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Premature Greying of Hair (Premature Canities): A Concern for Parent and Child
PK Nigam1* and Pallavi Nigam2
1Department of Dermatology and STD, Pt. J.N.M Medical College, Raipur, India
2Department of Dermatology, BVP Medical College, Pune, India
*Corresponding author: PK Nigam, Department of Dermatology and STD, Pt. J.N.M Medical College, Raipur, India, Tel: 91771 2220944; E-mail:
drpknigam@yahoo.co.in
Received date: February 21, 2017; Accepted date: March 04, 2017; Published date: March 11, 2017
Copyright: © 2017 Nigam PK, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted
use, distribution, and reproduction in any medium, provided the original author and source are credited.
Abstract
Hair goes grey with chronological aging. Premature hair greying may have significant adverse effects on the
appearance, self-esteem, and socio-cultural acceptance of the affected individual. The exact aetiopathogenetic
mechanism causing premature greying is still not clear and much speculative. Premature canities may appear alone
as an autosomal dominant trait or it may occur in association with certain other disorders. The genes Pax3 and
MITE play an important role in melanocyte stem cell maintenance and differentiation. Defective melanosomal
transfer to the cortical keratinocytes or melanin incontinence due to melanocyte degeneration is also believed to
contribute to greying. Despite the extensive molecular research being carried out to understand the pathogenesis of
canities, treatment options still remain far from satisfactory and no effective therapy is available. Premature greying
is a feature in a number of well recognised syndromes. A number of other conditions have also been observed to be
associated with premature greying of hair.
Keywords: Premature greying; Canities; Aetiopathogenesis;
Associations; New targets
Introduction
Hair plays a signicant role in people's physical appearance. Hair
goes grey with chronological aging and about half the population have
a signicant amount of grey hair by age of 50 years [1]. Typically, white
people start going grey in their mid-30s, Asians in their late 30s, and
African-Americans in their mid-40s [2]. Premature hair greying
(canities) may have a signicant adverse eect on the appearance, self-
esteem, and socio-cultural acceptance of the aected individual. Racial
variations exist as greying has an earlier onset in Caucasoids [1]. Also,
premature hair greying is less frequent in certain ethnic groups,
notably blacks, who also tend to have higher testosterone levels in both
sexes [3]. It is observed that grey hairs tend to be thicker and longer
than pigmented ones. Typically, grey hair rst develops at age 34.2 ±
9.6 years in Caucasians while for Black people the average age of onset
is 43.9 ± 10.3 years [4]. Both sexes are equally aected [5]. Greying of
hair appearing in a white person by age 20 years; grey before 25 years
for Asians and 30 years for African-Americans are considered to be
prematurely grey [6].
Aetiopathogenesis
e exact aetiopathogenetic mechanism causing premature greying
is still unclear and largely speculative. Follicular melanogenesis occurs
eectively up to 40 years of age in an individual [7]. Fewer
melanosome due to reduced melanocyte activity, defective
melanosomal transfers to cortical keratinocytes and melanin
incontinence due to melanocyte degeneration are believed to be factors
resulting in greying of hair. e tyrosinase enzyme is necessary for the
initial stages of melanin synthesis. e hair bulb tyrosinase activity
gradually peaks at middle age and the bulbs of grey or white hairs
appear to lack or be decient in tyrosinase [8]. Repetitive oxidative
stress causes apoptosis of hair follicle melanocytes, resulting in normal
hair greying and premature greying is related to exhaustion and poor
sustenance of the melanocyte stem cell pool [9]. e genes Pax-3 and
MITE play an important role in melanocyte stem cell maintenance and
dierentiation [10]. Electron microscopy of grey hairs has revealed a
normal number of melanocytes but with incompletely melanized
melanosomes, whereas white hairs show reduced or absent
melanocytes [11]. e follicles of grey hairs still have melanocytes
placed normally over the dermal papilla, but the cytoplasm may
contain large vacuoles and the melanosomes may be only lightly
melanized. e follicles of fully white hairs may completely lack
melanocytes. However, among grey or white hairs, there may be a few
normal bulbs producing dark hairs [8]. In grey hair, the pigmentary
unit becomes fuzzy, melanocytes are few and rounded, and lightly
pigmented oligodendritic melanocytes become detectable in the
proximal hair bulb below Auber's line [9]. e resultant pigment loss
in greying hair follicles due to a marked reduction in melanogenically
active melanocytes in the hair bulb of grey anagen hair follicles is
central to the pathogenesis of greying [12]. Defective melanosomal
transfer to the cortical keratinocytes or melanin incontinence due to
melanocyte degeneration is also believed to contribute to greying. It
has been suggested that loss of melanocyte stem cells can be observed
and temporarily precedes the loss of dierentiated melanocytes in the
hair matrix [10]. is incomplete maintenance of melanocyte stem
cells appears to cause physiologic hair greying through loss of
dierentiated progeny with aging [10].
