Ebook Vitiligo and other hypomelanoses of hair and skin: Part 2

SECTION 4. DISORDERS AFFECTING HAIR PIGMENTATION
WITHOUT AFFECTING SKIN PIGMENTATION
PREMOLAR APLASIA, HYPERHIDROSIS, AND CANITIES
PREMATURA
In 1950, Book [1] described 18 patients with a new autosomal dominant
syndrome with complete penetrance but somewhat variable expression and
characterized by bicuspid aplasia, premature whitening of the hair, and hyperhidrosis.
Early whitening of the hair was found in all 18 cases. Hair whitening began
in 14 patients before or at the age of 14 years, but onset varied from six to 23
years. The whitening was uniform and never patchy. The progression of whitening was usually slow, and in the older patients was always complete. The scalp
hair was most constantly affected but in six of the 18 cases. there was conspicuous whitening of axillary (five cases) and genital (six cases) hair and the
eyebrows and cilia (two cases). In 16 cases, the original hair color was specified
(seven were blond, four light brown, three dark brown, one red blond, and one
black). The hair was otherwise completely normal. No depigmentation of the
skin was observed. The author examined 63 members of this family and found
premature graying of the hair in seven who lacked other features of the syndrome. All 18 patients had blue irides, but this is such a common trait in
Sweden that this observation may represent only coincidence. Two-thirds of
the patients had a definite functional palmoplantar hyperhidrosis. The most
striking feature was the involvement of the bicuspid teeth. In nine patients, all
eight bicuspids were missing and no anlage could be detected by x-ray. The
other patients were missing one to seven bicuspids. In most cases, there was
a posterior displacement of the canines. Deciduous teeth were present in all
cases.
General health is unimpaired. The pathogenesis is unknown. No treatment
is available.

FANCONI SYNDROME
Fanconi syndrome is vitamin-D-resistant rickets or osteomalacia with hypophosphatemia, glucosuria, generalized aminoaciduria and generally chronic
acidosis, hypouricemia, and hypokalemia. It may occur early (infantile form)
or later (adult form) in life.
Fanconi syndrome may be idiopathic or associated with cystinosis, Lowe

syndrome, or tyrosinemia. In a series of 24 patients reported by Cowie [2], 19
patients had cystinosis, four had cirrhosis and no cystinosis, and one had
neither. Both groups of patients were found to have significantly fairer hair
electrospectrophotometrically than their siblings or than age-matched controls.
Schneider and Seegmiller [3] noted that although these patients with increased intracellular cystine often have blond hair and are significantly fairer
than their parents, they have much less tendency to sunburn than would be
expected for their degree of pigmentary dilution.

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The mechanism of hypopigmentation is unknown but may relate to cystine
binding of sulfhydryl-requiring enzymes.

ROTHMUND-THOMSON SYNDROME
Rothmund-Thomson syndrome is a rare, autosomal recessive disease which
is characterized by acquired erythematous patches that develop atrophy, telangiectasia, hypo- and hyperpigmentation, and sometimes warty keratosis [4,5].
Other features include alopecia, photosensitivity, bilateral cataracts, short stature, small skull, sometimes with birdlike features, and hypogonadism. Life
expectancy appears to be normal. Premature canities is an inconstant feature
of Rothmund-Thomson syndrome; it sometimes appears in adolescence and
progresses rapidly.

DYSTROPHIA MYOTONICA

Canities occurring in the second or third decade may be seen in dystrophia
myotonica [6], an entity that was first described in 1909 by Steinert [7]. This
rare disorder, which is inherited as an autosomal dominant disease, usually
appears in the second or third decade and is characterized by myotonia, severe
muscle wasting, cataracts, premature frontal baldness, and characteristic lugubrious physiognomy. Testicular atrophy, various disorders of ovarian function, and low basal metabolic rate are frequently observed. Few of these patients
survive beyond the sixth decade and death is often attributed to aspiration
pneumonia or to cardiac conduction defects.

PREMATURE AGING SYNDROMES
Two of the premature aging syndromes, Werner syndrome (pangeria) and
Hutchinson-Gilford syndrome (progeria), are characterized by premature graying of hair.

Werner Syndrome (Pangeria)
Werner syndrome, which is a rare autosomal recessive disorder, was first
described in 1904 in the thesis "Uber Kataract in Verbindung mit Sklerodermie"
(Cataract in Combination with Scleroderma) by Otto Werner [8]. Werner gave
a detailed description of four siblings with cataracts and sclerodermatous changes
as well as a senile appearance and graying beginning at about the age of 20.
Males and females are equally affected. The nature of the fundamental defect
responsible for the disease is unknown.
Pigmentary Disturbances
Graying of hair is one of the earliest characteristic signs of the disease.
From a survey of 125 cases, Epstein et al. [9] established that gray hair is first
seen at about 20 years of age, while the mean age of onset is 25.3 years for


alteration of the voice, 30 years for detection of cataract formation, 33 years
for skin ulcers, and 34.2 years for diabetes mellitus. Premature graying of hair
is rarely present before eight years of age.
The graying generally first affects the temples and eyebrows, may require

from five to 20 years for maximal loss of pigment, and often progresses to
complete whiteness. Baldness follows graying of the hair by several years.
Other Clinical Features

Patients with Werner syndrome have a characteristic habitus with a beakshaped nose, stocky trunk with slender extremities, and short stature first apparent in adolescence. A weak, high-pitched voice is characteristic. The skin
and subcutaneous tissues are atrophic with circumscribed hyperkeratosis. Indolent ulcers often develop over malleoli of ankles, Achilles tendon, heels and
toes. Most of the patients develop juvenile cataracts. Hypogonadism and diabetes mellitus are frequently observed. Generalized arteriosclerosis, osteoporosis, calcifications of ligaments, tendons, and subcutaneous tissues may develop prematurely. The incidence of malignancy is increased and the life
expectancy is decreased.
Diagnosis

The combination of the prematurely aged appearance, the other physical
features, the scleroderma-like skin changes, and the cataracts establish the
diagnosis [10]. The other premature aging syndromes (metageria, acrogeria, total
lipodystrophy, and progeria) have a different clinical picture [11]. Sclerosis of
the skin does not usually accompany Rothmund-Thomson syndrome. Observation of early graying may alert the physician to other possible features.

