Current Fungal Infection Reports (2018) 12:207–212

https://doi.org/10.1007/s12281-018-0331-z

FUNGAL INFECTIONS OF SKIN AND SUBCUTANEOUS TISSUE (A BONIFAZ, SECTION

EDITOR)

Onychomycosis in Children with Down Syndrome

Jade Castellanos 1 & Mirna Toledo-Bahena 1 & Carlos Mena-Cedillos 1 & Erika Ramirez-Cortes 2 & Adriana Valencia-Herrera 1

Published online: 29 October 2018

# Springer Science+Business Media, LLC, part of Springer Nature 2018

Abstract
Purpose of Review Fungal infection of the nail, known as onychomycosis, occurs more frequently in older age, showing a higher
prevalence in pediatric age in recent years. A high rate of dermatological infections befalls in patients with Down syndrome,
including onychomycosis, due to a decrease in T and B lymphocytes in number and function, resulting in a disarrangement of
cellular and humoral immunity. This has led to several investigations on onychomycosis in children with Down syndrome, so the
purpose of this review is to show the available evidence.
Recent Findings The etiological agents of onychomycosis can be dermatophytes, non-dermatophyte molds, and yeasts. Most
cases are related with dermatophytes; Trichophyton rubrum being the most common cause. In children with Down syndrome,
T. rubrum has been reported as the main cause, followed by T. mentagrophytes. Distal lateral subungual onychomycosis is the
most common variety of onychomycosis in children. The importance of identifying the fungus lies in selecting the appropriate
treatment, since not all antifungals have the same spectrum of action against molds and Candida. Terbinafine has showed to be
safe and effective for the treatment of onychomycosis in patients from special populations, including children with Down
syndrome. In patients with Down syndrome, treatment for onychomycosis has not been completely studied; so far, terbinafine
has shown the best results.
Summary The clinical presentations of children with Down syndrome and the rest of the general pediatric population are similar.
However, there are few studies about onychomycosis in children with Down syndrome. It is necessary to perform new
onychomycosis research in this study population, in order to establish recommendations.

Keywords Onychomycosis . Down syndrome . Children . Immunodeficiency . Trichophyton rubrum