Premature canities may appear alone as an autosomal dominant
trait or it may occur in association with certain organ-specic
autoimmune disorders like pernicious anemia, hyper- or hypo-
thyroidism or as part of various premature aging syndromes and atopic
diathesis [13]. A number of theories have been postulated but there are
not too much evidence proving any of the theories, besides heredity.
Premature greying of hairs may be induced by ectopic dierentiation
of melanocyte stem cells in the niche and or their death because of
Journal of Pigmentary Disorders Nigam and Nigam, Pigmentary Disorders 2017, 4:1
DOI: 10.4172/2376-0427.1000260
Review Article OMICS International
Pigmentary Disorders, an open access journal
ISSN:2376-0427
Volume 4 • Issue 1 • 1000260
deciencies in stemness-related genes with subsequent hair greying
[14]. A genome-wide association study has found a susceptibility
variant for vitiligo/Non-segmental vitiligo (NSV) in the tyrosinase
gene (TYR) in European whites, rarely found in patients with
melanoma [15], which suggests a genetic dysregulation of immune-
surveillance against the melanocytic system.
e association between premature greying and certain organ
specic autoimmune diseases is well recognized. Autoimmunity has
been proposed as the cause because of the higher frequency (about
50%) of greying in patients with pernicious anemia, a known
autoimmune disease [16]. In a controlled study of 125 patients with
pernicious anaemia, 11% had premature greying, dened as onset
before the age of 20, compared with 2% in the control group [16]. In a
recent Latent class analysis of a series of 717 patients with NSV an
early age onset (prepubertal onset) class vitiligo was signicantly more
associated with premature greying as compared to late age onset of
vitiligo [17]. Strikingly, in patients with early-onset disease, a higher
proportion of familial history of premature hair greying (PHG) was
also observed. us, a subset of PHG might be reconsidered as an
immune process targeting inappropriately the hair follicle melanocytic
compartment.
e hair appearance is known to change in childhood protein
deciency states and in inborn errors of amino-acid metabolism [18].
Patients with phenylketonuria have abnormally high phenylalanine
content in their imperfectly pigmented hair [19] and patients with
kwashiorkor have a deciency in the number of melanosomes in the
cornied hair [20] and a reduction in the amount of sulphur-
containing protein with corresponding depigmentation [21].
Although, there is no known association between premature greying of
the hair and the subsequent diagnosis of adult coeliac disease, Hill
observed reversal of premature hair greying in adult coeliac disease
aer starting a gluten-free diet [22]. Although the mechanism of the
hair colour changes in his cases is not clear, its connection with gluten
sensitivity is undoubted. e amino-acid content of 17 standard
amino-acids in dark and light zones of hair in their patient was similar
and within normal ranges. Hill hypothesised that perhaps this type of
premature greying is either the presenting sign of adult coeliac disease
or is a coincidental predictor of its later occurrence.
Besides these, reactive oxygen species (ROS) generated in melanin
synthesis places melanocytes under a higher oxidative stress load.
Impairment of antioxidant system with age probably leads to
accumulation of ROS and oxidative stress that damages the
melanocyte [23]. Catalase and methionine reductase A and B
expression and functional loss of methionine sulfoxide repair
mechanism in the grey hair follicle have also been demonstrated [24].
