SKIN - July 2021 - 1237 proof returned

SKIN

July 2021 Volume 5 Issue 4

IN-DEPTH REVIEW

Molecular Pathogenesis and Complications Associated with
Keratosis Follicularis: A Clinical Review

Hira Ghani, BA1, Stefani Cubelli, DO2, Raphia K. Rahman, BA, MBS3, Alexandra Chervonsky,
BA, MA1

1New York Institute of Technology College of Osteopathic Medicine, Old Westbury, NY
2St. John’s Episcopal Hospital, Far Rockaway, NY
3Rowan School of Osteopathic Medicine, Rowan, NJ

In 1889, Dr. James C. White, a professor of
Dermatology at Harvard University published
the first case report of a patient with Keratosis
Follicularis, whose skin appeared to be
occupied with a variety of lesions, some of
which were the “size of a pinhead, smooth
and firm”, while others were slightly larger,
but similar in appearance. The same year,
independently from Dr. White in Paris, Dr.
Darier published another case report of a
patient with a similar presentation. Keratosis
follicularis or Darier's disease (DD), a rare
autosomal dominant disorder, is
characterized clinically by the appearance of
multiple, pruritic, discrete, scaly papules
affecting seborrheic areas coupled with
palmar pits, nail changes and mucosal
involvement.1

These hyperkeratotic papules can be present
on the middle of the chest, upper shoulders,
neck and face.2 The papules coalesce into
plaques which can appear papillomatous and
may become hypertrophic, malodorous,
painful and prone to secondary infections.2, 3
The disorder is a relatively common
genodermatosis and affects approximately 1
in 36,000 individuals. It is characterized by
late age of onset and typically presents in the
first or second decade. Histologically, DD is
characterized by the presence of dyskeratotic
cells, also known as corps rounds, which are
small round keratinocytes with basophilic
nuclei, and acantholysis–loss of intercellular
connection between keratinocytes.3

Topical tazarotene, topical isotretinoin,
topical adapalene and oral retinoids have
been reported to be effective for the
treatment of mild-to-moderate keratosis

ABSTRACT

Keratosis follicularis or Darier's disease (DD) is a rare autosomal dominant disorder characterized by
the appearance of multiple scaly papules affecting seborrheic areas. It is a multisystem disorder that
occurs in the first or second decade of life, and extends beyond cutaneous involvement. It has been
reported to be associated with various basal cell carcinoma (BCC) and other skin cancers, nail changes,
ocular/mucosal manifestations and neuropsychiatric disorders. Additionally, individuals with DD have a
greater risk of being diagnosed with Type 1 Diabetes Mellitus as well as disease-specific risk of heart
failure. The goal of this review is to explore the molecular pathogenesis of keratosis follicularis, and to
investigate the extent and severity of various complications associated with this condition. Furthermore,
dermatologic practice recommendations will be reviewed for the management of DD.

INTRODUCTION

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follicularis.4-6 Surgical options for severe or
refractory disease include dermabrasion,
carbon dioxide laser, and Neodymium-doped
Yttrium Aluminum Garnet (YAG) laser. 7 More
recently, the role of naltrexone has also been
explored in treating DD. While low-dose
naltrexone has been quite successful in
treating Hailey-Hailey disease, a
genodermatosis similar to DD with a genetic
mutation coding for a loss of function of a
Ca2+ -ATPase pump (hSPCA1-pump), it has
shown worsening of symptoms after initial
treatment when used for severe DD.8
However, low-dose naltrexone has been an
effective and viable treatment option for the
treatment of mild-to-moderate spectrum of
DD.8 Further, DD may be exacerbated by
ultraviolet light exposure, particularly
ultraviolet B, as well as by heat, humidity, and
friction. Additionally, the use of topical
sunscreens and ascorbic acid have been
shown to be effective in the prevention of
disease flares.9

DD has been reported in association with
non-melanoma skin cancers (NMSC),
including various basal cell carcinomas
(BCC), as well as neuropsychiatric disorders
such as Bipolar disorder.10, 11 Moreover, rare
cases involving nail changes and ocular
manifestations have also been observed in
connection with DD. It was also found that
individuals with DD have an elevated risk of
being diagnosed with Type 1 Diabetes, and
show an increased risk of heart failure which
should be taken into account in patient
management. 12 Thus, the purpose of this
literature review is to explore the molecular
pathogenesis of DD, investigate the various
complications associated with DD, and to
elucidate the degree to which these
complications are observed in patients
suffering from DD.

