Proposal of Slovenian guidelines for the diagnosis of neonatal 
erythroderma with a case report of Omenn syndrome
Mateja Starbek Zorko1,2 ✉, Ana Štublar Krašovec1, Vlasta Dragoš1
1Department of Dermatovenereology, Ljubljana University Medical Center, Ljubljana, Slovenia. 2Faculty of Medicine, University of Ljubljana, Ljubljana, 
Slovenia.
57
2023;32:57-61
doi: 10.15570/actaapa.2023.11
Introduction
Erythroderma is a generalized and persistent erythema of the skin 
that involves at least 90% of the body surface. It is defined as an 
inflammatory skin disorder in which there is involvement of total, 
or near-total, body surface area with erythema and scaling (1, 2). It 
is a non-specific disease pattern induced by various etiologies (2).
Erythroderma, especially in the neonatal and infantile period, 
can be a potentially life-threatening condition due to complica-
tions of the condition itself or due to the underlying disease (2).
Neonatal and infantile erythroderma (NIE) is a clinical pheno-
type. The causes for it range from benign or transient skin con-
ditions to potentially fatal multiorgan disorders (3). Neonatal 
erythroderma (NE) presents in the first 28 days after birth and is a 
pediatric dermatological emergency that requires swift diagnosis 
and effective, multidisciplinary management (4). It is a diagnostic 
and therapeutic challenge. The differential diagnostic possibili-
ties of NE are summarized in Figure 1. In the past, erythrodermic 
neonates and infants were frequently misdiagnosed with eczema. 
Inappropriate topical steroid treatment can lead to the develop-
ment of Cushing’s syndrome. Delay in establishing the correct 
diagnosis can be fatal (5). NE is a potentially life-threatening con-
dition that can lead to hypernatremic dehydration, electrolyte im-
balance, hyperpyrexia, hypoalbuminemia, and sepsis (6).
According to Cuperus et al. (7), causes of NE can be divided 
into six main categories (Fig. 1): congenital ichthyoses (including 
Netherton syndrome), primary immunodeficiencies, metabolic 
disorders, drug use, cutaneous infections, ectodermal dysplasias 
and other miscellaneous causes, where many otherwise com-
mon skin conditions can be found (7–10). In comparison, Ott and 
Grothaus describe erythroderma as ichthyosiformic in general 
and then divide it into three main categories: primary skin dis-
eases, infections, and primary immunodeficiencies (4).
In a recent review article on neonatal erythroderma, a six-step 
flowchart for the diagnostic approach to neonatal erythroderma 
during the 1st month of life was proposed. According to that re-
search, all cases of neonatal erythroderma should be referred to 
teaching hospitals for a multidisciplinary approach and treat-
ment (7).
Proposed Slovenian guidelines for the diagnostic approach to 
neonatal erythroderma
Clinical guidelines for NE have not yet been proposed for Slove-
nia. We reviewed available guidelines and adapted a step-by-step 
approach proposed by Cuperus et al. (7) for use in Slovenia. The 
adapted approach is presented in Figure 2.
All cases of persistent neonatal erythroderma should raise a 
high level of suspicion in the attending physician. Because of the 
wide variety of underlying etiologies and the fields of medicine 
they encompass, all cases of neonatal erythroderma involve con-
sultation with a pediatric dermatologist and neonatologist (4). In 
Slovenia, this means all neonates presenting with NE should be 
referred to teaching hospitals (the medical centers in Ljubljana or 
Maribor), where a multidisciplinary approach is possible.
Every patient presenting with NE should undergo a full physi-
cal examination with a thorough medical history taken, and base-
line blood tests should be performed (3, 7).
In a recent study, Ott (3) proposed a flow chart that could lead 
to a working diagnosis, asking the following five questions: 1) Has 
widespread erythema with dry skin been present from birth? 2) 
Has the affected neonate or infant developed failure to thrive? 3) 
Does the child reveal extracutaneous complications; for example, 
neuropathy, enteropathy, or hepatopathy? 4) Have severe and/or 
atypical infections of the skin or other organs been observed? 5) 
Have bullous skin changes or pathologies of the skin appendages
Abstract
Diagnosing and treating neonatal and infantile erythroderma can be challenging due to the wide variety of potential causes. Neo-
natal erythroderma is rare and is associated with a high mortality rate due to complications of erythroderma itself and potential 
life-threatening underlying diseases. Prolonged erythroderma should always be a warning sign and an indication for referral to 
a hospital where a multidisciplinary team approach is possible. The role of a pediatric dermatologist is to keep in mind the wide 
spectrum of differential diagnoses that could be causing the condition and the determination of the final diagnosis. To avert a 
delay in establishing the correct diagnosis, we suggest adhering to specific guidelines. We reviewed available guidelines and 
adapted a step-by-step approach for use in Slovenia. We also discuss a case of a neonate with erythroderma to illustrate the ap-
plicability of the proposed guidelines. Our patient presented with persistent erythroderma, pustules on the trunk and limbs, and 
intertriginous dermatitis. Despite local corticosteroid treatment, the skin redness persisted. After the exclusion of a systemic 
infection and additional tests, Omenn syndrome was diagnosed as the underlying cause.