Introduction diseases ranges from 0.5–13%; however, in the pediatric pop-

Onychomycosis is the fungal infection that involves not only
the nail plate but also the nail bed. It is an infection that occurs
more frequently in older age groups, being common in adult-
hood and unusual in children, although there has been an
increase in the pediatric age [1•, 2]. Its prevalence among skin
This article is part of Topical Collection on Fungal Infections of Skin and
Subcutaneous Tissue
* Adriana Valencia-Herrera
adrianavalenciaherrera@gmail.com
1
Department of Dermatology, Hospital Infantil de México Federico
Gómez, Dr. Márquez 162, Col. Doctores, Del. Cuauhtémoc,
06720 Ciudad de México, México
2
Star Médica Hospital Infantil Privado, Ciudad de México, Mexico
ulation, it has a range of 0.2–0.44%, with an average of 0.3%
worldwide [3•]. The most affected group is 12- to 16-year-
olds, perhaps related to the use of athletic shoes, hormonal
changes of puberty, parental infection up to 65% and coinfec-
tion with tinea pedis in 46.2% [4].
The etiological agents of onychomycosis may be dermato-
phytes, non-dermatophyte molds, and yeasts. In most cases, it
is caused by dermatophytes [5]. In children with Down syn-
drome, this behavior has also been reported [6].
Down syndrome is the most frequent chromosomopathy
and the first cause of mental retardation of genetic origin [7].
A high rate of infections befalls in patients with Down syn-
drome, including dermatological infections such as folliculitis,
skin mycosis, and onychomycosis, all this due to a decrease in
T and B lymphocytes in number and function, resulting in a
disarrangement of cellular and humoral immunity, in addition
to a deficient phagocytosis [8].
208
Immune System in Children with Down Syndrome
Altered immunological aging is observed in patients with
Down syndrome so they can present not only alterations of
natural killer cells and lymphocyte subpopulations, but also
deficiency in phagocytosis and chemotaxis of polymorphonu-
clear leukocytes [9]. In patients with Down syndrome, studies
on lymphocyte subpopulations have shown a lower count of
CD3-CD16 and 56+ NK cells [10]. T lymphocyte subpopula-
tions can increase in number, so they can even reach normal
levels with increasing age, whereas B lymphocyte populations
remain severely decreased [11].
Moreover, during childhood, proliferation, clonal expan-
sion and differentiation are part of an adequate immune re-
sponse. A decreased expansion of T and B lymphocytes sug-
gests that patients with Down syndrome actually present an
intrinsically altered immune system and not as a result of
precocious aging. Thymus alterations have been reported also,
and this can explain a decreased count of T lymphocytes, but
not a reduced count of B lymphocytes found in these children
[11].
Antibody and immunoglobulins (Ig) production cannot be
well regulated. Therefore, a high incidence of
dysgammaglobulinemia [7] and decreased specific antibody
responses to immunizations [12] are observed in Down syn-
drome patients, which become more serious in adulthood [7].
Down syndrome is characterized also by a smaller size and
abnormal structure of the thymus, even in newborns. It also
shows a decreased proportion of mature T lymphocytes that
leads to overexpression of cytokines, suggesting a regulatory
failure in cytokine production in Down syndrome [10].
Cellular immunity is essential to counteract fungal infec-
tions [13]. Alterations in skin, hair, or nails have been ob-
served in patients with immunosuppression. These clinical
manifestations, including onychomycosis, are attributed to de-
terioration in cellular immunity and nail morphological alter-
ations that predispose to the acquisition of these infections
[14].
Other Risk Factor for Onychomycosis
Down syndrome has been described as a risk factor for acquir-
ing onychomycosis, due to the high frequency of infections in
early age attributed to immunosuppression coupled with over-
crowding and in some cases inability to perform daily person-
al hygiene by themselves, due to mental retardation. [15].
Local cutaneous factors are very important to determine
whether the infection will occur or not after exposure to
dermatophytic fungi [16]. These factors include the use of
occlusive and synthetic footwear, sports practice with more
injuries, having an affected relative or conditions such as dia-
betes mellitus and immunosuppression states [17].
Curr Fungal Infect Rep (2018) 12:207–212
Solís-Arias and García-Romero mention the importance of
checking relatives, looking for fungal infections, since in most
cases children have a family contact as a source of infection
and this condition can recur [1•]. The main recurrence factors
that have been described are a family history of onychomyco-
sis, immunosuppression coexisting clinical conditions (Down
syndrome), and acquired or inherent immunodeficiencies
[18].
Epidemiology
Onychomycosis is the fungal infection of the nail plate; in
fact, it has a prevalence of 0 to 2.6% in children, with an
average of 0.3% worldwide [3•]. Several studies show that
prevalence of onychomycosis has increased in children in re-
cent years [17, 19, 20]. A higher incidence is reported in the
male [2], most frequently during adolescence [21], with a
greater involvement of the toenails than of the hands [13,
17, 22]. It is one of the most frequent dermatological condi-
tions, consisting of 20 to 40% of all nail diseases [1•, 5].
It is known that onychomycosis is more frequent in adults
than in children, possibly because adults have a more time
exposing them to fungi in public places with a high amount
of hyphae and infectious spores (for example, swimming
pools and public showers in fitness centers), lower nail growth
compared to children population. In the case of children,
onychomycosis is less likely to happen in order to some other
conditions such as smaller nails that result in less possibility to
acquire a fungal colonization and also, a lower incidence of
