Hair and Skin Disorders as Signs of Mitochondrial Disease

[Guest guest]

Kim,

My had a problem with alopecia about 5 years ago. We treated with

anti-fungals and the hair did eventually grow back. Two years later it

happened again and we didn't treat and the hair slowly (very, very

slowly) grew back, but his hair is not the same color and texture on

that spot on his head (obviously darker and much curlier). It was about

6 months after the second episode of hair loss that he first ended up

in a wheelchair.

Here is a link for the full text of an article on hair and skin signs

of mito.

http://pediatrics.aappublications.org/cgi/content/full/103/2/428

Pediatrics. 1999 Feb;103(2):428-33.

Hair and skin disorders as signs of mitochondrial disease.

Bodemer C, Rotig A, Rustin P, Cormier V, Niaudet P, Saudubray JM,

Rabier D, Munnich A, de Prost Y.

Service de Dermatologie, INSERM U. 12, and Departement de Pediatrie,

Hopital Necker Enfants Malades, Paris, France.

ABSTRACT

Objective. To compare and explore the

skin manifestations of mitochondrial disorders in 14 children with

puzzling and unexpected cutaneous presentations.

Study Design. One hundred forty children with

mitochondrial disorders who had been under observation in our hospital

for the last 10 years, were carefully examined by the same

physicians.

Skin and hair characteristics were investigated by the same

dermatologist. All the children developed an early

unexplained

association of symptoms. Metabolic screening for abnormal

oxidative-reduction in plasma and mitochondrial enzyme

investigations

confirmed the diagnosis of oxidative phosphorylation

disorders.

Results. Fourteen children with mitochondrial disorders

(10% of the original cohort) developed specific hair and skin

abnormalities. Their cutaneous manifestations were similar,

and could

be classified into four categories: hair abnormalities,

rashes and

pigmentation disorders, hypertrichosis, and acrocyanosis.

In 3 cases,

skin disorders constituted the puzzling and unexpected

manifestations of mitochondrial disease. Respiratory chain

deficiencies in the cultured skin fibroblasts of 3 patients

and heteroplasmic mitochondrial DNA rearrangement in the

skin fibroblasts of 1 patient indicated that

mitochondrial disorders may be expressed in the skin.

Conclusion. Hair abnormalities and pigmented skin

eruptions might belong to the broad spectrum of presenting symptoms of

mitochondrial disease. The association of these

dermatologic lesions

with unrelated disorders should lead physicians to consider

a diagnosis

of mitochondriopathy as early as possible.

Key words:

mitochondrial

disease,

alopecia,

trichothiodystrophy,

pigmentation disorders.

Mitochondrial disorders have long been regarded as

exclusively neuromuscular. In fact, however, a number of

nonneuromuscular organs and tissues are also highly

dependent on the

mitochondrial energy supply. Consequently, a broad spectrum

of clinical

features might be present, usually involving skeletal

muscle, but

sometimes with predominant nonneuromuscular

manifestations.1,2

In addition, all modes of inheritance

can be expected, owing to the twofold genetic origin of

mitochondrial

respiratory enzymes that are encoded both by the nuclear

genome and by

the mitochondrial DNA (mtDNA).3

Partial deletions or

duplications of mtDNA, or maternally inherited point

mutations, have

been associated with well-defined clinical syndromes;

however,

phenotypes transmitted as Mendelian traits have also been

identified.4

That is why, given the complexity of

mitochondrial genetics and biochemistry, the clinical

manifestations of

mitochondrial disorders are extremely heterogeneous and the

diagnosis

is difficult to formulate early when the primary symptom is

the only

one present. For this reason, clinical clues to the

diagnosis of

mitochondrial disorders have been defined and it is now

well

established that mitochondrial disease should be considered

when

dealing 1) with an unexplained association of symptoms; 2)

with an

early onset and a rapidly progressive course; and 3) when

seemingly

unrelated organs are involved, which have no common

embryologic origin

or biological function.2

Skin disorders have been mentioned in a few cases of mitochondrial

disease but have never been systematically studied in this setting.

New

cases with puzzling and unexpected cutaneous manifestations of

mitochondrial disorders led us to group together and compare skin

manifestations. Based on the results, we postulate that hair abnormalities

and pigmented skin eruptions could be attributable to

mitochondrial disorders and belong to the broad spectrum of presenting

symptoms. Physicians must be aware of this novel presentation and

of

the need to envisage a diagnosis of mitochondrial disease when

dermatologic lesions are associated with unrelated disorders.

