Dermatology Online Journal

A hairy development in hypertrichosis: a brief review of Ambras syndrome
Rashid M Rashid¹, Lucile E White²
Dermatology Online Journal 13 (3): 8

1. Loyola University Medical Center, Maywood, IL2. Department of Dermatology, Northwestern University Medical Center, Chicago, IL

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Abstract

Ambras syndrome was described less than 20 years ago. The initial report focused on the subtle, but important distinguishing characteristics that separate this from other forms of congenital hypertrichosis. This review, we examine this fascinating syndrome, and the current scientific perspectives in discussion. This review will help increase and expand our knowledge base of this uncommon syndrome, and should encourage future dermatologic analysis and reports on Ambras syndrome.

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Ambras syndrome (AS) was first described by Baumeister et al. in 1993 in an attempt to clarify and further sub-classify the hypertrichosis terminology [1]. Currently, congenital hypertrichosis (CH) is described with multiple terms that are frequently used interchangeably. For example, terminology has included hypertrichosis universalis, hypertrichosis lanuginosa, congenital hypertrhicosis lanuginosa, and hypertrichosis universalis lanuginosa. The rarity of CH has made it even more difficult to elucidate the possible sub-classifications that may exist.

Current literature attempts to rectify this confusion by detailed analysis of the potential clinical and diagnostic spectrum that may be present within CH. The importance of organizing and regularly reappraising the hypertrichosis literature is underscored as new hypertrichosis entities are described. In this brief review, we hope to provide a detailed review on the concepts of the AS and further encourage analysis and examination of CH as a spectrum of pathologies.

Ambras syndrome: past and present

With the original description of AS, Baumeister et al. made the argument for distinguishing this as a distinct subtype of CH. They supported their argument with a review of nine other potential cases of AS within the CH literature.

Figure 1	Figure 2
Figure 1. Drawings based on the family paintings of the family of Ambras as depicted by Ecker in 1878 Figure 2. Late 19th century photo of Fedor, also known as Jo-Jo the dog-faced man

The first recorded case of AS is believed to be that of Petrus Gonzales (Fig. 1). Gonzales was born in the Canary Islands in 1556. Out of curiosity, Petrus was brought to France where he was presented as a gift to the nobles. Once it was realized Petrus was a bright young mind, he was educated and learned multiple classic and contemporary languages. He subsequently produced offspring with similar AS features. Eventually, this kindred was known as the family of Ambras (Fig. 1). The Ambras name was given because the family portraits were discovered in Ambras castle amongst an art collection started by the archduke Ferdinand II (1529-1595) [2]. Although Gonzales was born in the Canary Islands and lived in France, the Ambras castle is in modern-day Austria. Today, the same paintings hang in the Kunsthistorisches museum in Vienna. Just as stunning and remarkable are some of the examples noted by Buameister et al. that include the family of Schwe Maong, Stephan Bibrowski, and Adrian Jepticheff and his son Fedor (Fig. 2).

After the original 1993 report of AS, a second case was reported by Bladucci et al. [3]. The diagnosis has since been questioned because of the stringent diagnostic criteria designated by Baumesiter [4]. The current literature has similar reports, including a recent case of siblings with AS features [5].

Congential hypertrichosis is rare. The diagnosis has proved to be a fascination for science and [6] for science fiction [7]. Physicians should be aware of the serious pathologic consequences that may be associated with hypertrichosis [8].

Etiology and pathology

Human hair differentiates into lanugo, vellous, and terminal hair [9, 10]. Lanugo hair develops and sheds during fetal life and is immediately followed by vellous hair. Vellus is seen over the face and arms of children; it is shorter, softer, lightly pigmented, and may be medullated. Terminal hair is longer, coarser, and medullated; it is found on the scalp, eyebrows, and eyelashes from birth, and it comprises the new hair and the hair pattern formed in puberty and adulthood. Terminal hair arises from vellous hair follicles under the influence of androgens.

Baumesiter suggested the lifelong presence of hypertrichosis in AS lends credence to the theory that AS is a disturbance of development of vellus hair. Baumesiter postulates that AS is associated with a relative decrease of the telogen phase of the hair growth cycle.

