Erythematous Papules and Plaques in an Infant Receiving Glucagon Therapy

We present the case of a 2-month-old boy with suspected persistent hyperinsulinemic hypoglycemia of infancy (PHHI), complicated by hypoxic respiratory failure, sepsis, and acute respiratory distress syndrome. Since birth, he had recurrent hypoglycemia, managed with intermittent diazoxide, intravenous (IV) glucagon infusions, and octreotide. Genetic testing confirmed type 3 congenital hyperinsulinism (GCK mutation, p.V91L). He developed waxing and waning lesions on the scalp, face, trunk, upper and lower extremities, and groin, tending to disappear from one location and reappear in another. Clinical examination revealed diffusely scattered, well-demarcated, erythematous desquamative plaques, with disseminated erythematous papules on the trunk, extremities and intertriginous areas (Figure 1A,B). A 4-mm punch biopsy was taken from a lesion on the right thigh (Figure 2A,B). Iatrogenic necrolytic migratory erythema (due to exogenous glucagon). The biopsy revealed confluent parakeratosis with subcorneal clefting, loss of the granular layer, and focal pallor of keratinocytes. Zinc levels were unremarkable. Clinicopathologic correlation supported a diagnosis of iatrogenic necrolytic migratory erythema (NME). The glucagon infusion was gradually weaned and eventually discontinued. The eruption improved shortly thereafter. Glucose levels were closely monitored and remained stable. Unfortunately, the patient later developed multiorgan failure and succumbed to sepsis-related complications before a planned pancreatectomy. In contrast to our case, NME is classically associated with glucagonoma, an alpha-cell pancreatic tumour in 65%–70% of cases [1]. Glucagonoma syndrome, a paraneoplastic disorder, consists of a triad of diabetes mellitus, NME, and weight loss [2]. Other associations include liver cirrhosis, malabsorption syndromes, Crohn's disease, chronic pancreatitis, or other malignancies such as small cell lung cancer or duodenal neoplasms [1, 2]. In these instances, it can be categorised as ‘pseudoglucagonoma syndrome’ [2]. NME due to glucagon has been reported in neonates with congenital focal hyperinsulinism [3], PHHI [4], and in a 24-year-old female with acute pancreatitis [5]. In all cases, the lesions improved following glucagon cessation. It remains unclear whether the duration of therapy influences the development of lesions. A review found that reported cases ranged from 10 days to 5 months after glucagon initiation [3]. The clinical presentation, management, and outcome of cases of congenital hyperinsulinism treated with glucagon are listed in Table 1. Hyperglucagonemia is believed to play a key role in the pathogenesis of NME. The development of skin lesions is thought to be multifactorial, involving nutrient deficiencies, and the activation of inflammatory mediators within the epidermis [2]. A malnutrition model suggested that excess glucagon triggers a catabolic state, disrupting a metabolic pathway involving zinc, protein, amino acids, and essential fatty acids, with depletion of one or more of these nutrients contributing to NME. Supporting this theory, zinc and amino acid supplementation have been shown to resolve NME lesions [2, 6]. Additional mechanisms are hepatic insufficiency associated with impaired glucagon degradation, resulting in increased serum glucagon [7]. Clinically, NME presents in a cyclic pattern, with lesions waxing, waning, and migrating, as seen in our case. Lesions are prominent in areas of friction or pressure and may present as vesicles or bullae that evolve into arcuate or polycyclic erythematous, scaly patches or plaques, with centrifugal growth [1, 2, 8]. The perioral region, trunk, intertriginous areas, extremities and groin are usually involved [2]. Superimposed Staphylococcus aureus and Candida albicans infections may occur and alter the clinical presentation, potentially leading to misdiagnosis as an infectious aetiology [1]. Additional manifestations include angular cheilitis, glossitis, stomatitis, and onychoschizia [2]. A skin biopsy may aid in the diagnosis but is not crucial; histopathologic findings are psoriasiform dermatitis, with parakeratosis, an absent granular layer, pallor of keratinocytes in the upper epidermis and vacuolar degeneration of superficial epidermal keratinocytes [3]. Histologic mimickers include nutritional deficiencies or necrolytic acral erythema, the latter is usually localised to acral skin and associated with Hepatitis C [3]. Distinguishing nutritional deficiencies from NME can be challenging. Pellagra (vitamin B3 deficiency) is typically associated with diarrhoea and dementia, while zinc deficiency favours periorificial skin and presents with low serum zinc levels [3]. However, zinc levels alone are not a reliable marker for differentiation, as zinc deficiency may also be observed NME, often due to malabsorption or hypoproteinemia [2]. Additional differential diagnoses are seborrhoeic dermatitis, atopic dermatitis, or erythema anulare centrifugum-like psoriasis. Management of NME involves identifying the underlying cause. Resolution occurs once excess glucagon is eliminated, either through glucagon cessation or glucagonoma excision. Improvement has been observed as early as 48 h after discontinuation [3]. Congenital hyperinsulinism (CHI) can be transient, occurring in small for gestational age neonates or perinatal asphyxia, or genetic, as seen in Turner, Kabuki and Beckwith–Wiedemann syndromes [9]. Management is aimed at normalising plasma glucose levels, with glucagon being the first-line therapeutic option. Continuous subcutaneous glucagon infusions are often combined with octreotide, dextrose, diazoxide, somatostatin receptor analogues, or pancreatic surgery [9]. Glucagon therapy should be maintained in patients at risk of fluid overload, when IV therapy is not immediately available, in cases of PHHI being unresponsive to other treatments, and as an emergency rescue for children with ongoing hypoglycemia [10]. Glucagon is essential for managing CHI-related hypoglycemia, but the potential development of NME should be recognised to avoid diagnostic delays. The dose-dependence and optimal treatment for glucagon-induced NME remain unclear, highlighting the need for further case reporting. Sara Al Janahi and Alya Al-Ali contributed equally to the drafting of this manuscript and are designated as co-first authors. Meera Al Adawi, Yusra S. Al Ali, and Harish Bangalore were involved in the supervision and critical revision of the manuscript. The authors have nothing to report. The parents/guardians of minor patients have given written informed consent for their child's participation in the study, as well as for the use of their child's deidentified, anonymized, aggregated data, and case details (including photographs) for publication. The authors have nothing to report. The authors declare no conflicts of interest. The data that support the findings of this study are available from the corresponding author upon reasonable request.