Hutchinson-Gilford Syndrome (Progeria)
This autosomal recessive disease was first described in 1886 by Hutchinson
[12] who reported a boy who had been bald since infancy and whose skin was

atrophic and wrinkled. This child and another patient were subsequently reported by Gilford [13], who first used the name "progeria."
Progeria is a rare condition occurring equally in both sexes. The primary
defect responsible for the disease is unknown.
Pigmentary Disturbances

In progeria, the hair is sparse and prematurely gray. DeBusk [14] noted
that sparse, downy blond or white fuzz was present even if the original hair
was black.
Other Clinical Features

Patients with this disease usually appear normal at birth. During the first
year of life there is a profound failure to meet normal growth markers and

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during the second year of life the characteristic facies (plucked-bird appearance
with craniofacial disproportion, micronathia, and prominent eyes), alopecia,
loss of subcutaneous fat, stiffness of joints and bones, skeletal abnormalities
(pyriform thorax, coxa valga), cutaneous changes (diminution of subcutaneous
fat and sclerodermatous skin), and abnormal dentition become apparent. Motor
and mental development is normal. There is insulin resistance and increased
basal metabolic rate. Early death results from severe generalized arteriosclerosis.
Diagnosis

Progeria with its remarkably constant phenotypic expression can easily be
distinguished from other premature aging syndromes. Graying of the hair, when
present, appears sooner than in Werner syndrome. Cockayne syndrome differs
from progeria by the presence of light sensitivity, disproportionate dwarfism,
and absence of alopecia.
No treatment is available.

FISCH SYNDROME

Fisch [15] described a family with deafness and early, pronounced graying
of the hair. Among 21 members of this family, two of the 10 who had early
graying also had deafness. Two other young children had only deafness and
two others partial heterochromia irides. Fisch observed similar cases and believed this a genetically distinct syndrome. Soussi Tsafir [16], arguing that none
of the 13 affected members of this family had dystopia canthorum, drew the
same conclusion and distinguished this condition from Waardenburg syndrome, which has a penetrance of 40% to 99%. Other possible cases include
those of Ballantyne [17] who noted that many of his patients with progressive
high-tone deafness, among them a father and daughter and a brother and sister,
had strikingly light blond hair and light blue eyes.

KAPPA CHAIN DEFICIENCY
Bernier et al. [18] reported a young girl with recurrent respiratory infections, diarrhea, white hair, extremely long white eyelashes, and very pale skin.
This was associated with a decreased concentration of immunoglobulins of
one light chain type (kappa). Radiolabeled kappa and lamda type molecules
survived equally well, suggesting that the synthesis of molecules bearing kappa
chains was decreased.

HEREDITARY PREMATURE CANITIES
Premature graying of hair in individuals who are otherwise normal has
been reported as an hereditary autosomal dominant trait. Among six generations


in one family, nine individuals were involved. In these cases, graying of scalp
and body hair appeared during the second decade or earlier, but did not affect
the eyebrows and eyelashes [19].

BIRD· HEADED DWARFISM (SECKEL SYNDROME)
Bird-headed dwarfism is a rare autosomal recessive form of dwarfism characterized by a bird-head profile, trident hands, skeletal defects, hypodontia,
and pancytopenia with hypersplenism. Brown pigmentation with white macules has been reported in one Japanese infant [20] and premature senility has
been described in several patients with this disease [21]. Fitch et al. [21] reported premature graying of scalp hair that began at age 18 in one patient.

Though premature graying is most characteristic, hypo melanotic macules have
also been described.
In 1974, Tay et al. [22] reported such a recessive disorder in two Indian
teen-aged sisters from West Malaysia. The disease, probably inherited as a
recessive autosomal trait, was characterized by microcephaly, triangular-shaped
face, prominent eyes, hypoplastic alae nasi, small pinched nose, tiny mouth
and large pegged-shaped incisors, abnormal limbs characterized by trident hands,
hypoplastic transverse palmar creases, and large big toes and stubbed short
toes. One girl had a large number of cafe-au-Iait spots and depigmented lesions
on the shins, knees, extensor surfaces of the arms, and upper chest wall that
appeared at the age of nine. At the same time, hairs of the scalp, eyebrows,
eyelashes, and of the limbs turned prematurely gray. The skin biopsy of the
hypopigmented patches resembled vitiligo. The second patient showed similar
premature canities and depigmented macules, though fewer and less extensive.
In addition, these two girls had liver involvement with fatty infiltration and
hepatic cirrhosis with hypersplenism, raised serum immunoglobulins, and hyperaminoaciduria, mainly of taurine, beta-aminoisoleutyric acid, and glycine.
As there is a striking similarity between these cases and patients with "birdheaded dwarfism," the authors suggest that these cases may represent a variant
of the latter.

TREACHER COLLINS SYNDROME, PIERRE ROBIN SYNDROME,
HALLERMAN-STREIFF SYNDROME, DOWN SYNDROME,
CHROMOSOME FIVE P·SYNDROME
Lopez et al. [23] included Treacher Collins syndrome, Pierre Robin syndrome, and Hallerman-Streiff syndrome in the group of hereditary disorders
associated with hypomelanosis of the skin and hair. Porter and Lobitz [24] also
mention fine, light-colored hair in Pierre Robin syndrome and light-colored
hair in tyrosinemia and in Down syndrome (trisomy 21). However, these are
only isolated reports.
Several adult patients with chromosome five p-syndrome (cri-du-chat syndrome) have prematurely gray hair [25].

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PROLIDASE DEFICIENCY
Prolidase deficiency, a very rarely reported inborn error of metabolism,
has important and severe dermatologic manifestations, especially ulcers of the
lower extremities. Poliosis or premature graying of hair has been found in
several of these patients [26].