tinea pedis in childhood [3•].
Nail plate’s fungal infections are more frequent in Down
syndrome children, compared with the general pediatric pop-
ulation [1•]. This increase can be explained by the risk of
fungal infections, due to a disarrangement of the immune sys-
tem [13].
Araníbar L. et al. reported a frequency of onychomycosis
of 21% in Down syndrome children, from 1 to 19 years of age,
showing a statistically significant difference compared with
healthy children [23]. Schepis et al. found a lower frequency
(4.4%) in 203 patients with Down syndrome with an approx-
imate age of 11.7 years [6]. Carter and Jegasothy described a
prevalence of 67.8% of onychomycosis in children and adults
with institutionalized Down syndrome, with an age range be-
tween 12 and 48 years old [24••]. These studies have differ-
ences in age groups; in addition, there are no clinical and
laboratory data considered in order to perform and confirm
the diagnosis, nor are home care conditions mentioned, so
they are not completely comparable.
Polenghi et al. describe a prevalence of onychopathies of
8% in patients with Down syndrome from 14 to 53 years of
age, without defining the alterations they presented [25]. Only
50% of the nail dystrophy is caused by fungal infection, ac-
cording to these findings [26•].
Curr Fungal Infect Rep (2018) 12:207–212
Ercis et al. determined the incidence of dermatological
manifestations in 71 Down syndrome children, with an age
range of 2 months to 25 years, in which no case of
onychomycosis was present, this may be due to the fact that
the approximate age of the children patients was 2 years and
10 months [27] and onychomycosis is usually found in chil-
dren older than 6 years of age [3•]. However, Bonifaz et al.
reported the existence of onychomycosis in 16 toddlers with
an average age of 15 months, finding Down syndrome as a
main associated factor in seven cases (43.8%). The main eti-
ologic agent was Trichophyton rubrum in 87.5% of the cases,
predominating toenail onychomycosis and distal subungual
onychomycosis (87.5%). A correlation between onychomy-
cosis and tinea pedis was found in 14 parents, seven mothers,
and one sibling [28]. Velthuis and Nijenhuis evaluated 32
patients with Down syndrome and onychomycosis; out of
which, only 50% had positive cultures, 14 with Trichophyton
rubrum and two with T. mentagrophytes [13].
Onychomycosis is also associated with environmental fac-
tors and poor hygiene [1•, 29, 30]; Daneshpazhooh et al. men-
tion that better hygiene at home can reduce the condition in
children with Down syndrome. They studied 100 patients with
this syndrome, from 3 to 20 years old, without finding evidence
of onychomycosis [29]. Just like Rengasamy Sureshbabu et al.,
no onychomycosis was found in any case [30].
Pathogeny
The etiological agents of onychomycosis can be: dermato-
phytes, non-dermatophyte molds and yeasts. Dermatophytes
are the main causative agents; Trichophyton rubrum is the
most frequent etiology [31]. In children with Down syndrome,
T. rubrum has also been informed as the main etiological agent
[13, 28, 32], followed by T. mentagrophytes [13].
Candida and non-dermatophytic molds are also part of the
onychomycosis etiology. However, studies on onychomycosis
and Down syndrome do not report the development of these
fungi [13, 28, 32].
Case series of onychomycosis due to non-dermatophytic
molds do not describe associations with Down syndrome
[33–37], probably because this causal agent is rare and is not
necessarily associated with systemic diseases [33].
Clinical Features
Onychomycosis in children with Down syndrome has an iden-
tical clinical presentation compared to the general pediatric
population. Onychomycosis is divided by its clinical form into
the following types (Fig. 1) [38]:
1. Subungual
a. Distal
209
b. Lateral
c. Proximal
2. Superficial white onychomycosis
3. Endonyx
4. Total dystrophic
Distal and lateral subungual onychomycosis is the most
frequent type of onychomycosis in children [31], that is, the
one that begins at the free edge and extends forward the nail
matrix. In some cases, with chronicity, it results in the most
destructive form for the nail, known as total dystrophic
onychomycosis; presenting loss of consistency, brightness,
and pachyonychia. When dermatophytes start infection from
the proximal edge, they give way to proximal subungual
onychomycosis, usually in the form of a transverse
leukonychia; this form is seen more frequently in patients with
HIV-AIDS, transplants, and problems with blood circulation.
The least frequent form is superficial white onychomycosis, a
clinical variety that appears as discrete whitish areas, due to a
very superficial parasitization of the nail [38]. Endonyx
onychomycosis is characterized by milky white patches, la-
mellar peeling, pitting, and nail plate undulations [39].
Toenails are the most affected, and Trichophyton rubrum is
the main etiological agent that causes distal and lateral
subungual onychomycosis, as the most frequent clinical vari-
eties. The age group with the highest prevalence is 12 to
17 years [38].
Diagnosis
In children and adult population, the diagnosis of
onychomycosis should always be confirmed with a mycolog-
ical study, considering that 50% of distrophy cases in nails
find its cause in fungal infections. Also, clinically, it is impos-
sible to distinguish what fungal species caused onychomyco-
sis. Therefore, it is necessary to avoid delay in the specific
treatment [26•].
One of the most common methods used to confirm
onychomicosis is the potassium hydroxide (KOH) test. This
test determine neither the causal agent, nor the viability, it only
allows to differentiate the existence or absence of fungi [22].
Therefore, it may be erroneous if it is used as a test to deter-
mine resolution of onychomycosis [26•].
Positive cultures are the most specific tests to confirm the
diagnosis. They allow to identify the causative agent, with a