Keywords: neonatal erythroderma, immunodeficiency, Omenn syndrome
Acta Dermatovenerologica 
Alpina, Pannonica et Adriatica
Acta Dermatovenerol APA
Received: 21 February 2023 | Returned for modification: 27 February 2023 | Accepted: 7 March 2023
✉ Corresponding author: mateja.starbekzorko@kclj.si
58
Acta Dermatovenerol APA | 2023;32:57-61M. Starbek Zorko et al.
occured?
If no diagnosis is acquired, extended blood tests should be 
performed, skin biopsy taken, and hair sent for trichoscopy (7). A 
recent prospective study found that in 70% of NE cases a mutation 
could be discovered by next-generation sequencing (NGS), with a 
selected panel of 60 genes (12). The financial aspects and familial 
consent should always be taken into account when considering 
genetic analysis.
Skin biopsy is helpful for etiologic diagnosis of early erythro-
derma of infancy, particularly in immunodeficiencies and Neth-
erton syndrome (NS), the most common causative diseases (4). 
Consequently, these results justify an early skin biopsy for better 
and earlier management. In primary immunodeficiencies (PIDs), 
the sensitivity and specificity of these investigations were 58.5 and 
98.5%, respectively (13).
Trichoscopy, for example, can be prognostic in NS, where 
trichorrhexis invaginata (“bamboo hair”) is specifically observed 
(3, 4, 14, 15). In the case of trichothiodystrophies, trichoscopy 
shows linear fractures of the hair shaft (trichoschisis), and in 
Menkes disease kinky hair (pili tarti) can be seen on microscopic 
examination (15).
If no diagnosis is established and there are syndromic, extra-
cutaneous, or systemic symptoms, consult appropriate specialists 
to exclude PIDs, metabolic disorders, or syndromic ichthyosis (7). 
For example, a biotinidase deficiency can present as patchy alo-
pecia and acrodermatitis enteropathica, and it occurs earlier in 
breastfed babies than in formula-fed babies because human milk 
contains biotins. As with all metabolic disorders, it is more com-
mon that psoriasis-like scaling appears periorificially before it 
generalizes (7, 14, 16).
If no diagnosis can be made at this point, consider congenital 
non-syndromic ichthyosis or rare diagnoses in the neonatal peri-
od, such as generalized forms of atopic dermatitis, psoriasis, and 
seborrheic dermatitis (4, 7).
Atopic dermatitis (AD) presents within the first 6 months of life 
in 60% of children. (14). AD may have its onset in the 1st month; 
however, it is rarely erythrodermic in neonates (16).
When the diagnosis is established and appropriate treatment 
is started, perform regular-follow ups and re-evaluation of the pa-
tient to confirm the diagnosis (7).
Case report
A 5-week-old infant presenting with erythroderma, pustules of the 
trunk and limbs, and intertriginous dermatitis was transferred to 
the children’s ward of the Dermatovenerology Clinic for after be-
ing hospitalized at the Clinic for Infectious Diseases, where blood 
cultures for exclusion of a systemic infection were taken, skin 
smears were performed, and parenteral treatment with intrave-
nous flucloxacillin was started.
Ten days before admission, at 3.5 weeks of age, the child devel-
oped a red papular exanthem on his forehead (Fig. 3), which later 
spread across the entire face (Fig. 4) and then across the entire 
body. The skin intermittently improved, but later small pustules 
(Fig. 5) and scaling (Fig. 6) appeared. He had no signs of systemic 
involvement.
On admission to our ward, the skin of the entire body was dry, 
scaly, and erythematous (Fig. 4). The scalp was partially covered 
with white-yellowish scales. The skin behind the ears was macer-
ated, eroded, and covered with whitish-yellow scales. The trunk, 
mostly on the back, head, and limbs, was covered with tiny pus-
tules.
Apart from substantial white fluid that was obstructing the out-
er ear canal with no signs of ear infection and a distended belly, 
Figure 1 | Differential diagnosis of neonatal erythroderma (3, 7, 11).
59
Acta Dermatovenerol APA | 2023;32:57-61 Diagnosis of neonatal erythroderma in Slovenia
which was soft, painless on palpation, and with significant flatu-
lence, there were no signs of systemic involvement in the general 
examination.
