Painful, reappearing eruption in a medically complex 4-year-old
- Meredith Sooy 1 ,
- Rachel L Randell 2,
- Dmitry Tchapyjnikov 3,
- Klaus Werner 3 and
- Kristina Nazareth-Pidgeon 4
- 1 Department of Pediatrics, Duke University, Durham, North Carolina, USA
- 2 Division of Pediatric Rheumatology, Department of Pediatrics, Duke University, Durham, North Carolina, USA
- 3 Division of Pediatric Neurology, Department of Pediatrics, Duke University, Durham, North Carolina, USA
- 4 Pediatric Hospitalist Medicine, Department of Pediatrics, Duke University, Durham, North Carolina, USA
- Correspondence to Dr Meredith Sooy; meredith.sooy@duke.edu
Abstract
A 4-year-old boy with atypical, complete DiGeorge and CHARGE (coloboma, heart defects, atresia choanae, growth retardation, genital abnormalities and ear abnormalities) syndromes presented with frequent episodes of a painful, markedly erythematous eruption associated with swelling. Evaluation revealed non-specific findings on skin biopsy at the time of eruption and no pathogenic mutation in the SCN9A gene. The patient was diagnosed with secondary erythromelalgia based on clinical presentation. Erythromelalgia is a rare disorder characterised by recurrent episodes of pain and erythema typically affecting the distal extremities. This case represents the first case of erythromelalgia in the setting of DiGeorge and CHARGE syndromes.
Background
This is the first reported case of secondary erythromelalgia associated with DiGeorge and CHARGE (coloboma, heart defects, atresia choanae, growth retardation, genital abnormalities and ear abnormalities) syndromes.1 Our clinical experience with this patient impressed on us the significant morbidity of erythromelalgia, and the difficulty in diagnosing this rare condition due to lack of prior exposure. This case brought together paediatric hospitalists, rheumatologists, dermatologists and neurologists for its ultimate diagnosis and treatment. This complex case of an extremely rare problem will greatly aide current practitioners in expanding their clinical knowledge.
Case presentation
The patient is a 4-year-old boy, born at 34 weeks gestation with multiple congenital anomalies diagnosed with atypical complete DiGeorge and CHARGE (with CHD7 mutation) syndromes. His congenital defects included a left occult coloboma, ventricular septal defect and left choanal atresia. Additional medical history included hypothyroidism, chronic respiratory failure and chronic kidney disease. Prior surgical history included thymus transplant and tracheostomy placement at the age of 6 months.
He initially presented with frequent episodes of a painful, markedly erythematous eruption and swelling most commonly affecting the distal extremities (figures 1 and 2). Episodes started at 3 months of age. In the 2 months prior to diagnosis the episodes increased in frequency from weekly to daily. The severity of the episodes increased with more pronounced pain symptoms including irritability, exquisite sensitivity to light touch and oedema that resulted in cracking and bleeding skin. The episodes lasted from 20 min to several hours. There were no specific triggers identified. Symptom duration decreased with the use of a cooling fan.
Images taken by patient’s mother over time documenting variety of locations of reappearing eruption.
Clinical images showing right lower extremity (A) and left upper extremity (B) of patient at time of episode during admission. There is significant erythema, warmth and oedema of both, causing cracking of skin. There is well-demarcated line between erythema and normal skin. Patient had considerable pain associated with these episodes.
Investigations
Evaluation included a skin biopsy of an actively symptomatic lesion, which showed normal thickness epidermis without significant spongiosis or inflammation. The underlying dermis exhibited interstitial lymphocytic infiltrate. The underlying subcutis demonstrated focal lymphocytic inflammation with giant cell reaction and oedema. There was no evidence of vasculitis or thrombi. Laboratory studies were notable for elevated C reactive protein and positive lupus anticoagulant. Genetic sequencing studies for SCN9A mutations were obtained.
Differential diagnosis
The differential diagnosis for this painful eruption includes large and small fibre neuropathies, peripheral vascular disease, thrombosis, acrocyanosis, Raynaud phenomenon, infectious cellulitis and Fabry disease. Both large and small fibre neuropathies would have similarly painful symptoms, however, would be less likely to present with the skin colour changes seen in this patient.2
Thrombosis is another consideration especially in the presence of lupus anticoagulant. This patient had no evidence of thrombosis on skin biopsy and one would not expect transient changes with thrombosis.
Other causes of discoloured extremities should be considered including acrocyanosis, Raynaud phenomenon or infectious cellulitis. Acrocyanosis typically affects the distal extremities and is often present from early infancy. However, acrocyanosis would be expected to present with more of a bluish discoloration which was not seen in this patient.3 While the demarcated skin colour changes and pain are similar to the erythematous phase of Raynaud phenomenon, the patient lacked the skin pallor and cyanosis.4 The patient’s eruption was intermittent and in variable locations which would be very unusual for infectious cellulitis.
