This document summarizes research on Ambras syndrome, a rare condition characterized by excessive hair growth over the entire body. It discusses previous studies that have suggested genetic causes such as an X-linked dominant mutation located on chromosome Xq24-q27.1. A more recent study presented in this document found that rearrangements on chromosome 8 can cause a position effect on the TRPS1 gene, reducing its transcription and resulting in hypertrichosis. Understanding the genetic origins of such rare conditions could provide insight into more common hair disorders and shed light on human evolution and atavism.

1. The Ape-Man
Syndromes of Excessive Hair Growth
and their Genetic Causes
Presented by: Shana Milstein
Advised by: Dr. Uri Gat
Date: 15/5/2012
1

2. What is hair?
• Strong fibrous material composed of compacted
dead keratinocytes, produced by the hair follicle.
• Functions: thermoregulation, physical protection,
sensory activity, and social interactions.
• Unique ability to undergo complete regeneration.
2

3. Fuchs, 2008
Embryonic Stages of Hair Follicle
Morphogenesis
3

4. The Hair Cycle
4Schneider et al., 2009

5. Types of Hair
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• Lanugo – long, fine, and unpigmented embryonic
hairs that cover the body.
• Vellus – short, thin, fine, and lightly pigmented hairs.
Replace lanugo hairs on the body.
• Terminal – long, thick, pigmented hairs. Primarily on
the scalp and eyebrows. Exposure to androgens at
maturity can trigger a switch from vellus to terminal
hairs.

6. Diseases of Hair Growth
• Alopecia – abnormal loss of hair
• Hirsutism – excessive hair
growth in androgen-dependent
areas, in women.
• Hypertrichosis – excessive hair
growth beyond the normal
pattern.
6Schneider et al., 2009

7. Ambras Syndrome
• A form of congenital
generalized hypertrichosis.
• Body is covered with long,
fine, generally vellus-type
hair, accentuated on the
shoulders, face, and ears.
• Unique facial features.
7Baumeister et al., 1993

8. A History of Ambras Syndrome
8Baumeister et al., 1993
Family of Petrus Gonzales, who lived in the 16th century; drawings after the original paintings
shown in the castle of Ambras, Austria.

9. Some Observed Cases of Ambras
Syndrome
9Baumeister et al., 1993
Grandson of Schwe Maong Adrian JepticheffFedor
Stephan Bibrowsky Michael K. Sabine H.

10. Genetic Basis for Ambras Syndrome
• X-linked dominant mutation
• Rearrangement of chromosome 8
10

11. Pedigree of X-Linked Dominant
Congenital Generalized Hypertrichosis
11Macias-Flores et al., 1984

12. 24 Year Old Female with Congenital
Generalized Hypertrichosis
12Macias-Flores et al., 1984

13. 6 Year Old Male with Congenital
Generalized Hypertrichosis
13Macias-Flores et al., 1984
Later linkage studies mapped the gene to somewhere
in the Xq24-q27.1 region (Figuera et al., 1995).

14. Genetic Basis for Ambras Syndrome
• X-linked dominant mutation
• Rearrangement of chromosome 8
14

15. 3 Cases of Chromosome 8
Rearrangements and Deletions
• ME-1 → Pericentric inversion with breakpoints
at 8p11.2 and 8q23.1
• SS-1 → Translocation of 8q23-8q24 and a
large deletion within 8q23
• BN-1 → Deletion in 8q24
15Fantauzzo et al., 2008

16. Female (ME-1) with Ambras Syndrome as
Neonate and Age 3 (2 Weeks After Shaving)
16Baumeister et al., 1993

17. Chromosome 8: A Map of Ambras
Syndrome Breakpoints and Deletions
17Fantauzzo et al., 2008

18. Trichorhinophalangeal Syndrome 1
(TRPS1)
• Vertebrate transcription factor
• Contains nine zinc finger domains, including a
GATA-type zinc finger and two Ikaros-like zinc
fingers
• Mouse ortholog is contained in the mesenchymal
cells during mouse embryogenesis
• Homozygous and heterozygous mutations on the
gene result in phenotypes with sparse or no hair
and/or vibrissae
18Fantauzzo et al., 2008

19. Southern Blot Analysis Using a TRPS1
cDNA Probe
19Fantauzzo et al., 2008

20. Relative Expression of Genes
Surrounding Breakpoints in ME-1
20Fantauzzo et al., 2008

21. WT and Heterozygous Koa Mutant
Mouse Phenotypes
21Fantauzzo et al., 2008
Koa/+ mice have long hair on both surfaces of the pinnae of the ears and around the muzzle.