Oxidative stress generated outside hair follicle melanocytes by
exogenous factors, for example, by pollution, UV light, psycho-
emotional or inammatory stress, may add to this endogenous
oxidative stress and overwhelm the hair follicle melanocyte antioxidant
capacity resulting in enhanced terminal damage in the aging hair
follicle [25,26].
Apart from oxidative stress, other factors may also contribute to the
process of greying. Insucient neuroendocrine stimulation of hair
follicle melanogenesis by locally synthesized agents, such as
adrenocorticotrophic hormone, α-MSH and β-endorphin, has also
been hypothesized as a possible mechanism for hair greying [27,28].
Cervical and lumbar sympathectomy of long duration has also been
shown to retard the normal greying of scalp and pubic hair,
respectively, in two patients, suggesting that sympathetic denervation
somehow slows or prevents the normal greying of hair with increasing
age [29,30].
Smoking was reported to be signicantly associated with hair
greying, and impairment of stem cell regenerative capacity with
substance abuse was postulated to lead to greying of hair [31,32].
A connection has been suggested between premature greying and
lower bone density later in life. Premature greying may be a weak
marker for reduced bone mineral density (BMD) in women with a
history of Graves' disease, but it is not a marker in normal women [33].
But later studies showed no such link [34].
Extensive research in the eld of premature greying of hair is
underway at the molecular level. Bmpr-2, a known receptor for bone
morphogenetic proteins (Bmps) and Acvr2a, a known receptor for
Bmps and activins, are individually redundant but together essential
for multiple follicular traits [35]. Reduced Bmpr2/Acvr2, a function in
melanocytes in mutant mice was recently shown to result in grey hair
due to aberrant hair sha and melanosomes' dierentiation [36]. Stem
cell factor (SCF) and its receptor (KIT) were shown to have an
important role in signalling in the maintenance of human hair follicle
melanogenesis during the anagen cycle and in physiological aging of
the hair follicle pigmentary unit [37].
Both Notch 1 and Notch 2 signalling pathways are required for the
maintenance of melanoblasts and melanocyte stem cells and are
essential for proper hair pigmentation in mice [38]. Premature greying
of hair has been shown to signicantly predispose one for CAD less
than 35 years of age [39]. Aggarwal et al also reported a signicant
association of premature greying of hair and baldness in patients with
young CAD [40].
Premature Greying Hair Syndromes and
Hypomelanotic Hair Disorders
Premature Greying of hair is usually familial and may occur alone as
an autosomal dominant trait or in association with various
autoimmune or early aging syndromes. Premature greying is a feature
in a number of well recognised syndromes. A number of other
conditions have also been observed to be associated with premature
greying of hair. Besides these, isolated syndromic presentation has also
been reported.
Waardenburg’s Syndrome
Waardenburg’s syndrome (WS) is a rare autosomal-dominant
condition caused by mutations in the PAX3 gene, MITF gene, SOX10,
endothelin-3/EDNR3 gene PSX3 or SNAI2 genes [41,42]. In
Waardenburg’s syndrome premature greying may develop with or
without a congenital white forelock similar to that seen in Piebaldism
[43-49]. ese mutations aects neural crest cells and impair the ability
of melanoblasts to reach their nal target sites (inner ear, eye, skin)
during embryogenesis. ere is lateral displacement of the medial
canthi (dystopia canthorum), a hypertrophic nasal root, deafness, and
partial or total heterochromia of the iris [44]. WS accounts for 2% to
5% of all congenital deafness cases [45]. Skin histopathology reveals an
absence of melanocytes [44]. e irregular depigmented patches of WS
patients can be treated cosmetically with topical pigmenting agents
such as self-tanning products or with skin graing [44]. Nearly all
patients require ophthalmologic referral with appropriate
management.
