NeoQuest February 2024: Skin Lesions in a Newborn

A 2-day-old term male neonate presents acutely with an eruption of skin lesions on his face, chest, abdomen, and extremities, sparing his back (Figure 1A). His urine is discolored (Figure 1B). 

Figure 1: A. Infant’s skin findings 2 days after birth (left panel) and B. urine specimen (right panel). Image from: Jayaraj D, Ramdas V,  Al-Balushi AA,  Asiry SA, Yahmadi MA, Malviya MN, A 3-day-old neonate with generalized edema and a bullous rash. Neoreviews. 2024;25(2):e122–e126.¹

The urinalysis performed on the sample is normal. Which of the following is most likely to be associated with these clinical findings?

1. Congenital heart block
2. Multiple siblings with similar findings at birth
3. Nail dystrophy and mosaicism
4. Recent exposure to phototherapy
5. Skin biopsy showing cells with kidney-shaped nuclei

Answer: D. Recent exposure to phototherapy

Explanation:

The distribution of the infant’s bullous rash (Figure 1A) involving light-exposed areas, along with reddish/brown-colored urine in the absence of blood or red blood cells (Figure 1B), are due to the photosensitizing effects from elevated levels of porphyrins and the accumulation of uroporphyrin, respectively. These clinical features are consistent with the diagnosis of congenital erythropoietic porphyria (CEP). CEP is an autosomal recessive porphyria that is caused by a mutation in the gene encoding uroporphyrinogen III cosynthase, a necessary enzyme in the heme biosynthesis pathway.^2,3 Deficiency of this enzyme leads to elevated porphyrin levels within the body, causing heightened susceptibility to free radical injury. Classically, CEP manifests in the neonatal period as severe cutaneous photosensitivity with increased skin fragility, painful bullae and vesicle formation following exposure to the sun or phototherapy (Option D).^2-4

Affected skin areas in infants with CEP are at high risk for infection and may develop scarring, hypo- and hyperpigmentation, and hypertrichosis.^2,3 Other symptoms of CEP can include nonimmune hydrops fetalis in utero, hemolytic anemia, splenomegaly, and erythrodontia (reddish-brown discoloration of the teeth).² When examined under a Wood’s lamp, the urine and stool of affected individuals will exhibit a coral-red fluorescence due to porphyrin accumulation (Figure 2).^1,2 The diagnosis for hereditary porphyrias includes serial measurements of plasma, urine, and stool porphyrin, as well as genetic testing.^3,4 The management of CEP consists of lifelong avoidance of skin exposure to visible light, utilizing sunscreen, sun-protective clothing, and other light-protective accessories (e.g., window filters, sunshades, and sunglasses).⁵ 

Figure 2: Coral-red fluorescence under Wood’s lamp illumination of urine in a diaper from an infant with CEP. Image from: Jenkins SM, Cipriano S, Fung C. Rash associated with phototherapy in a 2-day-old preterm male infant. Neoreviews. 2016;17(1): e55-e59.³

Congenital heart block (Option A) can present as a serious complication of neonatal lupus syndrome (NLS).⁶ Neonatal rash is one of the most frequently observed clinical manifestations of NLS. Common characteristics of an NLS rash include ring-shaped erythematous papulosquamous lesions with raised borders and a central clearing (Figure 3).^6,7 The rash most commonly affects the head in 95% of cases, but the rash can also be found throughout the entire body.⁷ Although infants with NLS may also exhibit photosensitivity, the classic NLS rash is distinct from that seen in CEP. Additionally, the dermatologic manifestations of NLS are typically transient and resolve upon clearance of maternal antibodies.⁶ Infants with NLS may develop glomerulonephritis and nephrotic syndrome, but they do not have reddish/brown-colored urine negative for blood and red blood cells on urinalysis.⁶

Figure 3: Neonatal rash associated with NLS. Round, erythematous lesions with central clearing that affect multiple areas including the periorbital, malar, scalp, neck, trunk, extremities, and intertriginous areas. Image from: Frankovich J, Sandborg C, Barnes P, Hintz S, Chakravarty E. Neonatal lupus and related autoimmune disorders of infants. Neoreviews. 2008;9(5):e206–e217.⁶

Multiple siblings with similar findings at birth (Option B) is suggestive of an inherited autosomal dominant disease, such as epidermolysis bullosa (EB) simplex, the most common EB subtype.² The EB simplex rash is involves clear fluid-filled blisters in arcuate clusters (Figure 4).^2,8 Other EB subtypes such as junctional EB are inherited in an autosomal recessive manner, like CEP. However, unlike the infant in this vignette, infants with EB develop bullae in areas of friction or mild trauma (e.g., intravenous line insertion sites) and do not produce discolored urine.⁸

Figure 4: Neonatal rash associated with epidermolysis bullosa simplex with large areas of blistering and denuded skin. Image from: Hampton C, Pacella M, Wangia M, Zori R, Weiss M. Case 1: Newborn with skin and other abnormalities. Neoreviews. 2016;17(7):e403–e405.⁸

