presence of atypical vascular involvement and genetic confirmation, remains crucial for timely ERT. Further studies are warranted to explore the concept of metabolic storage aortopathies and their implications for prognosis and therapy.