"Alopecia and significant hair shaft abnormalities (trichoshisis, pili

torti, longitudinal grooving, and trichorrhexis nodosa) were observed

in 6 patients. We believe that cellular energy supply might play an

important role in human hair growth and that mitochondrial disorders

could account for pathologic follicular growth and development. In 1

patient (patient 1), the specific hair shaft defect with tiger-tail

pattern and trichoshisis (LM and EM) and the low sulfur content of the

hair, characterize the diagnosis of trichothiodystrophy (Table 1).

Although hair abnormalities are the key to the identification of

patients with trichothiodystrophy, it is not yet certain whether the

different syndromes, of which brittle hair with a low sulfur content

is a constant feature, constitute a single entity or multiple

entities.14 This particular hair shaft defect has never been described

in patients with mitochondrial disorders. It was striking that

trichothiodystrophy was the first symptom in this patient and that its

appearance was preceded by a symptom-free period (7 months). The

relationship between respiratory deficiency and trichothiodystrophy,

two rare genetic diseases, remains unexplained.

Rashes with disorders of pigmentation were observed in 6 cases. The

significance of this cutaneous disorder on photoexposed areas is

unclear. It may be that light exposure increases the proportion of

deleted mtDNA molecules in the skin of patients with respiratory

deficiencies as observed by Pang et al15 in patients with skin tumors.

In our view, exposure to light might favor the cutaneous expression of

mitochondrial deficiencies in photoexposed areas by increasing the

number of mtDNA deletions.

....

Our study shows that respiratory chain deficiencies accounted for hair

abnormalities and for skin disorders after photoexposure. Cutaneous

manifestations can be the presenting symptom of genetic disease or may

appear at any age during the course of disease. Mitochondrial

disorders are difficult to diagnosis early, when the primary

nonspecific symptom, whether or not it is dermatologic, is the only

one present. However, the possibility of mitochondrial disorders

should be considered as soon as new and seemingly unrelated symptoms

are observed. Of course these disorders are not the only diagnosis to

be envisaged and metabolic screening for abnormal oxidation-reduction

status in plasma, ie, estimation of L/P and ketone body molar ratios,

under both fasted and fed conditions), as well as careful clinical

assessment for multiorgan involvement, can help to identify patients

who should be further investigated by mitochondrial respiratory enzyme

assays. In the future, mitochondrial disorders will probably account

for certain unexplained conditions, especially those associating

seemingly unrelated symptoms. Further investigations would have to

specify the role of energetic cellular mechanisms in hair growth and

hair shaft formation and in photosensitivity.

Alopecia and Hair Shaft Abnormalities (6 Cases) During careful

examination of these children with

mitochondrial disorders, we often noticed a specific type of hair,

which was brittle and thick, with a large diameter. For the

present study we only selected children with obvious

abnormalities like alopecia. Hair shaft abnormalities were

consistently observed in

samples from different areas of the scalp. By LM and EM we observed

transverse fractures across the hair shaft through the cuticle

and the

cortex (trichoshisis), involving hairs with a tiger tail

pattern

(patient 1; Fig

1), and hairs displaying twists (pili torti),

longitudinal grooving (Fig

2), cuticle loss, and trichorrhexis

nodosa (Table

1). Amino acid analyses of hairs were normal in these

patients, except in 1 case with the sulfur content of the

hair reduced

to more than 50% of its value (patient 1).

Eur J Pediatr.

2003 Jul;162(7-8):459-61. Epub 2003 Apr 24.

Hair anomalies as a sign of

mitochondrial disease.

Silengo M, Valenzise M, Spada M, Ferrero GB, Ferraris S, Dassi P,

Jarre L.

I

Divisione di Clinica Pediatrica, Universita' di Torino, Piazza Polonia

94, 10126 Torino, Italy. margherita.cirillosilengo@...

In 8

out of 25 children with a mitochondrial disorder, slow growing, sparse

and fragile hair was observed as an early sign of their disease.

Microscopic examination of the hair showed the presence of

trichorrhexis nodosa and pili torti. Hair abnormalities can be added to

the wide clinical spectrum of mitochondrial disorders. CONCLUSION:

Microscopic hair examination is an easy, first level diagnostic tool

that can lead to a suspected mitochondrial defect in the early stages

of the disease, before symptoms of progressive multi-organ involvement

develop.

[Guest guest]

All three of my kids fit into these symptoms, two of my kids have a

rectangular patch at the crown of their head that has no hair, my son

also has two more patches at the sides of his head. they have cafe

au lait marks and ash leaf marks and one girl has hyper pigmentation

and brown marks that look like someone splattered brown paint on her

arms and shoulders, she also has excessive hair on her back..she is

very fuzzy...

>

>

> ABSTRACT

>

>

> /Objective./ To compare and explore the skin manifestations of

> mitochondrial disorders in 14 children with puzzling and unexpected

> cutaneous^ presentations.