Citation: Nigam PK, Nigam P (2017) Premature Greying of Hair (Premature Canities): A Concern for Parent and Child. Pigmentary Disorders 4:
260. doi:10.4172/2376-0427.1000260
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Pigmentary Disorders, an open access journal
ISSN:2376-0427
Volume 4 • Issue 1 • 1000260
Werner’s Syndrome (Adult Progeria, Pangeria)
Werner’s syndrome is a rare autosomal recessive premature aging
disorder due to biallelic inactivating mutations in WRN gene on 8p12–
p11.2 encoding a RecQ DNA helicase/exonuclease involved in DNA
replication and repair [46]. Its prominent features include premature
ageing, “bird-like” facies, scleroderma-like skin changes, bilateral
cataracts, subcutaneous calcication, short stature, premature
arteriosclerosis, diabetes mellitus, and premature greying of scalp hair
[47] and a predisposition to malignancy [48].
Ataxia Telangiectasia (Louis–Bar Syndrome)
Ataxia telangiectasia is an autosomal-recessive disorder due to
mutations in a single gene on chromosome 11 (ATM) localized to
chromosome 11q22.3 [49]. It is a DNA repair disorders characterized
by progressive cerebellar ataxia, oculocutaneous telangiectasiae,
variable immunodeciency and an increased risk of lymphoid
malignancy [50]. e clinical features of the patients are progressive
ocular and cutaneous telangiectasias, premature aging, and progressive
neurodegeneration. e characteristic skin changes comprise
cutaneous non-infectious granulomas (which can be ulcerative and
painful), loss of subcutaneous fat, premature grey hair, large irregular
café-au-lait spots, vitiligo, seborrheic dermatitis. Hypomelanotic
macules accompany premature greying in ataxia-telangiectasia; there
are signs of immunodeciency and an increased risk for malignancy.
Ataxia and cerebellar signs are always present and neurological
degeneration is progressive. Cellular and humoral immunodeciency
aects 60–80% of cases, with low levels of IgA, IgG2 [51].
Rothmund–omson syndrome (Poikiloderma
congenital, RTS)
RTS is a rare autosomal-recessive disorder due to compound
heterozygous mutations in a DNA helicase gene, known as RECQL4,
on chromosome 8q24.3, although in around 40% of patients, no
mutations have been identied [52,53]. e skin appears normal at
birth and then poikiloderma appears including atrophy, irregular
pigmentation and telangiectasias beginning during the rst 3–6
months of age. Plaques of erythema and oedema, or more transitory
diuse erythema, are succeeded by varying combinations of atrophy,
telangiectasia, pigmentation and depigmentation. Characteristically,
the arms and legs are aected, with sparing of the antecubital and
popliteal fossae; palmoplantar hyperkeratosis; and sensitivity to
sunlight. Scalp, hair eyebrows and eyelashes, and pubic and axillary
hair are oen sparse or absent. Premature greying of hair is frequently
observed. Nails and teeth are oen normal [54]. Cataracts occur in a
small percentage of patients in childhood or young adult life. In many
cases keratosis develop on exposed skin from adolescence onwards and
large warty keratosis of hands, wrists, feet, ankles and elsewhere may
restrict the patient’s activities [55]. Squamous or basal cell carcinoma
may develop in the keratosis or in the surrounding atrophic skin [56].
Skeletal abnormalities include short stature, saddle nose and radial ray
defects or complete absence of the radius [57]. ere is a recognized
risk of osteosarcoma, especially in the bones of the lower leg, which
can present in childhood [58-60].
Cri Du Chat Syndrome (Chromosome 5, Short-Arm
Deletion Syndrome)
Cri du chat syndrome is a clinically heterogeneous syndrome.
Characterised by mentally decient microcephalics with a cat-like cry,
pre-auricular skin tag and low-set malformed ears [61,62]. One-third
of patients with cri du chat syndrome have prematurely grey hair [63].
Book’s Syndrome
Book’s syndrome is an autosomal dominantly inherited trait. e
premature greying is associated with premolar hypodontia and
palmoplantar hyperhidrosis [64].