REFERENCES
1. Book JA: Clinical and genetical studies of hyperdontia. I. Premolar aplasia, hyperhidrosis and
canities prematura. A new hereditary syndrome in man. Am J Hum Genet 2:240-263, 1950
2. Cowie V: Hair colour in the infantile Fanconi syndrome. Ann Hum Genet 21: 170-176, 1956
3. Schneider JA, Seegmiller JE: Cystinosis and the Fanconi syndrome, in Metabolic Basis of
Inherited Disease, 3rd ed. Edited by JB Stanbury et al. New York, McGraw-Hill, 1972, pp
1581-1604
4. Rook A, Wells RS: Genetics in dermatology, in Textbook of Dermatology. Edited by A Rook
et al. London, Blackwell, 1969, pp 57-60
5. Tannhauser SJ: Werner's syndrome (progeria of the adult) and Rothmund's syndrome: two
types of closely related heredofamilial atrophic dermatoses with juvenile cataracts and endocrine features. A critical study of five new cases. Ann Intern Med 23:559-626, 1945
6. Touraine A: (Progres Medical 73:47, 1945). Quoted in Ebling EJ, Rook A: Premature canities,
in Textbook of Dermatology. Edited by A Rook et al. London, Blackwell, 1969, pp 1413-1414
7. Steinert H: Myopathologische Beitrage I. Dber das klinische und anatomische Bild des Muskelschwunds der myotaniker. Dtsch Z Nervenh 37:58-104, 1909
8. Werner 0: Dber Katarakt in Verbindung mit Sclerodermie. Doctoral Dissertation, Kiel University. Kiel, Schmidt and Klaunig, 1904

9. Epstein DJ et al: Werner's syndrome. Medicine (Baltimore) 45:177-221, 1966
10. Rook A: Disorders of connective tissues, in Textbook of Dermatology. Edited by A Rook et al.
London, Blackwell, 1969, pp 1287-1288
11. Gilkes JJH et al: The premature aging syndromes. Br J Dermatol 91:243-262, 1974
12. Hutchinson J: Congenital absence of hair and mammary glands. Medico-Chirurg Trans 69:473,
1886. Quoted by Gilkes JJH et al: The premature aging syndromes. Br J Dermatol 91:243-262,
1974
13. Gilford H: Progeria: a form of senilism. Practitioner 73:188-217,1904
14. DeBusk FL: The Hutchinson-Gilford progeria syndrome. J Pediatr 80:697-724, 1972
15. Fisch L: Deafness as part of an hereditary syndrome. J Laryngol Otol 73:355-382, 1959
16. Soussi Tsafir J: Light-Eyed Negroes and the Klein-Waardenburg Syndrome. London, MacMillan, 1974
17. Ballantyne JC: Deafness. London, Churchill, 1960
18. Bernier GM et al: Kappa chain deficiency. Blood 40:795-805, 1972
19. Hare HJH: Premature whitening of hair. J Hered 20:31-32, 1929
20. Seckel HPG: Bird-Headed Dwarfs. Basel, S Karger, 1960
21. Fitch N et al: A form of bird-headed dwarfism with features of premature senility. Am J Dis
Child 120:260-264, 1970
22. Tay CH et al: A recessive disorder with growth and mental retardation, peculiar facies, abnormal
pigmentation, hepatic cirrhosis and aminoaciduria. Acta Paediatr Scand 63:777-782, 1974
23. Lopez B et al: Trastornos de la pigmentaci6n, in Actas Del VI Congresso Ibero-Latino Americano
de Dermatologia (Barcelona, Spain, 1967). Barcelona, Editorial Cientifico Medica, 1970, pp
157-179
24. Porter PS, Lobitz WC: Human hair: a genetic marker. Br J Dermatol 83:225-241, 1970
25. Breg WR: Abnormalities of chromosomes 4 and 5, Endocrine and Genetic Diseases of Childhood
and Adolescence. Edited by 11 Gardner. Philadelphia, Saunders, 1975, pp 1505-1515
26. Der Kaloustian VM et al: Prolidase deficiency: an inborn error of metabolism with major
dermatological manifestations. Dermatologica 164:293-304, 1982


2

Hypomelanoses Associated with
Nutritional and Metabolic Disorders
KWASHIORKOR
Kwashiorkor is a result of dietary deficiency of protein in the weaning and
early postweaning stage of childhood. In underdeveloped nations it remains a
significant cause of death among children from one to four years of age.
Credit for the first description of kwashiorkor is generally given to Williams
[1], who, in 1953, reported five "Gold Coast children," four of whom died. The
origin of the term "kwashiorkor" is not precisely known.
Kwashiorkor has been reported in every part of Africa, and also in China,
India, Malaya, Indonesia, Fiji, the Philippines, Caribbean Islands, Hungary,
Italy, and various parts of South America. Henington et al. [2], in 1958, reported
four cases from Louisiana. The general prevalence of kwashiorkor is 0.5% to
1.5% in various community surveys [3]. It is said to be much higher in primitive
cultures.

Depigmentation in Kwashiorkor
Clinical Description

Depigmentation, according to Williams [1] may precede by weeks other
dermatologic features of kwashiorkor. It may present in the early stages of the
disease-before the rash is well circumscribed. The hypopigmentation of
kwashiorkor usually first involves the face and, after the appearance of a shiny
epidermis, resembles a background of fair skin on a red baby. As the eruption
evolves over one to two days, except on the face, red raised plaques gradually
darken until they take on a shiny black appearance.
Exfoliation is followed by depigmentation. Enamel-plaque areas or ulcerations develop to suggest the de pigmented skin is readily predisposed to destructive processes. These depigmented macules do later repigment, often with
hyperpigmentation. Lesions most typically occur on pressure points.

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Banerjee and Dutta [4] noted that there may be generalized pallor with
extensive hypo- and hyperpigmentation, the latter mostly in the diaper area,
buttocks, back, thighs, and elbows-as opposed to the sun-exposed areas of
pellagra.
Dyschromic hair is a common feature of kwashiorkor. Mukherjee and Jelliffe [5] found the changes minimal in India compared to those seen in Africa,
where hypochromotrichia is pronounced. Others [6] reported only 13% with
hair discoloration, yet Jelliffe [7] reported as high as 82% among African infants
in Jamaica. In the latter, curled jet black hair is replaced by sparse dry hair
varying from red-brown to gray in color.
Henington et al. [2] noted golden to reddish coloration at the ends of
normally black hair in their four black patients. There is often such minimal
dilution of color-a fringe effect-and the color may be brown, red, golden,
gray, or white. The "signe de bandera" or "flag sign"-which is striped hairmay represent a recurrence. Thinning of eyebrows or loss of the outer thirds
may occur. The hair also becomes dry, thin, and brittle and may be removed
painlessly with little effort [8]. Partial or total alopecia may result. Hair production is 59 /-Lm 3 per follicle in kwashiorkor vs. 514 /-Lm 3 for controls [9].
Cystine levels are also reduced but return to normal after therapy.
Histology of Depigmentation