Similar symptoms can be seen in metabolic disorders such as Fabry disease, however, the patient did not display other signs such as hypohidrosis, angiokeratomas or characteristic corneal dystrophy.5
Treatment
Prior to diagnosis, the patient was taking gabapentin 11 mg/kg/day divided into two times per day. When the episodes increased in severity and frequency, gabapentin was increased to 40 mg/kg/day divided into two times per day with some initial improvement in severity of symptoms. After diagnosis of erythromelalgia, treatment with oral amitriptyline 1 mg/kg/day was initiated and gabapentin was continued. Subsequently, symptoms severity decreased but frequency remained unchanged. Gabapentin was discontinued after a 9-month trial due to lack of sustained improvement in symptoms. A 6-month trial of midodrine cream 2% was conducted without change in symptoms. At this time, he continues on amitriptyline only.
Outcome and follow-up
Genetic sequencing of the SCN9A gene did not reveal any pathogenic mutations or variants of unknown significance. The patient was clinically diagnosed with secondary erythromelalgia given his age, classic clinical presentation and genetic conditions of DiGeorge and CHARGE syndromes. The patient continues to have intermittent eruptions though severity has improved with pharmacological treatment with amitriptyline.
Discussion
Erythromelalgia is a rare disorder characterised by recurrent episodes of pain and erythema typically affecting the distal extremities. Erythromelalgia can be divided into a primary, inherited form and a secondary form.6
Hereditary or primary erythromelalgia is a rare autosomal dominant disorder caused by mutations in the SCN9A gene, which results in a gain of function of the voltage gated sodium channels expressed in the peripheral nervous system.7 8 This gain of function results in increased excitability in peripheral neurons leading to easier activation and slower deactivation.9 Secondary erythromelalgia is caused by a variety of underlying medical conditions such as malignancies, connective tissue disorders, haematological disease and many others.6
Clinically, erythromelalgia causes intermittent attacks of pain, erythema and warmth of skin, mostly commonly in the extremities. Age of onset of primary erythromelalgia is variable with one case series finding 18 months to 17 years for onset of symptoms, however, all occurred within the first two decades of life.8 A variety of comorbidities including hypertension, impaired growth and hypotonia have been reported, however, to our knowledge and review of the current literature, there have been no reports of erythromelalgia with either DiGeorge or CHARGE syndromes.9
Diagnosis of erythromelalgia is made clinically based on typical symptoms.10 Genetic testing is increasingly being used to determine the presence of a pathogenic mutation in SCN9A. While SCN9A is the most commonly implicated gene, other pathogenic variants have been reported in other genes encoding sodium channels, such as SCN10A and SCN11A.11 12 In a series of 13 paediatric patients diagnosed with erythromelalgia, only four patients had pathogenic mutations in SCN9A.9 Given that the majority of reported paediatric patients diagnosed with erythromelalgia do not have the pathogenic mutation, there may be several unidentified genetic or other causes. We are suspicious for a genetic cause in this patient given the age of symptom onset and other genetic abnormalities.
Treatment for erythromelalgia is varied with inconsistent results. To our knowledge, there are no randomised control trials evaluating treatment. Reported treatments include sodium channel blockers (such as mexiletine), antineuropathic drugs (such as gabapentin and antidepressants) and vasoactive medications (such as atenolol) with varying degrees of response.13
Because of the severe pain associated with erythromelalgia, there is a significant impact on quality of life and function. One case series reports physical activity was limited in 66% of paediatric patients and school attendance was affected in 34% of paediatric patients with erythrmomelalgia.14 Given significant morbidity, further investigations are needed into specific therapies for treatment, aimed specifically at SCN9A and other potential mutations.
Patient’s perspective
Being a parent of a medically complex child is a challenge. The hardest part of having a child with erythromelalgia was watching our son have severe pain and the inability to use his hands and legs when these episodes occur. It is horribly painful to watch. It has interfered with his development. This frustrates him greatly as well. I hope soon we can come up with a successful treatment so that we can help our son to live a more full life, that is most importantly pain-free. It is difficult to have another rare disorder in addition to his many medical needs. However, we know he will keep moving forward. He never backs down.
Learning points
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Erythromelalgia is an intermittent, painful, erythematous eruption most commonly seen on the distal extremities.
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With distal extremity colour change, erythromelalgia can be a mimic of acrocyanosis and Raynaud phenomenon.
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Primary erythromelalgia is most commonly caused by an SCN9A mutation which results in increased excitability of peripheral neurons leading to easier activation and slower deactivation.
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Secondary erythromelalgia is caused by a variety of underlying medical conditions including malignancy, connective tissue disorders and haematological disorders.
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Erythromelalgia can result in severe morbidity and decreased quality of life due to significant associated pain.
Acknowledgments
We would like to thank that patient’s mother for contributing images and providing her unique perspective on being the parent of a child with complex medical needs.
This work was supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health under award number R38HL143612 and by the Duke Pediatric Research Scholars Program.
Footnotes
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Contributors MS conceptualised the case, provided investigation into case details and topic research, and contributed to writing original manuscript draft. RLR was involved in conceptualization of case, writing of original manuscript draft, and critically reviewed and revised the manuscript. KW provided supervisions of case preparation and critically reviewed and revised the manuscript. DT provided supervisions of case preparation and critically reviewed and revised the manuscript. KN conceptualised the case, provided supervision of case preparation, and critically reviewed and revised the manuscript.
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Competing interests None declared.
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Patient consent for publication Parental/guardian consent obtained.
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Provenance and peer review Not commissioned; externally peer reviewed.
- © BMJ Publishing Group Limited 2021. No commercial re-use. See rights and permissions. Published by BMJ.
References
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