Upon admission, the infant was bathed in an antiseptic bath 
and the skin lesions were treated locally with a combination of a 
corticosteroid and antibiotic ointment. As recommended by the 
infectious disease specialist, we switched to enteral antibiotic 
treatment. The next day, the pustular lesions started drying, but 
the erythema persisted despite local corticosteroid treatment.
Basic blood tests revealed a mildly elevated serum level of CRP 
(24 mg/l, reference range up to 5 mg/l)), the number of lympho-
cytes was on the lower end of normal values (2.8 × 109/l, reference 
range 2.5-8.0 × 109), there was mild monocytosis, pronounced eo-
sinophilia (29% in the differential blood count, reference range 
0-5 %), and extremely elevated levels of serum IgE (1,300 IU/ml, 
reference range less than 4.1 IU/ml). Specific sensitization to ali-
mentary allergens (cow’s milk, eggs, and wheat) was excluded, 
and liver enzyme tests and serum bilirubin levels were normal. 
Skin smear analysis was negative for enteroviruses and showed 
no eosinophilic granulocytes, but it was positive for bacterial 
flora (Morganella morganii, Acinetobacter pittii, Escherichia coli, 
Staphylococcus aureus, Streptococcus pyogenes, and Enterococcus 
faecalis). A Hep-2 test was negative.
Based on all the results and the clinical picture, immunode-
ficiency was suspected and an additional analysis of peripheral 
lymphocyte populations was ordered. The test revealed a low 
Figure 2 | Proposed Slovenian guidelines for the diagnostic approach to neonatal erythroderma. Adapted from Cuperus et al. (7).
60
Acta Dermatovenerol APA | 2023;32:57-61M. Starbek Zorko et al.
level of CD3+ T cells, absent CD19+ B cells, a low level of CD4+ 
T cells among CD3+ T cells, and a normal level of CD8+ cytotoxic 
T cells among CD3+ T cells. The concentration of CD16+ CD56+ 
NK cells was elevated. These results were diagnostic for a specific 
type of severe combined immunodeficiency (SCID) called Omenn 
syndrome (OS). The infant was promptly transferred to the pediat-
ric immunology ward for appropriate care and treatment.
OS is a rare form of SCID. Clinically it can manifest as exfo-
liative dermatitis, erythroderma, alopecia, lymphadenopathy, 
hepatosplenomegaly, intractable diarrhea, and recurrent infec-
tions. In the analysis of peripheral lymphocyte populations in OS, 
B cells are typically absent and oligoclonal autoreactive T cells are 
increased, resulting in eosinophilia and elevated IgE. Mortality is 
high due to opportunistic infections (17, 18). In recent decades, 
the survival rate has improved, especially with hematopoietic 
stem cell transplant therapy (17–19).
Discussion
Neonatal and infantile erythrodermas are associated with a wide 
range of cutaneous and systemic disorders, one of them being PID.
As demonstrated by our case report, a step-by-step approach 
proposed by Cuperus et al. (7) was adapted for use in Slovenia and 
is essential for achieving a timely working diagnosis.
Our patient with erythroderma, intertriginous inflammation, 
and pustules on the trunk was admitted to the infectious dis-
eases clinic, where blood cultures and skin smears were taken to 
exclude systemic infection and antibiotic treatment was started. 
After transferring the infant to our ward, a detailed clinical exami-
nation was made, which excluded systemic infection. Erythroder-
ma persisted despite local corticosteroid treatment, and the skin 
smears showed colonization with multiple pathogenic bacteria. 
Basic blood tests failed to present us with a working diagnosis. We 
decided on further extensive blood tests and an analysis of periph-
eral lymphocyte populations. The results showed high IgE levels, 
eosinophilia, and hypogammaglobulinemia. In connection with 
typical results in peripheral lymphocyte populations and a failure 
to respond to corticosteroid treatment, this is diagnostic for OS.
After establishing the correct diagnosis, the patient was trans-
ferred to the immunology ward at the pediatric clinic for further 
assessment of the disease and appropriate definitive treatment.
Conclusions
Prolonged erythroderma should always be a warning to a physi-
cian, and the role of a pediatric dermatologist is to bear in mind 
the wide spectrum of differential diagnoses that could be caus-
ing the condition. In the case of PID, the diagnostic process must 
be swift, and referral of the patient to the appropriate pediatric 
ward must occur as soon as possible to avoid any possible com-
plications and start the appropriate treatment. This can only be 
achieved through a multidisciplinary approach, which is always 
needed in such rare and potentially life-threatening cases.
Figure 3 | Red papular exanthem on the forehead.
Figure 4 | Red papular exanthem of the baby’s face.
