A teenager with painful extremities

CASE PRESENTATION

A 14-year-old boy of European and Latino heritage presented to the Emergency Room for an acute episode of intense ‘stabbing and burning’ pain to his hands and feet. Similar episodes had been occurring almost every month for several years and lasted for a few hours. Triggers included stress and cold temperature.

Previous medical history was remarkable for short stature, hypothyroidism, hearing impairment, and anxiety. Family history included maternal side hearing loss.

Because of his pain, the patient was wheelchair bound and needed to be carried to the examination table. He appeared in more significant pain when his parent was present. He had mild tachycardia and borderline low blood pressure on arrival. His physical examination was otherwise unremarkable.

Investigations showed normal complete blood cell count, thyroid stimulation hormone, kidney and hepatic enzymes, non-fasting glucose, creatinine kinase, C reactive protein, and gas. An electrophoresis of his hemoglobin and anti-transglutaminase were pending.

Tylenol, Ibuprofen, and brief observation were provided. Significant improvement of the patient’s symptomatology was noted. A provisional diagnostic of somatization was given. Arrangements were made for a follow-up at the Youth Clinic. The case was discussed with a wise colleague. One supplemental investigation revealed the diagnosis.

Discussion

A month later, his α-galactosidase A level in leukocytes was nondetectable. The patient was assessed by a metabolic disease physician and genetic testing confirmed the diagnosis of Fabry disease. The patient was evaluated by paediatric subspecialists for multisystem involvement. His initial work up showed no cardiac, ophthalmologic, respiratory, or kidney complications. Due to his hearing impairment and associated tinnitus, he was a candidate for enzymatic replacement therapy and has been receiving an infusion bimonthly. Familial screening has been completed. Neuropathic pain and anxiety continue to be issues.

Fabry disease is an X-linked lysosomal storage disease. Newborn screening suggest that its incidence could be as high as 1:5,000, an increase from previous reports (1). The condition is characterized by the partial or complete deficiency of the enzyme α-galactosidase A which leads to the accumulation of glycosphingolipids in vascular endothelium and smooth muscle cells causing irreversible organ damage (2). The disease expression is highly heterogenous, depending mostly on the degree of residual enzymatic activity and, in women, on the chromosome X inactivation.

Initial manifestations of the classical form of Fabry disease begin in childhood (2). Symptoms include acute episodes of pain in extremities, called acroparesthesia, hypohidrosis with limited exercise tolerance, abdominal discomfort and diarrhea, hearing impairment, fatigue, and delayed growth (1,2). These symptoms tend to be associated with significant impact on quality of life (1). As the symptoms tend to be nonspecific, and Fabry relatively rare and not a well-known disease, the diagnosis is often delayed. Teenagers may present with hallmark signs including angiokeratoma—dark nonblanchable papules, and cornea verticillate—asymptomatic corneal opacities (1). Endocrine abnormalities, including antibody negative hypothyroidism, have been described. Serious complications of the disease include ischemic cerebrovascular events, renal failure, and cardiac complications (hypertrophic cardiomyopathy, rhythm, and conduction disturbances), usually present between the third and fifth decade, and are associated with significant morbidity (2).

Acroparesthesia can be intermittent or continuous. Pain is exacerbated by extreme environmental temperature, fever, exercise, or stress. Their differential diagnosis includes pain crises seen in sickle cell disease, complex regional pain syndrome, rheumatologic conditions, growing pains, and other causes of small fiber neuropathy, such as diabetes, vitamin B12 deficiency, hypothyroidism, chronic kidney disease, infections (e.g., HIV), toxin and drug-related causes, channelopathies, celiac disease, and inflammatory bowel disease.

The diagnosis of Fabry disease is based on the presence of a combination of typical clinical features, reduced or absent α-galactosidase A activity on peripheral blood white cells or cultured skin fibroblasts, increase plasma or urine metabolites and/or genetic testing (1,2). The baseline clinical workup includes a complete ophthalmologic and dermatologic examination, hearing evaluation, electrocardiogram, echocardiogram, kidney function and ultrasound, and thyroid studies (1). Family screening is recommended.

Enzyme replacement therapy is available based on eligibility criteria in Canada. Paediatric studies are limited but show a reduction in the accumulated metabolites, improve gastrointestinal and pain-related symptoms and a slow down of disease progression (1,2). Paediatric guidelines emphasize the importance of early treatment to stabilize and prevent irreversible organ damage (1). Treatment should also include lifestyle modification to reduce cardiovascular risks and psychological support.

CLINICAL PEARLS

1. Fabry disease is more common than previously thought and should be considered in the differential diagnosis of a broad range of enigmatic paediatric symptomatology.

2. Taking the time to think systematically about atypical cases and discussing it with colleagues can be of great value.

3. Stress can exacerbate mental health conditions but also organic ones such as Fabry disease.

Informed Consent: Patient consent was obtained in writing prior to the redaction of this case.

Funding: There are no funders to report for this submission.

Potential Conflicts of Interest: All authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.