Hirsutism is hairiness associated with abnormal androgen secretion. Hypertrichosis is hair growth that is abnormal in quantity or location. The hypertrichosis associated with AS is believed to involve an increased percentage of follicles in the anagen phase or more hair follicles per unit area of skin, respectively [9]. It is not known what triggers or initiates this hypertrichosis.

Reports of multiple affected relatives suggest a genetic basis for AS [11]. It has also been noted that AS cases involve full-term births from non-consanguineous parents and no other family history of hypertrichosis. Regardless of the inheritance pattern, a genetic alteration is believed to play a central, but still unresolved role, in AS. In the original 1993 description, the specific genetic alteration was that of be a pericentric inversion (8)(p11.2; q22). Because the historic cases could not be genetically analyzed, the Baumeister case is the only one to have this specific genetic alteration confirmed. Another patient with similar clinical features has been described by Balduci [3], but with a slightly different paracentric inversion, this case being at 8q23-24 [4]. Based on the genetic alteration, and the more universal hypertrichosis present in the Balducci case, Baumeister argued this case to be classified as congenital hypertrichosis universalis and not the more specific AS [12]. These discoveries bring into question how exact the genetic alteration needs to be for a case to be described as AS. But regardless, it is clear that a genetic alteration in the 8q22-24 is involved in these cases of hypertrichosis.

Diagnosis

The diagnosis of AS is made on the basis of hari pattern, analysis of hair type by histology, genetic analysis, and absence of endocrinologic abnormality. In addition, AS may be associated with dysmorphisms.

Hair pattern

The patient's whole body is covered with silky lightly colored hair, most prominent at the shoulders, face, and ears. Hair uniformly covers the eyelids, nose, cheeks, periauricular regions and shoulder. The length of hair can reach several centimeters. Hair is absent in regions that do not normally grow hair. In the Baumeister case, the patients "ventral trunk hair converged to a crest mimicking a triangular shawl around her shoulders."

Hair type

Analysis of hair type histology is critical to determine if the hypertrichosis represents either vellus or lanuginosa type hair. Patients with AS have vellus hair.

Endocrine abnormality

Unlike other forms of congential hypertrichosis, none of the AS cases reported have metabolic or endocrine defects. Thus androgen levels should be drawn in suspected cases.

Genetic analysis

Genetic alteration was viewed as a central part of AS in the original Baumeister description. Although there are very few reports regarding the genetic alterations, it appears that inversions of chromosome 8 are associated with hypertrichosis.

Dysmorphisms

A variety of dimorphisms have been recorded, most involving the head. For example, dismorphic triangular coarse face, broad intercantha, broad palpebral fissures, long nose with round tip, broad interalar distance, anteverted nares, short integumental lower lip, and flat sulcus mentolabialis. Occasional patients have hexadactyly and supranumery nipples. Other facial anomalies and abnormalities including retarded first and second dentition, and absence of teeth [1].

Differential diagnosis

Hypertrichosis has to be distinguished from hirsutism. Hirsutism is associated with an androgen-dependent hair pattern, something not present in AS. Therefore, hirsutism can be ruled out with normal androgen levels. The differentiation of subtypes of CH is central to prognosis and early management of other anomalies later.

Acquired generalized hypertrichosis

In acquired hypertichosis, the patients present after birth, usually during childhood [13]. The diagnosis of acquired hypertrichosis should be considered when a detailed perinatal history is not available. It should be noted that the lanuginosa variant of acquired hypertrichosis is usually a paraneoplastic manifestation [14].

Congenital hypertrichosis universalis

This subset is characterized by hair accentuation in the frontal temporal and peri-auricular regions. A patient will have bushy eyebrows but the ear is not hairy. On the back, hair is present universally and wraps around with a midline convergance. A hair whorl forms at the spine.

Hypertrichosis with gingival fibromatosis (osteochondrodysplasia)

This form of hypertrichosis is associated with a well defined set of anomalies, including redundant skin and enlarged, pink, pebbly gingival nodules [15].