Sims [9] compared the epidermis of 10 Zulu infants with kwashiorkor to
five unaffected infants. He reported decreased thickness of the epidermis and
normal cell volumes and concluded there were changes in the kinetics of cell
migration. Desmosomes were found to be shorter than controls, and this may
explain the epidermal fragility.
Pathogenesis of Depigmentation

Protein deficiency in hair, infection, and multiple nutritional deficiencies
have been invoked to explain the pigmentary abnormality. Rao and Gopalan
[10] found no correlation between hair color and amino acid content. Nor could
hair color or cystine content be correlated with severity of clinical disease.
Bradfield and Jelliffe [11] emphasized that tuberculosis and malnutrition may
coexist in underprivileged populations and that the two together cause greater
loss of skin and hair pigment than does either alone. Partial de polymerization
of melanin has also been suggested. Riboflavin or pantothenic acid deficiency
and deficiency of sulfur or of sulfur-containing amino acids have been implicated [10]; this fits with the observation that cystine and glutathione as well
as other reducing enzymes affect the conversion of tyrosine to melanin by
inhibiting tyrosinase and by regulating the oxidation reduction potential of
melanocytes [12]. That the pigment in the discolored hair behaves chromatographically like oxidized melanin [13], coupled with the above observation,
supports the theory that lowering the SH concentration in melanocytes accelerates the conversion of tyrosine to melanin; further oxidation of melanin to a
brown or colorless product results.


TABLE 111. Kwashiorkor: Associated Findings
Skin

"Crazy-pavement" dermatitis
Bullae, ulceration
Purpura

Mucous membrane

Angular stomatitis
Cheilosis

Nails

Thinning, softening, ridging

Eyes

Xerophthalmia
Bitot's spots
Blepharitis, conjunctivitis, photophobia

Systemic changes

Growth retardation
Psychic disturbances and mental retardation
Muscle wasting
Edema
Gastrointestinal disorders (anorexia, diarrhea)
Hepatomegaly

Laboratory findings

Hypoalbuminemia
Anemia
Hypovitaminosis

Associated Clinical Findings
See Table 111.

Diagnosis
Leukoderma is not a primary or essential feature of kwashiorkor, the diagnosis of which is based on the history of malnutrition in an infant from an
endemic area plus the presence of the many clinical features noted. Bands of

de pigmented or dyschromic hair may correspond to relapses and those of repigmentation to treatment. Other nutritional deficiency syndromes may also
be present.

Treatment
Kwashiorkor responds to dietary protein and the skin is said to repigment
slowly [4].

GENERALIZED DYSCHROMIA IN A MALNOURISHED INFANT
Petrozzi [14] reported a 20-month-old black girl who presented several
months after birth with multiple episodes of infectious diarrhea associated with
febrile seizures. At the age of two months, she developed asymptomatic, small,

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hypopigmented macules in the diaper area, upper legs, and lower abdomen.
During the next two months, similar lesions continued to appear on the trunk
and spread to the distal extremities. No inflammation preceded the hypopigmented eruption but the father and an older sister had a history of infantile
eczema.
Examination revealed a generalized mottling of the skin which had irregularly scattered hyperpigmented and hypopigmented macules.

As poor dietary intake and recurrent diarrhea had been present in the first
months of life, the author suggested that the dyschromia may result from malnutrition. However, amino acid, copper, and vitamin B12 studies were not done.

PIGMENTARY CHANGES IN THE HAIR OF PATIENTS WITH
NEPHROSIS, ULCERATIVE COLITIS, OR EXTENSIVE RESECTION

OF THE GUT

As in kwashiorkor, chronic protein loss may result in pigmentary changes
of the hair [15]. This can be observed in nephrosis [16] and also in malabsorption
syndromes [16].
Mellinkoff [17] reported a 26-year-old Caucasian with ulcerative colitis
whose hair turned red with malnutrition and returned to its normal dark brown
color after he had gained weight. Silverblatt and Brown [16] observed a kwashiorkor-like syndrome with change of the hair from black to red associated with
"burning feet" in a 45-year-old black male in whom, 10 years after a gastrectomy
for intractable duodenal ulcer, progressively severe diarrhea and pronounced
malnutrition developed.

SEVERE IRON DEFICIENCY
Tasker and Polunin [18] reported a 10-year-old aboriginal Malayan male
with extremely severe iron deficiency anemia (hemoglobin level of 0.7 g per
100 ml). This boy had light brown hair, a very unusual feature among the
usually dark brown-haired peoples of Malaya. As the plasma protein values
were grossly normal, the authors attributed the pigmentary disturbance to severe iron deficiency. Treatment with intravenous iron oxide did not alter the
hair color. Clinical features of copper deficiency were not present in this patient
but blood copper levels were not obtained.

COPPER DEFICIENCY
Acquired copper deficiency is discussed with Menkes kinky hair syndrome
(see "Copper Deficiency" in Chapter 1).

VITAMIN B12 DEFICIENCY (PERNICIOUS ANEMIA)
Pernicious anemia is associated with vitiligo in a significant number of
cases (see "Vitiligo" in Chapter 1). Premature graying is also a clinical feature
of pernicious anemia [19].
Dawber [20] found premature graying of the hair to be more frequent in
patients with pernicious anemia than in controls. Among 125 patients with
pernicious anemia, 14 (11.2%) had graying of the hair before the age of 20,
compared to only three out of 132 controls (2.2%). Furthermore, early graying
of the hair (between 20 and 50 years of age) was more frequent in pernicious
anemia. Thirty-eight of the 132 controls (20.8%) and 69 out of 125 patients
with pernicious anemia (55.2%) had early graying of the hair. In the same group
of pernicious anemia patients, blond hair and blue eyes seemed common.
A family with premature graying of the hair and pernicious anemia has
been reported. One member of this family had both pernicious anemia and
premature graying of the hair. Another had only pernicious anemia, and three
others only premature graying of the hair. Another had diabetes mellitus and
an autoimmune hemolytic anemia in addition to premature graying of the hair.
Several family members with or without premature graying had antinuclear
antibodies [21].