Molecular Pathogenesis of Keratosis
Follicularis
DD is caused by genetic defects in ATP2A2
encoding the sarcoplasmic/endoplasmic
reticulum Ca(2+)-ATPase isoform 2
(SERCA2). 13 SERCA2 is a calcium pump of
the endoplasmic reticulum (ER) transporting
Ca(2+) from the cytosol to the lumen of ER.
ATP2A2 mutations lead to loss of Ca(2+)
transport by SERCA2 resulting in decreased
ER Ca(2+) concentration in Darier
keratinocytes. 13 This eventually results in
loss of cell-to-cell adhesion and abnormal
keratinization. 13

The alternative splicing of ATP2A2 gene
gives rise to two isoforms of SERCA2 pump:
SERCA2a, which is predominantly found in
skeletal and cardiac muscles, and SERCA2b,
which is found in all cell types but abundantly
in smooth muscle cells. 14, 15 SERCA2b is
different from SERCA2a by the presence of
the “2b tail”. 16 It has been suggested that
wildtype SERCA2b in keratinocytes exhibits
high calcium affinity with the low transport
rate, while mutations in SERCA2b lead to
increased cytosolic calcium with the
decreased peak calcium, and thus impairs
the dynamic of calcium signaling. 16

A high concentration of calcium inside of the
ER is needed for the posttranslational
processing of proteins that are destined to
reach the plasma membrane. Depletion of
calcium concentration in ER is associated
with the accumulation of misfolded proteins in
ER, which leads to initiation of stress
response. 17 It has been shown that constant
ER stress response leads to decreased
adherens junction formations between the
cells. 17 It has been also observed that loss of
SERCA2b leads to formation of defective
adherens junctions and desmosomes, which

RESULTS

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results in diminished intercellular adhesion. 17
In other words, mutations in ATP2A2 that
cause defective SERCA2b lead to low
calcium concentration inside of ER, and thus
impair proper processing of proteins that are
responsible for cell-to-cell adhesion.

DD and Basal Cell Carcinoma
According to a variety of literature, an
association has been found between DD and
basal cell carcinoma (BCC). While no
molecular link between DD and BCC has
been established, the imbalance of cellular
survival and apoptosis due to the DD
mutation or other genodermatoses may
contribute to the presence of BCC in
individuals with DD. Darier's disease is
caused by a loss-of-function mutation in the
ATP2A2 that leads to a disruption of
Ca2+homeostasis within the keratinocytes. A
decreased SERCA activity leads to an
upregulation of the transient receptor
potential canonical 1 Ca channel that
increases cell proliferation and resistance to
apoptosis. 18 Additionally, it has been
demonstrated that patients with DD have
reduced expression of the antiapoptotic
proteins Bcl-2 and Bcl-XL, which may
activate apoptosis and lead to increased cell
turnover. 19 Although quite rare, cases of
squamous cell carcinoma (SCC) have also
been seen in patients with DD. Robertson
and Sauder report that at least 7 cases of
SCC have been observed in association with
DD since 1981. 20 However, no association
was determined between DD and melanoma,
Merkel cell cancer or any other kind of skin
cancer. More investigation needs to be done
to establish a relationship between DD and
cutaneous malignancies that are not NMSC.
20 Moreover, alteration of ATP2A2 gene has
been reported in the development of various
other human carcinomas including colon and
lung cancers. 21

DD and Cutaneous, Ocular & Mucosal
Manifestations
Nail involvement in individuals suffering from
DD is not uncommon, and is frequently
characterized by red or white longitudinal
bands of varying width ending in a
pathognomonic notch at the free margin of
the nail, and subungual hyperkeratosis.
Usually, the nails are found to be very fragile
and brittle. Mucosal membrane involvement
may occur as white papules on the buccal
mucosae, palate, and gingiva with a
cobblestone appearance. 22 Being a
predominantly dermatological disease,
ocular manifestations are rare in keratosis
follicularis. They can present as punctuate
corneal epithelial defects (photophobia),
asymptomatic opacities in periphery of
cornea, bilateral corneal subepithelial
infiltrations, corneal ulcerations, or
conjunctival keratosis.23-25 Patients with
Darier's are also prone to recurrent herpes
keratitis and episcleritis. 26 There have been
rare reports of other abnormalities including
cataracts, basal cell carcinoma, retinal
detachment, and in some patients, typical
retinitis pigmentosa and even horn-like
growths along the lid margin. 27-29