Nail dystrophy and mosaicism (Option C) are exhibited in incontinentia pigmenti (IP), which is an X-linked dominant neuroectodermal disorder affecting multiple organ systems.² Nearly all patients with IP will present with skin lesions in the neonatal period that may change and progress through multiple stages over time into adulthood.² The IP neonatal rash can often first present as bullous or pustular lesions in a linear or whorled pattern tracking along Blaschko lines (Figure 5).^2,9 Patients with IP are almost all females with mosaicism.² Males affected by IP are extremely rare but have been described in the setting of an XXY genotype.²

Figure 5: Neonatal rash associated with incontinentia pigmenti (IP) with erythematous vesicles tracking along Blaschko lines on the left upper extremity. Image from: Pal S, Jain A, Chopra A, Singh M. Case 2: A newborn with a changing rash. Neoreviews. 2019; 20(12): e740–e743.⁹

A skin biopsy demonstrating cells with kidney-shaped nuclei (Option E) indicates the presence of Langerhans cells, consistent with a diagnosis of Langerhans cell histiocytosis (LCH).10 LCH has a wide spectrum of clinical presentations, severity, and prognoses.¹⁰ The LCH Hashimoto-Pritzker variant is limited only to the skin and typically resolves spontaneously by 2 to 3 months of age.¹⁰ Infants affected by the Hashimoto-Pritzker variant develop skin lesions, varying in appearance (e.g., macules, papules, nodules, and vesiculopustules), distribution, and number (Figure 6).¹⁰ The skin lesions are not typically bullous nor do they exhibit photosensitivity.  

Figure 6: Neonatal rash associated with Langerhans cell histiocytosis Hashimoto-Pritzker variant with maculopapular lesions on the left upper extremity. Image from: Angusamy S, Vandenbelt A, Tekkanat K. Newborn rash: a diagnostic dilemma. Neoreviews. 2021; 22(7):e487–e491.¹⁰

Did you know?
Severe cases of CEP have been cured with bone marrow and hematopoietic stem cell transplantation. Future therapies for CEP, including gene therapy and proteasome inhibition, are currently being studied.⁵

What wound care management strategies are specific to neonates?
To find the answer, please refer to the following article: Amer Y, Bridges C, Marathe K. Epidemiology, pathophysiology, and management strategies of neonatal wound care. Neoreviews. July 2021; 22 (7): e452–e460.¹¹

NeoQuest Feburary 2024 Authors:

Angelina June MD, FAAP, Fairfax Neonatal Associates, Fairfax, VA
Neena Jube-Desai, MD, MBA, FAAP, University of Maryland

References

1. Jayaraj D, Ramdas V,  Al-Balushi AA,  Asiry SA, Yahmadi MA, Malviya MN. A 3-day-old neonate with generalized edema and a bullous rash. Neoreviews. 2024;25(2):e122–e126
2. Gleason CA, Juul SE, Bayart C, Branding-Bennett H. Congenital and hereditary disorders of the skin. In: Avery's Diseases of the Newborn. Philadelphia, PA: Elsevier; 2018
3. Jenkins SM, Cipriano S, Fung C. Rash associated with phototherapy in a 2-day-old preterm male infant. Neoreviews. 2016;17(1):e55-e59
4. Paller AS, Eramo LR, Farrell EE, Millard DD, Honig PJ, Cunningham BB. Purpuric phototherapy-induced eruption in transfused neonates: relation to transient porphyrinemia. Pediatrics. 1997;100(3 Pt 1):360-364
5. Erwin AL, Desnick RJ. Congenital erythropoietic porphyria: recent advances. Mol Genet Metab. 2019;128(3):288-297
6. Frankovich J, Sandborg C, Barnes P, Hintz S, Chakravarty E. Neonatal lupus and related autoimmune disorders of infants. Neoreviews. 2008;9(5):e206–e217
7. Diaz-Frias J, Badri T. Neonatal Lupus Erythematosus. In: StatPearls. Treasure Island, FL: StatPearls Publishing; 2023 Jan. Available from: www.ncbi.nlm.nih.gov/books/NBK526061/
8. Hampton C, Pacella M, Wangia M, Zori R, Weiss M. Case 1: Newborn with skin and other abnormalities. Neoreviews. 2016;17(7):e403–e405
9. Pal S, Jain A, Chopra A, Singh M. Case 2: a newborn with a changing rash. Neoreviews. 2019;20(12): e740–e743
10. Angusamy S, Vandenbelt A, Tekkanat K. Newborn rash: a diagnostic dilemma. Neoreviews. 2021; 22(7):e487–e491
11. Amer Y, Bridges C, Marathe K. Epidemiology, pathophysiology, and management strategies of neonatal wound care. Neoreviews. 2021; 22(7):e452–e460