REFERENCES
1. Williams CD: Kwashiorkor. JAMA 153:1280-1285, 1953
2. Henington VM et al: Kwashiorkor. Arch Dermatol 78:157-170, 1958

3. Ebrahim GJ: The skin in malnutrition, in Essays on Tropical Dermatology. Edited by J Marshall.
Amsterdam, Excerpta Medica, 1972, vol 2, pp 124-128
4. Banerjee BN, Dutta AK: Malnutrition in the tropics: dermatoses in nutritional disorders, in
Clinical Tropical Dermatology. Edited by 0 Canizares. Oxford, Blackwell, 1975, pp 273-277

5. Mukherjee KL, Jelliffe DV: Clinical observations on kwashiorkor in Calcutta. J Trop Pediatr
1:61-66, 1955

6. Venhalachalam PS et al: Clinical features of nutritional edema syndrome in children. Indian
J Med Res 42:555-568, 1954
7. Jelliffe DV: Hypochromotrichia and malnutrition in Jamaican infants. J Trop Pediatr 1:25-33,
1955
8. Scrimshaw NS, Behar M: Protein malnutrition in young children. Science 133:2039-2047,
1961

9. Sims RT: The ultrastructure of depigmented skin in kwashiorkor. Br J Dermatol 80:822-832,
1968
10. Rao BS, Gopalan C: Some aspects of the hair changes in kwashiorkor. Indian J Med Res
45:85-93, 1957
11. Bradfield RB, Jelliffe DB: Hair-colour changes in kwashiorkor (letter). Lancet 1:461-462, 1974
12. Lerner AB, Fitzpatrick TB: Biochemistry of melanin formation. Physiol Rev 30:90-126, 1950
13. Nagchandhuri J, Platt BS: Malnutrition in African mothers, infants and young children, in

Report of the Second Inter-African [CCTA) Conference on Food and Nutrition, Gambia. London, Her Majesty's Stationery Office, 1954, p 215
14. Petrozzi JW: Unusual dyschromia in a malnourished infant. Arch Dermatol103:515-519, 1971
15. Rook A: Nutritional, metabolic, and chemical influences of hair colour, in Textbook of Dermatology. Edited by A Rook et al. London, Blackwell, 1969, pp 1631-1632

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16. 8ilverblatt CW, Brown HE: "Kwashiorkor-like" syndrome, associated with burning feet syndrome, in one adult male. Am J Med 28:847-854, 1960
17. Mellinkoff 8M: Temporary redness of the hair in ulcerative colitis. Am J Dig Dis 2:738-739,
1957
18. Tasker P, Polunin I: Extreme anaemia with recovery associated with pigmentary changes in
the hair (case report). Br Med J 2:465, 1954
19. Wintrobe MM: Pernicious anemia and related macrocytic anemias, in Clinical Hematology,
6th ed. Philadelphia, Lea & Febiger, 1967, pp 502-576
20. Dawber RPR: Integumentary associations of pernicious anemia. Br J Dermatol 82:221-223,
1970
21. Wintrobe MM: Pernicious anemia and related macrocytic anemias, in Clinical Hematology.
London, Kimpton, 1967, p 509


3
Hypomelanosis Associated with
Endocrine Disorders
HYPERTHYROIDISM

The association of vitiligo with hyperthyroidism has been discussed (see
"Vitiligo" in Chapter 1). Premature graying of hair may also accompany hyperthyroidism [1].
HYPOPITUITARISM

Decreased or absent skin pigmentation occurs in panhypopituitarism. This
clinical finding may help distinguish primary Addison disease from secondary

Addison disease due to hypopituitarism [2]. In hypopituitarism, there is an
increased sensitivity to sunburn with reduced melanin content and delayed
tanning [1]. Decreased MSH and ACTH production is probably responsible.
ADDISON DISEASE

The association of vitiligo and Addison disease has been discussed (see
"Vitiligo" in Chapter 1).
CUSHING SYNDROME

Brooks and Richards [3] reported depigmentation in two black women with
Cushing syndrome. In both patients, depigmentation occurred on the exposed
areas (extensor surfaces of the hands and feet) but returned to normal after
adrenal surgery.
The authors suggested the depigmentation may be due to suppression of
melanocyte-stimulating hormone (MSH) by high circulating levels of cortisol.
But as only two cases are reported, any association must be considered tentative.
473


474

HYPOGONADISM

CHAPTER 3

Male eunuchs have pale skin [4]. One eunuch who failed to tan after sun
exposure has been reported. Five months later, after administration of testosterone, deep pigmentation developed in the normally sun-exposed areas [5].
This suggests that testosterone deficiency decreases melanin pigmentation and
decreases the capacity of the melanin pigmentary system to respond to solar
stimulation. However, while orchidectomy has been reported to decrease melanin pigmentation of the skin in men [6], there are experimental results which

suggest that testosterone has no effect on the melanin pigmentation of the skin
[4].

HYPOPARATHYROIDISM, ADDISON DISEASE, AND CHRONIC
MUCOCUTANEOUS CANDIDIASIS
There are several reported cases of a syndrome of hypoparathyroidism,
Addison disease, chronic mucocutaneous candidiasis, and vitiligo [7,8]. (See
"Vitiligo" in Chapter 1.)

GOITER AND PARATERTIARY BUTYLPHENOL
DEPIGMENTATION
Two reports from Germany [9,10] mention the occurrence of thyroid abnormalities in workers with vitiligo-like depigmentation attributed to exposure
to paratertiary butylphenol. (See Chapter 5.)

REFERENCES
1. Freinkel RK, Freinkel N: Dermatologic manifestations of endocrine disorders, in Dermatology

in General Medicine. Edited by TB Fitzpatrick et al. New York, McGraw-Hill, 1971, pp 1434-1459
2. Sheehan HL: Simmond's disease due to post-partum necrosis of the anterior pituitary. Q JMed
8:277-309, 1939
3. Brooks VEH, Richards R: Depigmentation in Cushing's syndrome. Arch Intern Med 117:677~80,
1966
4. Lorincz AL: Pigmentation, in Physiology and Biochemistry of the Skin. Edited by S Rothman.
Chicago, Univ of Chicago Press, 1954, pp 515-563
5. Hamilton JB, Hubert G: Photographic nature of tanning of the human skin as shown by studies
of male hormone therapy (letter). Science 88:481, 1938
6. Edwards EA et al: Cutaneous vascular and pigmentary changes in castrate eunuchoid men.
Endocrinology 28:119-128, 1941
7. Fields JP et al: Hypoparathyroidism, candidiasis, alopecia and vitiligo. Arch Dermatol
103:687-689, 1971