DD and Neuropsychiatric Conditions
It has been observed that DD is associated
with multiple neuropsychiatric conditions,
such as major depression, bipolar disorder,
schizophrenia, and suicidal ideations. 30 It
was found that individuals with DD have a
higher chance of being diagnosed with
bipolar disorder and schizophrenia (4.3 and
2.3 fold higher, respectively). 11 It is thought
that the genetic variability within the ATP2A2
gene which causes DD confers susceptibility
for bipolar disorder in some patients suffering
from DD. 11 Another study, that analyzed the
results of standardized neuropsychiatric tests
of one hundred individuals diagnosed with
DD, suggests that neuropsychiatric
symptoms of DD are rather the result of

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ATP2A2 gene mutation, than the
psychological response of the individuals to
the cutaneous manifestation of DD. 30 Even
though multiple mutations of ATPA2A2 are
linked to DD, only specific locations of
ATP2A2 mutations are associated with
neuropsychiatric symptoms. 31 This
relationship can be explained by the
pleomorphic effect of ATPA2A loss of
function mutations. 32

DD and Diabetes
The relationship between DD and diabetes
has also been observed. In a study
conducted by Cederlöf et al, it was found that
individuals with DD had a higher risk of being
diagnosed with type 1 diabetes (risk ratio,
1.74; 95% confidence interval, 1.13-2.69)
than those having type 2 diabetes (risk ratio,
0.88; 95% confidence interval, 0.37-1.36). 12
Given that most individuals with DD have
mutations in ATP2A2, it is possible that the
increased risk of Type 1 Diabetes is
associated with ATP2A2 mutations and
SERCA2 dysfunction. 12 Moreover, in the
recent cross-sectional clinical study of
metabolic phenotype of DD, it has been
found that DD patients have lower fasting
glucose level and higher c-peptide and
HOMA2-%beta compared to their matched
control group. 33

This indicates that DD patients have a higher
secretory capacity of islet cells and a higher
basal insulin level. The authors emphasize
that increased basal insulin is associated with
worse control of glucose, and with time, may
lead to type 2 diabetes. 33 The relationship
between glucose metabolism and DD may be
due to the fact that among different SERCA
isoforms, SERCA2b is most abundantly
expressed in pancreatic beta-cells. 14 It has
been shown that the loss of SERCA2b due to
mutations in ATP2A2, as seen in individuals
with DD, leads to secretory dysfunction, and
defect in proliferation and survival of beta-

cells. 34 Additionally, inhibition of SERCA2b in
beta-cells leads to initiation of the stress
response by ER that induces apoptosis. 35

DD and Heart Disease
Furthermore, it has been hypothesized that
DD may be associated with heart diseases.
This observation also strengthens the clinical
evidence of the important role of SERCA2 in
heart failure pathophysiology. 36 For
example, even though patients with DD
present with a normal clinical heart
phenotype, they have a 59% higher chance
of being diagnosed with heart failure
compared to those without DD. 36
Interestingly, the loss of the ATPA2A allele by
itself does not affect cardiac performance,
however, the development of heart
conditions may be worsened in patients with
ATPA2A mutation. 37

It can be concluded that DD is a multisystem
rare autosomal dominant disorder that occurs
typically in the first or second decade of life,
and goes beyond involving the skin. While
neuropsychiatric manifestations, diabetes
mellitus type 1 and heart diseases are more
commonly observed, rare instances of
mucosal, nail and ocular changes have also
been reported to occur in association with
DD. Since UV light exposure exacerbates the
condition, we recommend individuals with DD
to avoid direct sunlight and apply sunscreen
when going out. Furthermore, mild to
moderate DD management includes the use
of oral and topical retinoid as well as
naltrexone. Dermabrasion and carbon
dioxide or YAG laser are reserved for severe
and refractory cases. It is crucial for
dermatologists to anticipate and discern the
extracutaneous manifestations associated
with DD in order to be able to provide a timely
and appropriate referral to other specialists,

CONCLUSION

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including psychiatrists, endocrinologists and
cardiologists, for further management.

Conflict of Interest Disclosures: None

Funding: None

Corresponding Author:
Hira Ghani, BA
259 Palsa Avenue
Elmwood Park, NJ 07407
Phone: 201-925-5165
E-mail: hghani01@nyit.edu

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