Progeria (Hutchinson–Gilford Syndrome)
Progeria occurs due to de novo mutations of the lamin A gene
(LMNA) which encodes for a major constituent of the inner
membrane lamina [65]. Progeria is a rare disorder characterized by
accelerated aging, dwarsm, alopecia, generalized atrophy of the skin
and muscles, enlarged head with prominent scalp veins, and a high
incidence of generalized atherosclerosis, usually fatal by the second
decade. e large bald head and lack of eyebrows and eyelashes are
distinctive. e skin is wrinkled, pigmented and atrophic. Generalized
alopecia oen begins in the rst year of life. Premature greying may
occur. e nails are thin and atrophic. Most patients lack subcutaneous
fat, which produces the appearance of premature senility. ere are
usually sclerodermatous plaques on the extremities. e dentition is
abnormal and delayed, and there may be skeletal abnormalities Sexual
maturation is absent but intelligence is normal. Death usually occurs in
the second decade as a result of severe, generalized atheroma [66]. e
intelligence remains intact. Arteriosclerosis, anginal attacks, and
hemiplegia may occur, followed by death from coronary heart disease
at an early age. Mutations in LMNA and mosaicism have been
identied [67]. In progeria, the child is oen small but otherwise
normal during the rst year; thereaer, development is delayed. Scalp
hair, eyebrows and eyelashes are lost and the skin assumes an
increasingly senile appearance [68].
Fisch’s Syndrome
Auditory-pigmentary syndromes are caused by physical absence of
melanocytes from the skin, hair, eyes, or the stria vascularis of the
cochlea. Dominantly inherited examples with patchy depigmentation
are usually labelled Waardenburg syndrome (WS). Type I WS,
characterised by dystopia canthorum, is caused by loss of function
mutations in the PAX3 gene [69]. Klein-Waardenburg syndrome or
Waardenburg syndrome type 3 (WS-III; MIM 148820) is characterized
by the presence of musculoskeletal abnormalities in association with
clinical features of Waardenburg syndrome type 1 (WS-I). Since the
description of the rst patient in 1947 [70], a few cases have been
reported. Only occasional families have demonstrated autosomal-
dominant inheritance of WS-III [71]. Fisch Syndrome is similar
to Klein-Waardenburg syndrome, distinguished there from by the
presence of early grey hair and congenital deafness.
Seckel’s Syndrome (Microcephalic Primordial
Dwarsm)
Seckel syndrome is an autosomal recessive [72] disorder caused by
a mutation in the SCKL gene on chromosome 3 and 18 [73]. e
Citation: Nigam PK, Nigam P (2017) Premature Greying of Hair (Premature Canities): A Concern for Parent and Child. Pigmentary Disorders 4:
260. doi:10.4172/2376-0427.1000260
Page 3 of 6
Pigmentary Disorders, an open access journal
ISSN:2376-0427
Volume 4 • Issue 1 • 1000260
disease is characterized by growth retardation, dwarsm,
microcephaly with mental retardation, and unique facial features such
as narrow bird-like face with a beak-like nose, large eyes, and receding
lower jaw [73,74]. Premature greying and blood abnormalities may be
present [72,74].
Vogt–Koyanagi–Harada Syndrome (Vkhs)
e VKHS is a cell-mediated autoimmune, condition with bilateral
uveitis, labrynthine deafness, tinnitus, vitiligo, poliosis and alopecia
areata [75,76]. e auto antigen(s) is supposed to be solely expressed in
tyrosinase or tyrosinase-related protein or melanin-containing cells in
the eyes, skin, inner ears, and central nervous system (CNS). Clinically,
the features are meningismus, headaches, mental status changes,
tinnitus, and dysacusis, uveitis, choroiditis, frontal non-cicatricial
alopecia, vitiligo, poliosis and premature greying of the hair [75,77].
Sensorineural hearing loss, early greying, and essential tremor:
Karmody et al. reported a syndrome composed of sensorineural
hearing loss, early greying of scalp hair, and adult-onset essential
tremor [78]. All individuals had blue eyes without heterochromia.
Molecular genetic testing also suggested this is not a variant of
Waardenburg syndrome.