8. Fisher M, Fitzpatrick TB: Candidiasis, vitiligo, Addison's disease and hypoparathyroidism.
Arch Dermatol102:110-111, 1970
9. Goldmann PJ, Thiess AM: Berufsbedingte Vitiligo durch para-tertiar Butylphenol, eine Ames
Trias von Vitiligo, Hepatose und Struma. Hautarzt 27:155-159, 1976
10. Rodermund DE, Wieland H: Vitiligo, Hepatosplenopathie und Struma nach Arbeit mit paratertiiirem Butylphenol. Dtsch Med Wochenschr 100:2216-2222, 1975


4
Hypomelanosis Secondary to
Irradiation and Physical Trauma
Melanocytes are vulnerable to nonspecific trauma. In animals or in humans,
dark skin or hair may lose pigment in areas exposed to various types of injury
(x-rays and ionizing radiations, ultraviolet rays, thermal burns, freezing, physical traumas) (Fig. 190).
X-rays have long been known to cause changes in melanin pigmentation.
In animals, x-ray exposure causes depigmentation of feathers [1,2] or hair [3-6].
In humans, cutaneous depigmentation with atrophy may follow x-ray therapy
[7]. Human hair color changes following x-radiation were reported just after
the turn of this century [8,9]. Regrowth of white hair has been observed in
white or black children [10,11] following epilating doses of x-rays for the treatment of tinea capitis.
X-ray depigmentation results from a loss of functioning melanocytes. Straile
[12] observed that x-ray irradiation decreases the number of melanocytes in
the hair follicles of mice. Other changes included alterations of the length of
the dendrites, decrease in the transfer of pigment granules, alteration in the
distribution of melanin in the hair, and changes in the color of melanin granules.
However, the mechanism by which follicular melanocytes seem to disappear
after irradiation is unknown.
The epithelium target theory suggests that x-rays alter the epithelium of
the hair follicle [13]; subsequently, there is either a failure of the induction of
follicular melanogenesis or a disturbance in the regulation of the differentiation
of the secretory melanocytes at the beginning of the hair growth cycle. Cohen

[14] suggested from studies of tissue culture of irradiated growing feathers
and transplant experiments that the action of x-rays is upon the melanoblast-ectoderm relationship. Chase et al. [6] observed radiation effects remote
from the site of original exposure; depigmentation was delayed until the second
growth cycle after irradiation. They concluded that there is an indirect effect
of x-rays on melanocytes.
The melanocyte theory suggests that melanocytes are individually and
directly killed or inactivated by x-rays [13].
Still another theory is that proposed by Straile [12], who suggested a more

475


476
CHAPTER 4

FIGURE 190. Top: Clip in position on the shaved back of the rat. Bottom: One month after
application of the clip. the hair in the previously ischemic area is white and longer than in the
surrounding areas where regeneration after shearing is irregular and slow. (From: Selye H: Ischaemic depigmentation. Experientia 23:524.1967. Copyright. 1967. Birkhauser Verlag. Used with
permission.)

complicated mechanism. In his view, x-ray-induced depigmentation results in
part from a complete block in the differentiation of the melanoblasts, possibly
related to an injury to the follicular epithelium, and also from direct or indirect
destruction or inactivation of the melanocytes on an individual basis.
Gamma and neutron radiation from atomic weapons also alters the melanin
pigmentation, and depigmentation induced in animals by these radiations has
been used for biologic radiation dosimetry [15].
Nonionizing radiation and photosensitization may lead to pigment loss; a
single PUVA (psoralen plus UVA) reaction was observed to lead to depigmentation of an exposed square in a Dutch belted black rabbit U. A. Parrish, unpublished observations).
Thermal burns which cause severe epidermal damage may destroy melanocytes to leave a depigmented scar. Freezing can be followed by cutaneous

depigmentation, and, with the increased use of liquid nitrogen in dermatologic


practice, this phenomenon is increasingly observed. Taylor [16] observed in
black rats that hair growing from skin treated by cryotherapy lacked pigmentation and also noted that in skin that survived freezing the melanocytes were
selectively destroyed. This suggested the increased vulnerability of melanocytes to freezing.
Experimental ischemia of the skin, produced by compression of a skin fold
in rubber-covered umbilical clamps for eight hours in rats [13], resulted in longstanding depigmentation of the hair.
Physical trauma also often leaves depigmentation which is most apparent
in dark-skinned patients.
The reason for the increased sensitivity of melanocytes to a wide variety
of injuries is unknown. The low-density, self-perpetuating melanocyte population in the skin may be responsible. Furthermore, cells are most sensitive to
trauma in mitosis and the turn-over rate of melanocytes is probably very low
[17].

REFERENCES
1. Cole LJ, Finley HE: Production of somatic mutations in the pigeon with x-rays. Anat Rec
[Suppl] 81:48-49, 1941

2. Espinasse PC: The responses of some developing feathers to x-ray. J Embryol Exp Morphol
7:165-172, 1959

3. Chase HB: Graying of hair. I. Effects produced by single doses of x-rays on mice. J Morphol
84:57-80, 1949
4. Chase HB: Number of entities inactivated by x-rays in graying of hair. Science 113:714-716,
1951

5. Chase HB, Raugh H: Graying of hair. II. Response of individual hairs in mice to variations in
x-irradiation. J Morphol 87:381-392, 1950
6. Chase HB et al: Evidence for indirect effects of radiation of heavy ions and electrons on hair

depigmentation. Ann NY Acad Sci 100:390-399, 1963
7. Ladanyi E: Nach Riintgenbestrahlung entstandene, "White Spot Disease." Hautarzt 21:328-330,
1970
8. Danysz J: De I'action du radium sur les differents tissus. C R Acad Sci (Paris) 136:461-464,
1903
9. Ellinger F: Medical Radiation Biology. Springfield. Ill. Thomas. 1907. p 173
10. Hazen H: Results of repeated epilation with roentgen rays in tinea tonsurans. Arch Dermatol
56:539-540, 1947

11. Zeligman I: Graying of hair following epilating doses of x-rays. Arch Dermatol 66:627-628,
1952
12. Straile WE: A study of the hair follicle and its melanocytes. Dev Biol10:45-70, 1964
13. Selye H: Ischemic depigmentation. Experientia 23:524, 1967
14. Cohen J: The nature of the effect of x-irradiation in depigmentation. Ann NY Acad Sci 100:400-412,
1963
15. Moshman J, Upton A: Depigmentation of hair as a biological radiation dosimeter. Science
119:186-187, 1954
16. Taylor AC: Survival of rat skin and changes in hair pigmentation following freezing. J Exp
2001110:77-112, 1949