>

> /Study Design./ One hundred forty children with mitochondrial

disorders

> who had been under observation in our hospital for the last 10

years,^

> were carefully examined by the same physicians. Skin and hair^

> characteristics were investigated by the same dermatologist. All^

the

> children developed an early unexplained association of symptoms.^

> Metabolic screening for abnormal oxidative-reduction in plasma^ and

> mitochondrial enzyme investigations confirmed the diagnosis^ of

> oxidative phosphorylation disorders.^

>

> /Results./ Fourteen children with mitochondrial disorders (10% of

the

> original cohort) developed specific hair and skin abnormalities.^

Their

> cutaneous manifestations were similar, and could be classified^

into

> four categories: hair abnormalities, rashes and pigmentation^

disorders,

> hypertrichosis, and acrocyanosis. In 3 cases, skin^ disorders

> constituted the puzzling and unexpected manifestations^ of

mitochondrial

> disease. Respiratory chain deficiencies in the^ cultured skin

> fibroblasts of 3 patients and heteroplasmic mitochondrial^ DNA

> rearrangement in the skin fibroblasts of 1 patient indicated^ that

> mitochondrial disorders may be expressed in the skin.^

>

> /Conclusion./ Hair abnormalities and pigmented skin eruptions

might

> belong to the broad spectrum of presenting symptoms of

mitochondrial^

> disease. The association of these dermatologic lesions with

unrelated^

> disorders should lead physicians to consider a diagnosis of

> mitochondriopathy^ as early as possible. / Key

words: /mitochondrial

> disease/, /alopecia/, /trichothiodystrophy/, /pigmentation

disorders/. /

>

>

> Mitochondrial disorders have long been regarded as exclusively

> neuromuscular. In fact, however, a number of nonneuromuscular^

organs

> and tissues are also highly dependent on the mitochondrial^ energy

> supply. Consequently, a broad spectrum of clinical features^ might

be

> present, usually involving skeletal muscle, but sometimes^ with

> predominant nonneuromuscular manifestations.^1

>

<http://pediatrics.aappublications.org/cgi/content/full/103/2/428#B1>

> ^,2

>

<http://pediatrics.aappublications.org/cgi/content/full/103/2/428#B2>

^

> In addition, all modes of inheritance can be expected, owing to^

the

> twofold genetic origin of mitochondrial respiratory enzymes^ that

are

> encoded both by the nuclear genome and by the mitochondrial^ DNA

> (mtDNA).^3

>

<http://pediatrics.aappublications.org/cgi/content/full/103/2/428#B3>

> Partial deletions or duplications of mtDNA,^ or maternally

inherited

> point mutations, have been associated^ with well-defined clinical

> syndromes; however, phenotypes transmitted^ as Mendelian traits

have

> also been identified.^4

>

<http://pediatrics.aappublications.org/cgi/content/full/103/2/428#B4>

> That^ is why, given the complexity of mitochondrial genetics and

> biochemistry,^ the clinical manifestations of mitochondrial

disorders

> are extremely^ heterogeneous and the diagnosis is difficult to

formulate

> early^ when the primary symptom is the only one present. For this

> reason,^ clinical clues to the diagnosis of mitochondrial disorders

> have^ been defined and it is now well established that

mitochondrial^

> disease should be considered when dealing 1) with an unexplained^

> association of symptoms; 2) with an early onset and a rapidly^

> progressive course; and 3) when seemingly unrelated organs are^

> involved, which have no common embryologic origin or biological^

> function.^2

>

<http://pediatrics.aappublications.org/cgi/content/full/103/2/428#B2>

>

> Skin disorders have been mentioned in a few cases of mitochondrial

> disease but have never been systematically studied in this^

setting. New

> cases with puzzling and unexpected cutaneous manifestations^ of

> mitochondrial disorders led us to group together and compare^ skin

> manifestations. Based on the results, we postulate that hair^

> abnormalities and pigmented skin eruptions could be attributable^

to

> mitochondrial disorders and belong to the broad spectrum of^

presenting

> symptoms. Physicians must be aware of this novel presentation^ and

of

> the need to envisage a diagnosis of mitochondrial disease^ when

> dermatologic lesions are associated with unrelated disorders.

>

>

>

> " Alopecia and significant hair shaft abnormalities (trichoshisis,

pili

> torti, longitudinal grooving, and trichorrhexis nodosa) were

observed

> in 6 patients. We believe that cellular energy supply might play an

> important role in human hair growth and that mitochondrial disorders

> could account for pathologic follicular growth and development. In 1

> patient (patient 1), the specific hair shaft defect with tiger-tail

> pattern and trichoshisis (LM and EM) and the low sulfur content of

the

> hair, characterize the diagnosis of trichothiodystrophy (Table 1).