Figure 5 | Exanthem of the face with small pustules.
Figure 6 | Dry, scaly, and erythematous skin of the baby’s entire body.
61
Acta Dermatovenerol APA | 2023;32:57-61 Diagnosis of neonatal erythroderma in Slovenia
References
1. Khaled A, Sellami A, Fazaa B, Kharfi M, Zeglaoui F, Kamoun MR. Acquired eryth-
roderma in adults: a clinical and prognostic study. J Eur Acad Dermatol Venereol. 
2010;24:781–8.
2. Sarkar R, Garg VK. Erythroderma in children. Indian J Dermatol Venereol Leprol. 
2010;76:341–7.
3. Ott H. Guidance for assessment of erythroderma in neonates and infants for the 
pediatric immunologist. Pediatr Allergy Immunol. 2019;30:259–68.
4. Ott H, Grothaus J. Das rote, schuppende Baby: ein kinderdermatologischer 
Notfall: Klinik und Differenzialdiagnosen neonataler Erythrodermien. Hautarzt. 
2017;68:796–802. German.
5. Hoeger PH, Harper JI. Neonatal erythroderma: differential diagnosis and manage-
ment of the “red baby.” Arch Dis Child. 1998;79:186–91.
6. Fraitag S, Bodemer C. Neonatal erythroderma. Curr Opin Pediatr. 2010;22:438–
44.
7. Cuperus E, Bygum A, Boeckmann L, Bodemer C, Bolling MC, Caproni M, et al. Pro-
posal for a 6-step approach for differential diagnosis of neonatal erythroderma. J 
Eur Acad Dermatol Venereol. 2022;36:973–86.
8. Al-Dhalimi MA. Neonatal and infantile erythroderma: a clinical and follow-up 
study of 42 cases. J Dermatol. 2007;34:302–7.
9. Pruszkowski A, Bodemer C, Fraitag S, Teillac-Hamel D, Amoric JC, de Prost Y. 
Neonatal and infantile erythrodermas: a retrospective study of 51 patients. Arch 
Dermatol. 2000;136:875–80.
10. Sarkar R, Sharma RC, Koranne RV, Sardana K. Erythroderma in children: a clinico-
etiological study. J Dermatol. 1999;26:507–11.
11. Eichenfield LF, Frieden IJ, Mathes EF, Zaenglein AL. Neonatal and infant dermatol-
ogy. 3rd ed. London (UK): Elsevier Saunders; 2014. Chapter 18, Erythrodermas, 
immunodeficiency, and metabolic disorders; p. 266.
12. Cuperus E, Sigurdsson V, van den Akker PC, Bolling MC, van Gijn ME, Pasmans 
SGMA. Diagnostic next generation sequencing in neonatal erythroderma. J Dtsch 
Dermatol Ges. 2021;19:612–4.
13. Leclerc-Mercier S, Bodemer C, Bourdon-Lanoy E, Larousserie F, Hovnanian A, 
Brousse N, et al. Early skin biopsy is helpful for the diagnosis and management 
of neonatal and infantile erythrodermas. J Cutan Pathol. 2010;37:249–55.
14. Kotrulja L, Murat-Susić S, Husar K. Differential diagnosis of neonatal and infantile 
erythroderma. Acta Dermatovenerol Croat. 2007;15:178–90.
15. Silengo M, Valenzise M, Sorasio L, Ferrero GB. Hair as a diagnostic tool in dys-
morphology. Clin Genet. 2002;62:270–2.
16. Dhar S, Banerjee R, Malakar R. Neonatal erythroderma: diagnostic and therapeu-
tic challenges. Indian J Dermatol. 2012;57:475–8.
17. Cutts L, Bakshi A, Walsh M, Parslew R, Eustace K. Diagnosing Omenn syndrome. 
Pediatr Dermatol. 2021;38:541–3.
18. Scheimberg I, Hoeger PH, Harper JI, Lake B, Malone M. Omenn’s syndrome: dif-
ferential diagnosis in infants with erythroderma and immunodeficiency. Pediatr 
Dev Pathol. 2001;4:237–45.
19. Hönig M, Schwarz K. Omenn syndrome: a lack of tolerance on the background 
of deficient lymphocyte development and maturation. Curr Opin Rheumatol. 
2006;18:383–8.
62
Acta Dermatovenerol APA | 2023;32:57-61M. Starbek Zorko et al.
63
Acta Dermatovenerol APA | 2023;32:57-61 Diagnosis of neonatal erythroderma in Slovenia
64
Acta Dermatovenerol APA | 2023;32:57-61M. Starbek Zorko et al.
65
Acta Dermatovenerol APA | 2023;32:57-61 Diagnosis of neonatal erythroderma in Slovenia