Congenital hypertrichosis lanuginosa

This is a form of hypertrichosis in which the body is covered with fine hair except for hands and feet. The lanugal hair sheds, beginning at about 1 year of age.

Management and prognosis

The current literature focuses predominantly on diagnosis of AS cases rather than management. The first described patient, Petrus Gonzales, lived a long life and was able to procreate [1]. The Baumeister case presented at age 3 years, and living a relatively normal lifestyle with hair shaving every few weeks [1]. However, some AS patients develop associated anomalies, such as dental anomalies, which may require management. Given the rarity of patients with AS, there may be complications that have not been reported because of diagnostic and technical limitations.

References

1. Baumeister FA, Egger J, Schildhauer MT, Stengel-Rutkowski S. Ambras syndrome: delineation of a unique hypertrichosis universalis congenita and association with a balanced pericentric inversion (8) (p11.2; q22) Clin Genet. 1993 Sep;44(3):121-8. PubMed

2. Ambras Castle. Alfred Auer et al. Milan: Electa and Kunsthistorisches Museum, Vienna, 2000.

3. Balducci R, Toscano V, Tedeschi B, Mangiantini A, Toscano R, Galasso C, Cianfarani S, Boscherini B. A new case of Ambras syndrome associated with a paracentric inversion (8) (q12; q22) Clin Genet. 1998 Jun;53(6):466-8. PubMed

4. Tadin-Strapps M, Warburton D, Baumeister FA, Fischer SG, Yonan J, Gilliam TC, Christiano AM. Cloning of the breakpoints of a de novo inversion of chromosome 8, inv (8)(p11.2q23.1) in a patient with Ambras syndrome. Cytogenet Genome Res. 2004;107(1-2):68-76. PubMed

5. Belengeanu V, Rozsnyai K, Gug C, Banateanu M, Farcas S, Belengeanu A. Ambras syndrome: report on two affected siblings with no prior family history.Clin Dysmorphol. 2004 Oct;13(4):265-7. PubMed

6. Bondeson J, Miles AE. The hairy family of Burma: a four generation pedigree of congenital hypertrichosis lanuginosa. J R Soc Med. 1996 Jul;89(7):403-8. PubMed

7. Baumeister FA. Differentiation of Ambras syndrome from Hypertrichosis Universalis. Clin Genet. 2000 Feb;57(2):157-8. PubMed

8. Tadin-Strapps M, Salas-Alanis JC, Moreno L, Warburton D, Martinez-Mir A, Christiano AM. Congenital universal hypertrichosis with deafness and dental anomalies inherited as an X-linked trait. Clin Genet. 2003 May;63(5):418-22. PubMed

9. Paus R. Principles of hair cycle control. J Dermatol. 1998 Dec;25(12):793-802. PubMed

10. Dawber rp. Aetiology and pathophysiology of hair loss. Dermatologica. 1987;175 Suppl 2:23-8. PubMed

11. Macias-Flores MA, Garcia-Cruz D, Rivera H, Escobar-Lujan M, Melendrez-Vega A, Rivas-Campos D, Rodriguez-Collazo F, Moreno-Arellano I, Cantu JM. A new form of hypertrichosis inherited as an X-linked dominant trait. Hum Genet. 1984;66(1):66-70. PubMed

13. Wendelin DS, Pope DN, Mallory SB. Hypertrichosis. cJ Am Acad Dermatol. 2003 Feb;48(2):161-79; quiz 180-1. PubMed

14. Hegedus SI, Schorr WF. Acquired hypertrichosis lanuginosa and malignancy. A

12. Baumeister FA. Diagnosis of Ambras syndrome: comments on complex cytogenetic rearrangement of chromosome 8q in a case of Ambras syndrome. Am J Med Genet. 2002 Apr 15;109(1):77-8. PubMedclinical review and histopathologic evaluation with special attention to the "mantle" hair of Pinkus. Arch Dermatol. 1972 Jul;106(1):84-8. PubMed

15. Witkop CJ Jr. Heterogeneity in gingival fibromatosis. Birth Defects Orig Artic Ser. 1971 Jun;7(7):210-21. PubMed

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