22. Mapping of the Koa Inversion
Mutation
22Fantauzzo et al., 2008

23. Relative Expression of Trps1 in WT and
Koa Mutant Mice
23Fantauzzo et al., 2008

24. Trps1 Expression as Detected by
Whole Mount in situ Hybridization and
Immunofluorescence
24Fantauzzo et al., 2008
Whole Mount in situ Hybridization Immunofluorescence

25. Mapping of the Altered Configuration
of Transcription Factor Binding Sites
Due to Koa Inversion
25Fantauzzo et al., 2008

26. To Summarize
• Hypertrichosis is a disease of increased hair
density on any part of the body that goes
beyond the normal hair pattern.
• Ambras syndrome is a congenital generalized
hypertrichosis, where the body is covered in
long vellus-type hairs most excessive on the
upper part of the body.
• There are many suggestions as to genetic
origins of Ambras syndrome, both on
autosomal and sex chromosomes.
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27. To Summarize
• A study of a multigenerational Mexican family
proposes an x-linked dominant pattern of
inheritance, located within the Xq24-q27.1
region of the chromosome.
• Another study presents a position effect on
the gene Trps1, caused by rearrangements on
chromosome 8, which may result in additional
Sp1 binding sites, ultimately repressing Trps1
transcription.
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28. Why is it Important to Find the Genetic
Origin of Such a Rare Disease?
• Further understanding of the developmental
genetics of hair.
• Get insight into more common hair diseases of
the opposite extreme (i.e. alopecia) and
possible leads on strategies for a cure and/or
treatment.
• To gain a further understanding of the
evolution of man and how/why atavistic
features may arise.
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29. Further Research
• Further testing to determine why reduced
Trps1 expression caused by mutation on the
gene itself exhibits an alopecic phenotype,
whereas downregulation of Trps1 by a
position effect causes hypertrichosis.
• Mapping of Trps1 orthologs in other mammals
to determine whether Ambras syndrome is
the result of atavism.
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30. Acknowledements
Thank you to my advisor Dr. Uri Gat!
30

31. References
Baumeister, F.A., Egger, J., Schildhauer, M.T., Stengel-Rutkowski, S. Ambras syndrome: delineation of a unique
Hypertrichosis Universalis congenital and association with a balanced pericentric inversion (8) (p11.2; q22). Clin.
Genet. 1993;44:121–128.
Fantauzzo K.A., Tadin-Strapps M., You Y., Mentzer S.E., Baumeister F.A., Cianfarani S., Van Maldergem L.,
Warburton D., Sundberg J.P., Christiano A.M. A position effect on TRPS1 is associated with Ambras syndrome in
humans and the Koala phenotype in mice. Hum. Mol. Genet. 2008;17:3539–3551.
Figuera L.E., Pandolfo M., Dunne P.W., Cantú J.M., Patel P.I. Mapping of the congenital generalized hypertrichosis
locus to chromosome Xq24-q27.1. Nat. Genet. 1995;10:202–207.
Fuchs, E. Skin stem cells, rising to the surface. J. Cell Biol. 2008;180:273–284.
Macías-Flores M.A., García-Cruz D., Rivera H., Escobar-Luján M., Melendrez-Vega A., Rivas-Campos D., Rodríguez-
Collazo F., Moreno-Arellano I., Cantú J.M. A new form of hypertrichosis inherited as an X-linked dominant
trait. Hum. Genet. 1984;66:66–70.
Schneider M.R., Schmidt-Ullrich R., Paus R. The hair follicle as a dynamic miniorgan. Curr Biol. 2009;19:R132–
R142.
Shimomura Y., Christiano A.M. Biology and genetics of hair. Annu Rev Genomics Hum Genet. 2010;11:109–132.
Stenn K.S. Molecular insights into the hair follicle and its pathology: a review of recent developments. Int. J.
Dermatol. 2003;42:40–43
Stenn K.S., Paus R. Controls of hair follicle cycling. Physiol Rev. 2001;81:449–494.
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