17. Jimbow K et al: Mitotic activity in non-neoplastic melanocytes in vivo as determined by

histochemical. autoradiographic and electron microscopic studies. JCell Bio166:663-671, 1975

477

HYPOMELANOSIS
SECONDARY TO
IRRADIATION
AND PHYSICAL

TRAUMA


5
Chemical Hypomelanosis

A large number of chemical compounds induce depigmentation in humans
and in experimental animals (Fig. 191, Table 112). Cutaneous chemical depigmentation, which often resembles vitiligo in clinical appearance, may result
from direct contact or from systemic exposure (ingestion or particularly inhalation) to various phenol derivatives, sulfhydryl compounds, and others (Fig.
192). Some of these compounds have also purportedly been found in commercially available consumer products, and accidental exposures have occurred historically in the course of many industrial processes. Both careful
research discovery and serendipity seem to increase the growing list of known
chemical depigmenting agents. There are likely important and common depigmenting agents yet to be revealed.
Leukoderma has been attributed to the mono benzyl ether of hydroquinone
contained in rubber-covered wire-disk trays [1,2]' adhesive tape [3,4], hat bands
[3], contraceptive diaphragms [2], rubber finger cots [3,], rubber clothing [5],
rubber aprons [3], powdered rubber condoms [6,7], rubber dolls [8], neoprene
(a synthetic rubber) [9], fabric-lined rubber gloves [10], and shoes (rubber cement) [11].
Paratertiary butyl phenol is used as an intermediate in the processing of
varnish and lacquer resins, as an ingredient in motor oil demulsifier, as a soap
antioxidant, as a plasticizer for cellulose acetate, as a rubber antioxidant, as an
intermediate in synthetic oil, and as an ingredient in insecticides, deodorants,
commercial detergents, germicidal disinfectants, writing ink, and latex adhesives [12].
Paratertiary amyl phenol is used in the manufacture of oil-soluble resins,
and as a plasticizer, commercial germicide, and fumigant [12].
The germicidal phenolic detergents in Tables 113 and 114, which contain
paratertiary butyl phenols and paratertiary amylphenols, are potential depigmenting agents.
Ortho-benzyl-para-chlorophenol (chlorophene) is used widely as a disinfectant, cleaner, and preservative. Ortho-phenylphenol is used as a germicide
and as an intermediate in the production of dyes [12].
479

480
CHAPTER 5

0
0
OH

0

0
OH

OH

Hydroquinone

OOH
OH

CH. C CH.
CH.
p-tertiary
Butylcatechol

CH,

Monobenzylether
of
Hydroquinone

0
OH

0

CH.
Monomethylether
of
Hydroquinone

0
OH

CH. C CH.
CH.

p-tertiary
Butylphenol

0
OH

CH. C CH.
CH,
CH.

p-tertiary
Amylphenol

COMPARED TO

o
OH

CH,
NH, CH COOH
Tyrosine

FIGURE 191. Structures of some depigmenting phenol derivatives.


TABLE 112. Chemicals Implicated
in Induction of Leukoderma in
Humans
Paratertiary butylphenol
Paratertiary butylcatechol
Paratertiary amylphenol
Alkyl phenol
Monobenzylether of hydroquinone
Hydroquinone
Dihydroxyphenylmethane
Butylated hydroxytoluene
Heavy metals (mercury, bismuth, zinc)

FIGURE 192. Extensive depigmentation attributed to industrial exposure to monobenzylether of
hydroquinone.

481

CHEMICAL
HYPOMELANOSIS


TABLE 113. Germicidal Phenolic Detergents Containing
Para tertiary Amylphenolo

482
CHAPTER 5

Product
Bactophene
Beaucoup
Chlorocide
Galahad
Listophene
Matar
Microphene
Phenocide
Phenomycin
Staphene
i-Stroke Vesphene
Tergisyl
Tri-Kem
Ves-Phene
Ves-Phene 0
a

Manufacturer
Sanfax Corporation

Huntington Laboratories
Center Chemicals
Puritan Chemical
Enterprise Paint Manufacturing
Huntington Laboratories
Sanfax Corporation
Center Chemicals
Franklin Division of Purex
Vestal Laboratories
Vestal Laboratories
Lehn and Fink Division, Sterling Drug
Airwick Industries
Vestal Laboratories
Vestal Laboratories

Source: Fisher AA: Vitiligo due to contactants. Cutis 17:431--437,1976. Copyright, 1976, Donneley Publishing Corporation. Used with permission.

PHENOLIC COMPOUNDS
The basic structural requirements for a depigmenting phenolic compound
seem to be hydroxylation of the benzene ring, particularly in the para-position,
and a nonpolar side chain in the one position [13]. The presence of an ether
link at the 1 position increases the effective depigmenting potency [13]. Many
of these phenol derivatives resemble tyrosine or dihydroxyphenylalanine in
their molecular structure.

Clinical Features
The leukodermas arising from chemical exposure are clinically similar.
Chemical exposure of as little as two weeks' duration may cause depigmentation, but four to six months is a more commonly cited exposure period.

TABLE 114. Germicidal Phenolic Detergents

Containing Paratertiary Butylphenolo
Product
Bactophene
Microphene
O-Syl
Penocide
a

Manufacturer
Sanfax Corporation
Sanfax Corporation
Lehn and Fink Division, Sterling Drug
Center Chemicals

Source: Fisher AA: Vitiligo due to contactants. Cutis 17:431--437, 1976.
Copyright, 1976, Donneley Publishing Corporation. Used with permission.


483

CHEMICAL
HYPOMELANOSIS

FIGURE 193. Leukomelanoderma after application of monobenzylether of hydroquinone.

Contact dermatitis may precede whitening but is not necessary for development
of depigmentation. Depigmentation begins as confetti-like or small, round to
oval macules which may be more or less grouped in a particular anatomic
region. Predisposed sites are a function of direct occupational contact, so that
the hands, forearms, perioral skin, neck, and lower legs are among the first to

depigment. Satellite lesions (Fig. 193) may occur in areas not directly exposed
to the chemical. In extensive cases, which certainly resemble vitiligo, genital
and perianal skin may be affected. Extensive and symmetrical depigmentation
of the trunk may also occur. A leukomelanoderma may result. Graying of scalp
and body hair is rare. Eye color is unchanged. Repigmentation may occasionally
occur from the margins or from hair follicles after the chemical is withdrawn,
but more often depigmentation is permanent.