specificity of 99–100% [40]. The best standard for the diag-
nosis of onychomycosis is the isolation of the etiologic agent.
It has a disadvantage; it can give false negatives from an
insufficient nail sample or inadequate sample collection.
False positives can be caused by polluting organisms, such
as several molds [26•]. There is still a high failure rate in
culturing the nail, because many times the collected material
210
Fig. 1 Onychomycosis in
children with Down syndrome. a
Proximal subungual
onychomycosis. b Proximal
subungual onychomycosis of left
great toe. c Total dystrophic
onychomycosis. d Fingernails
onychomycosis
of study may be old or non-viable when it is from the distal
part of the nail [5]. Therefore, direct microscopy vision and
culture are required to be done in order to definitively identify
the etiological agent [41], having together a sensitivity of 74%
[1•].
Histopathology uses direct microscopic examination of tis-
sue stained with special stains. Periodic acid–Schiff (PAS)
staining is particularly sensitive when combined with fungal
culture, increasing sensitivity to 96%. Gomori’s methenamine
silver (GMS) staining has been shown to be better than PAS
staining and the most sensitive technique used to identify der-
matophytes [26•]. The histopathology of affected nails con-
firms the diagnosis but is much more invasive, so it is not
always used [4].
The importance of identifying the fungus lies in selecting
the appropriate treatment, since not all antifungals have the
same spectrum against molds and Candida [26•].
Treatment
For suspected cases of onychomycosis, the American
Academy of Dermatology (AAD) recommends the identifica-
tion of causal agent and the confirmation of the diagnosis to
prescribe an antifungal treatment. In addition, the factors that
have an impact in choosing therapy include the etiological
organism, cost of therapy, severity of the disease, medical
treatment in the patient, clinical pattern possibility of adverse
events in the patient, and the doctor’s familiarity with antifun-
gal medications [3, 14, 42].
Fungal infections of toenails are currently recommended to
be treated with terbinafine and itraconazole as first-line treat-
ments [18, 43], and out of both, terbinafine is preferred [44].
Curr Fungal Infect Rep (2018) 12:207–212
Studies have shown the superiority of a continuous treatment
over pulse doses of terbinafine. Therefore, the preferred ther-
apeutic mode for onychomycosis is a continuous therapy [45].
Terbinafine was associated with a higher remission rate than
triazoles when compared directly [44]. The mycological cure
rate showed a meta-analysis with 76% for a terbinafine con-
tinuous dose, 63% for itraconazole with pulse dose, 59% for a
continuous dose of itraconazole and 48% for fluconazole [14].
Debridement of the damaged nails further increases the
cure rates. Topical ciclopirox has a failure rate greater than
60%, which makes it less effective than other medical treat-
ments [14].
Pulse therapy reduces costs of systemic treatment and can
reduce adverse effects [45]. De Doncker et al. proved that
fingernail and toenail onychomycosis can be successfully
treated with two and three pulses respectively [46, 47]. Pulse
therapy can be indicated for 1 week per month, 1 day per week
or as a single dose [42].
Bonifaz et al. reported a remission rate close to 70% using
bifonazole-urea in children. Therefore, they recommended
topical treatment as an option for children under 2 years of
age [28]. Friedlander et al. also demonstrated the efficacy of
topical treatment with ciclopirox in patients from 2 to 16 years
of age with non-matrix onychomycosis [48].
Onychomycosis in immunocompromised patients tends to
be more widespread, making the treatment difficult some-
times, which justifies the use of systemic therapy. It has been
shown that conventional antifungals are helpful for treatment
of older patients, children, and immunocompromised individ-
uals with onychomycosis [42]. Onychomycosis has been
treated effectively and safely in patients from special popula-
tions with the use of terbinafine, including Down syndrome
Curr Fungal Infect Rep (2018) 12:207–212
children [49]. Velthuis and Nijenhuis showed that the remis-
sion rate when using terbinafine in patients with Down syn-
drome is as high as in healthy patients and that the alteration of
cellular immunity does not affect its therapeutic effect [13].
Onychomycosis treatment in patients with Down syn-
drome has not been completely studied because they are ex-
cluded from the study groups; so far, terbinafine has shown
better results [50]. Studies in patients with Down syndrome
and onychomycosis are needed to establish more accurate
recommendations.
For prevention, treating the family members is necessary to
prevent reinfection among children and the rest of the family,
since in many cases the carrier is a close contact [1•].
Conclusions
Onychomycosis is the fungal infection that involves the nail
and has had an increase in pediatric age in the past years.
Dermatological infections are highly rated in patients with
Down syndrome, including onychomycosis, due to a decrease
in T and B lymphocytes in number and function.
Onychomycosis can be caused mainly by dermatophytes,
Trichophyton rubrum being the most frequent etiology.
T. rubrum, followed by T. mentagrophytes, has been the main
cause of onychomycosis reported in children with Down syn-
drome. Although terbinafine has been used to treat
onychomycosis effectively and safely in patients from special
populations, studies in patients with Down syndrome are
needed in order to establish specific recommendations.
Compliance with Ethical Standards
Conflict of Interest The authors declare that they have no competing
interests.
Human and Animal Rights and Informed Consent This article does not
contain any studies with human or animal subjects performed by any of
the authors.
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