> Although hair abnormalities are the key to the identification of

> patients with trichothiodystrophy, it is not yet certain whether the

> different syndromes, of which brittle hair with a low sulfur content

> is a constant feature, constitute a single entity or multiple

> entities.14 This particular hair shaft defect has never been

described

> in patients with mitochondrial disorders. It was striking that

> trichothiodystrophy was the first symptom in this patient and that

its

> appearance was preceded by a symptom-free period (7 months). The

> relationship between respiratory deficiency and trichothiodystrophy,

> two rare genetic diseases, remains unexplained.

>

> Rashes with disorders of pigmentation were observed in 6 cases. The

> significance of this cutaneous disorder on photoexposed areas is

> unclear. It may be that light exposure increases the proportion of

> deleted mtDNA molecules in the skin of patients with respiratory

> deficiencies as observed by Pang et al15 in patients with skin

tumors.

> In our view, exposure to light might favor the cutaneous expression

of

> mitochondrial deficiencies in photoexposed areas by increasing the

> number of mtDNA deletions.

>

> ...

>

> Our study shows that respiratory chain deficiencies accounted for

hair

> abnormalities and for skin disorders after photoexposure. Cutaneous

> manifestations can be the presenting symptom of genetic disease or

may

> appear at any age during the course of disease. Mitochondrial

> disorders are difficult to diagnosis early, when the primary

> nonspecific symptom, whether or not it is dermatologic, is the only

> one present. However, the possibility of mitochondrial disorders

> should be considered as soon as new and seemingly unrelated symptoms

> are observed. Of course these disorders are not the only diagnosis

to

> be envisaged and metabolic screening for abnormal oxidation-

reduction

> status in plasma, ie, estimation of L/P and ketone body molar

ratios,

> under both fasted and fed conditions), as well as careful clinical

> assessment for multiorgan involvement, can help to identify patients

> who should be further investigated by mitochondrial respiratory

enzyme

> assays. In the future, mitochondrial disorders will probably account

> for certain unexplained conditions, especially those associating

> seemingly unrelated symptoms. Further investigations would have to

> specify the role of energetic cellular mechanisms in hair growth and

> hair shaft formation and in photosensitivity.

> *

>

> Alopecia and Hair Shaft Abnormalities (6 Cases) During careful

> examination of these children with mitochondrial disorders, we

often

> noticed a specific type of hair, which^ was brittle and thick, with

a

> large diameter. For the present^ study we only selected children

with

> obvious abnormalities like^ alopecia. Hair shaft abnormalities were

> consistently observed^ in samples from different areas of the

scalp. By

> LM and EM we^ observed transverse fractures across the hair shaft

> through the^ cuticle and the cortex (trichoshisis), involving hairs

with

> a^ tiger tail pattern (patient 1; Fig 1

>

<http://pediatrics.aappublications.org/cgi/content/full/103/2/428#F1>)

,

> and hairs displaying^ twists (pili torti), longitudinal grooving

(Fig 2

>

<http://pediatrics.aappublications.org/cgi/content/full/103/2/428#F2>)

,

> cuticle^ loss, and trichorrhexis nodosa (Table 1

>

<http://pediatrics.aappublications.org/cgi/content/full/103/2/428#T1>)

..

> Amino acid^ analyses of hairs were normal in these patients, except

in

> 1 case^ with the sulfur content of the hair reduced to more than

50% of^

> its value (patient 1).*

>

> Eur J Pediatr. 2003 Jul;162(7-8):459-61. Epub 2003 Apr 24.

> <http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?

db=pubmed & cmd=Display & dopt=pubmed_pubmed & from_uid=12712334>

> <javascript:PopUpMenu2_Set(Menu12712334);>

>

> *Hair anomalies as a sign of mitochondrial disease.*

>

> *Silengo M, Valenzise M, Spada M, Ferrero GB, Ferraris S, Dassi P,

Jarre L.*

>

> I Divisione di Clinica Pediatrica, Universita' di Torino, Piazza

Polonia

> 94, 10126 Torino, Italy. margherita.cirillosilengo@u...

>

> In 8 out of 25 children with a mitochondrial disorder, slow

growing,

> sparse and fragile hair was observed as an early sign of their

disease.

> Microscopic examination of the hair showed the presence of

trichorrhexis

> nodosa and pili torti. Hair abnormalities can be added to the wide

> clinical spectrum of mitochondrial disorders. CONCLUSION:

Microscopic

> hair examination is an easy, first level diagnostic tool that can

lead

> to a suspected mitochondrial defect in the early stages of the

disease,

> before symptoms of progressive multi-organ involvement develop.