Prolidase Deciency
Prolidase deciency, an autosomal-recessive inherited inborn error
of metabolism, is characterised by dermatologic manifestations,
mental deciency and abnormal facies. Skin changes occur in about
85% of cases in the form of skin fragility; ulceration and scarring,
mainly of the lower extremities. ere may be photosensitivity,
telangiectasia, poliosis, purpuric lesions, premature greying, and
lymphoedema [79]. Antinuclear antibodies (ANA) and anti-ds-DNA
may be positive [80].
Matzner Syndrome
Matzner et al. reported a case of primary hypo-parathyroidism in
association with pernicious anemia, premature greying, reversible
immunodeciency and hypoadrenalism [81].
Other Conditions
Greying of hair is the main dermatologic manifestations along with
glossitis and hyperpigmentation in Vitamin B12 deciency.
Kwashiorkor produces hair and skin changes, edema, impaired growth,
and the characteristic potbelly. e hair is hypopigmented, varying in
color from a reddish-yellow to grey or even white. Patients with HIV
infection have recently been reported to develop rapid and premature
greying (PMG) as well as androgenetic alopecia (AGA) as well as PMG
has also been reported in patients with hyperthyroidism,
hypothyroidism, cystic brosis, Hodgkin's lymphoma, myotonic
dystrophy and acrodermatitis enteropathica-like dermatitis [82-85].
Interferon-alpha therapy has also been observed to cause canities [86].
Beral et al. [87] in their study of Cutaneous factors related to the risk
of malignant melanoma observed that presence of red hair colour at
age 5 years was associated with a tripling of risk of developing
melanoma while the presence of premature greying of the hair was
protective to the risk of developing malignant melanoma.
Can Anything Be Done?
Despite the extensive molecular research being carried out to
understand the pathogenesis of canities, treatment options still remain
far from satisfactory and no eective therapy is available. Few oral
therapies including p-aminobenzoic acid (PABA), calcium
pantothenate, nutritional supplements, (alone or in combination),
Psoralen combined with solar ultraviolet light (PUVASOL) have been
tried with rather inconsistent results. Prolonged (around 3 years) use
of latanoprost, a PGF2 alpha eye drops has shown repigmentation of
grey hair [88]. Hair darkening has also been described aer X-ray
irradiation and following electron beam therapy [89]. However, reports
of successful treatment are anecdotal and have never been conrmed
by other trials. Paucity of systemic or topical therapies in this condition
has rendered camouage techniques using hair colorants as the
mainstay of therapy. Major types of hair colours currently used are:
temporary (textile dyes), natural colouring (e.g. henna), semi-
permanent and permanent [90]. e future of treatment options for
premature canities lies with targeting genes and proteins involved in
hair follicle melanocyte biology. ere is an increasing interest in the
hair follicular route for delivery of active compounds aecting the hair.
Current research activities focus on topical liposome targeting for
melanins, genes, and proteins selectively to hair follicles for therapeutic
and cosmetic modication of hair [91]. Topical liposome selective
delivery to hair follicles has demonstrated the ability to color hair with
melanin [92]. e discovery of potential targets and the development
of both selective and eective delivery systems following topical
application indicate further rational strategies for maintenance of
healthy hair and scalp in the young and old [93].
Conclusion
Premature canities may appear alone as an autosomal dominant
trait or in association with certain organ-specic autoimmune
disorders or as part of various premature aging syndromes and atopic
diathesis and has always remained a cause of worry for parents and
adolescents. A number of modalities have been tried to correct the
problem but none has succeeded to full satisfaction. Targeting genes
and proteins involved in hair follicle melanocyte biology and liposome
selective drug delivery to hair follicles has created a lot of hope to
repigment these hairs.
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Citation: Nigam PK, Nigam P (2017) Premature Greying of Hair (Premature Canities): A Concern for Parent and Child. Pigmentary Disorders 4:
260. doi:10.4172/2376-0427.1000260
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Volume 4 • Issue 1 • 1000260
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Citation: Nigam PK, Nigam P (2017) Premature Greying of Hair (Premature Canities): A Concern for Parent and Child. Pigmentary Disorders 4:
260. doi:10.4172/2376-0427.1000260
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Pigmentary Disorders, an open access journal
ISSN:2376-0427
Volume 4 • Issue 1 • 1000260