Monobenzylether of Hydroquinone (MBEH)
In the late 1930s, the rubber industry began to use a phenol derivative,
monobenzylether of hydroquinone (MBEH), as an antioxidant. Oliver et al. first


484
CHAPTER 5

reported in 1939 [14] depigmentation of skin occurring among factory workers
exposed for several months to rubber gloves containing an antioxidant, "Agerite
Alba." The leukoderma occurred mainly on the hands and half-way up the
forearms, often with a sharp cut-off line corresponding to areas outlined by the
heavy gauntlet type of gloves worn. Other areas of the face and trunk were also
involved. This depigmentation was attributed to direct contact with the antioxidant. About 50% of the workers were affected and the severity was a
function of the duration of exposure. Patch tests confirmed that MBEH caused
the depigmentation in the affected workers. McNally [15] at the same time
reported the same phenomenon in 34 black employees in a tannery. Leukoderma observed at remote sites was attributed to accidental direct contact with
the gloves. A mild inflammatory reaction and hair loss in the depigmented
macules was observed in one patient. Yet, the occurrence of leukoderma in
only nine of 200 workers exposed to oil droplets containing the antioxidant
material suggested that exposure alone was not the sole factor required for
depigmentation to occur [16].

These observations precipitated attempts to induce depigmentation with
MBEH. Application of MBEH to guinea-pig skin induced cutaneous depigmentation, whereas oral feedings over five months did not [17]. Later, production of depigmentation from oral feedings was observed by another group of
investigators [18] who attributed the different results to a different strain of
guinea pigs or to a higher dosage of MBEH.
Clinically, MBEH was reported to cause pigmentary lightening in melasma
[18-22], postinflammatory hyperpigmentation [22], benign acanthosis nigricans
[22], idiopathic melanoderma [22], congenital eyelid melanosis [22], pigmented
nevi [22,23], Riehl melanosis [24], cafe-au-Iait spots [22], generalized lentigines
[22], senile lentigines [22], seborrheic keratoses [22], berloque dermatitis [22],
hyperpigmented scars [21], and normally melanized skin in vitiligo patients
[22].

Monomethylether of hydroquinone (4-hydroxyanisole) is also a potent depigmenting agent [25].
The histology of MBEH-induced total depigmentation is identical to that
of vitiligo; the epidermis is normal except for an absence of identifiable melanocytes. The dopa reaction is negative. Electron microscopy reveals a total
absence of melanosomes.
Most chemical depigmenting agents appear to act by destroying melanocytes rather than by mere inhibition of melanin formation [26]. Studies in guinea
pigs have shown that MBEH inhibits melanogenesis. The number and size of
melanocytes is decreased. The content of melanocytes and keratinocytes is
diminished. The effect was observed to last four weeks after application. Prolonged application would be expected to cause irreversible loss of all melanocytes. Snell [27], like Peck and Sobatka [17], found no change in melanin
content of hairs and suggested MBEH may not penetrate skin so far as the
follicular melanocytes. Patients bleached with MBEH generally are permanently depigmented but may on occasion develop perifollicular repigmentation; these observations suggest that at least the potential for· perifollicular
melanocyte activation may remain.


Hydroquinone (HQ)
Oettel [28], in 1936, noted that black-haired cats developed reversible graying of hair after six to eight weeks of hydroquinone (HQ) feedings. Martin and
Ansbacher [29] noted that achromatrichia developed after four to 20 weeks of
oral HQ in mice. HQ fed to guinea pigs did not cause depigmentation, whereas
subcutaneous injection resulted in depigmentation at the injection sites [18].

Workers exposed to large amounts of HQ do not develop depigmentation, but
depending on the length of exposure may develop a reddish discoloration of
hair and exposed skin, particularly on the palms and soles [30]. This may result
from oxidation and polymerization of absorbed HQ [30] or from conversion of
HQ to a melanin-like product similar to that in the conjunctivae in ochronosis
[31]. HQ has also been found to be a quite effective de pigmenting agent but,
unlike MBEH, it does not cause satellite depigmentation and the depigmentation is usually reversible once application of HQ is discontinued (Fig. 194).
Furthermore, total depigmentation has never been reported. Large quantities
of HQ creams have been used in Africa for over 15 years; no reports of vitiligolike depigmentation have been reported despite annual sales of several million
dollars.
Jimbow et al. [32] found evidence of destruction of melanocytes with HQ;
there was decreased formation of melanosomes, alteration of internal structure,
increased melanosome degradation, and destruction of membranous organelles.

Paratertiary Butylphenol (PTBP) and Paratertiary Amylphenol
(PTAP)
In 1962 Russian researchers [33] observed depigmentation in 23 of 52
factory workers exposed to paratertiary butylphenol (PTBP) and paratertiary
amyl phenol (PTAP) formaldehyde resin. The depigmentation was symmetrical
and resembled vitiligo. Three of the cases occurred after a year of exposure.
Forty percent of those exposed for more than two years were depigmented. The
exposure was attributed to inhalation of various phenol vapors in combination
with formaldehyde and to exposure to the resin dust.
Daily injection of PTBP into black rabbits also induced graying of hair
[34,35]. The observation that daily application of PTBP in propylene glycol
caused capillaritis suggested depigmentation remote to directly exposed areas
could be secondary to a generalized capillaritis [36]. Subcutaneous and oral
administration also caused depigmentation in C-57 black mice [37,38].
Five housekeeping employees in a Denver hospital developed depigmentation of the hands and forearms after six months' use of O-Syl, a PTBP-containing detergent disinfectant [12].
Rodermund and Wieland [39] reported three men with vitiligo-like skin

changes, hepatosplenomegaly, and diffuse goiter (grade III), all of which developed after one to two years' work in a factory producing PTBP. Liver function
tests showed BSP elevation and a slight increase in the SGOT and SGPT levels.
Liver biopsy showed polymorphism of the hepatocytes, disintegration of the

485

CHEMICAL
HYPOMELANOSIS


486

CHAPTER 5

FIGURE 194. a: Patient with melasma before treatment with hydroquinone. b, c: Same patient
during and after treatment. The hypomelanosis is much less apparent.