Hypertrichosis Universalis Congenita, Ambras Type

Description

Hypertrichosis is defined as hair growth that is excessive for a particular site of the body or age of the patient and that is not hormone-dependent (summary by Fantauzzo et al., 2012).

Genetic Heterogeneity of Congenital Generalized Hypertrichosis

HTC1 has been mapped to chromosome 8q. HTC2 (307150) is caused by palindrome-mediated interchromosomal insertion at chromosome Xq27. HTC3 (135400), which can occur with or without associated gingival hyperplasia, is caused by deletion or duplication at chromosome 17q24 or by mutation in the ABCA5 gene (612503) on chromosome 17q24.

Also see lanugo-like generalized congenital hypertrichosis (145700).

Clinical Features

Baumeister et al. (1993) found 9 observations of a unique form of hypertrichosis which they suggested should be called Ambras syndrome in reference to the first documented case. Furthermore, they reinvestigated a Greek girl with this disorder, described as a newborn by Sigalas et al. (1990). The girl was found to have a pericentric inversion (8)(p11.2q22). Her persistent generalized hypertrichosis was most excessive on the face, ears, and shoulders. The fine silky hair was of the vellus, not the lanugo type. Baumeister et al. (1993) stated that the first well-documented observation concerned a man named Petrus Gonzales, who was born in the Canary Islands in 1556. (Wiesner-Hanks (2009) stated that Petrus Gonzales was born in 1537.) Two daughters, a son, and a grandchild were similarly affected. The family was also referred to as 'the family of Ambras,' after the castle near Innsbruck where their portraits are still shown (e.g., Cockayne, 1933). One of the documented reports selected by Baumeister et al. (1993) was that by Macias-Flores et al. (1984) of a family in which X-linked dominant inheritance was suggested (307150). Figuera and Cantu (1994) insisted that the disorder in the kindred reported by Macias-Flores et al. (1984) was clinically and genetically distinct from the Ambras syndrome. In the apparently X-linked disorder, the overgrowth of hair involves mainly the upper part of the body and the hair is short and curly without other alterations, while in Ambras syndrome, there is a more diffuse distribution of the hypertrichosis, the hair is fine and long, other skin appendages are involved, and dysmorphic features are present.

Balducci et al. (1998) likewise described Ambras syndrome associated with an inversion of chromosome 8 but a paracentric rather than pericentric inversion: inv(8)(q12q22). The girl presented in the newborn period with abundant dark hair on the face and ears, shoulders and arms; the other parts of the body were covered with fine, lightly pigmented hair. No alterations were found in plasma antigen levels.

Baumeister (2000) suggested that the patient reported by Balducci et al. (1998) had hypertrichosis universalis (145700) and not Ambras syndrome. He stated that Ambras syndrome differs from other forms of congenital hypertrichosis by its associated anomalies and its pattern of hair distribution, especially on the face. The forehead, eyelids, nose (an especially important site of involvement), cheeks, and preauricular regions are uniformly covered with hair, reaching a length of several decimeters if not shaved. The hypertrichosis of the external ears is typical; if not cut, long curls protrude from the external auditory canal. In the patient reported by Balducci et al. (1998), the facial hair was not uniformly distributed; it was accentuated in the frontal, temporal, and preauricular regions. Hypertrichosis of the nose was not present and hypertrichosis of the ears was not prominent. Baumeister (2000) provided a photograph of a 16-year-old boy with extraordinary facial hypertrichosis.

In a rebuttal to Baumeister (2000), Cianfarani (2000) pointed out that in both the case reported by Balducci et al. (1998) and that reported by Baumeister et al. (1993) there was a chromosome abnormality involving 8q22. He pointed out further that 'modern genetics teaches us that identical mutations result in highly variable combinations of clinical features: phenotypic heterogeneity.'

Population Genetics

Fantauzzo et al. (2012) stated that hereditary hypertrichoses are very rare, affecting as few as 1 in 1 billion individuals.

Cytogenetics

Tadin et al. (2001) found that the rearrangement of chromosome 8 in patient 'SS-1,' originally reported by Balducci et al. (1998), was more complex than initially reported. They detected an insertion of the q23-q24 region into a more proximal region of the long arm of chromosome 8 as well as a large deletion in 8q23. Given the large number of breakpoints and the presence of a substantial deletion, it was surprising that the proposita did not show anomalies other than those characteristic of Ambras syndrome.

Baumeister (2002) reiterated his insistence that the patient studied by Balducci et al. (1998) and reinvestigated by Tadin et al. (2001) did not have Ambras syndrome because she did not present with hypertrichosis of the ears and the pattern of hair distribution in general was not identical to that previously described. Baumeister (2002) stated that his position was further strengthened by the finding of Tadin et al. (2001) that the rearrangement in the patient originally reported by Balducci et al. (1998) did not involve 8q22.

In a patient (ME-1) with Ambras syndrome associated with a de novo pericentric inversion of chromosome 8 first described by Baumeister et al. (1993), Tadin-Strapps et al. (2004) cloned the breakpoints of the inversion and generated a detailed physical map. To determine the precise nature of the rearrangement, they used FISH analysis. Analysis of transcripts mapped to the vicinity of the breakpoints showed that the inversion did not disrupt a gene, and suggested that the phenotype was caused by a position effect.

Fantauzzo et al. (2008) analyzed the cytogenetic breakpoints of 3 patients with hypertrichosis universalis congenita, Ambras type, including patients ME-1 and SS-1, originally reported by Baumeister et al. (1993) and Balducci et al. (1998), respectively. They identified a pericentric inversion in chromosome 8q23.1 that lies 7.3 Mb downstream of the TRPS1 gene (604386) in patient ME-1, a 6.7-Mb deletion that encompasses the TRPS1 gene in patient SS-1, and a 1.5-Mb deletion in chromosome 8q24.1 that lies 2.1 Mb upstream of the TRPS1 gene in patient BN-1. There was no overlap between the breakpoints in the 3 patients, so the authors defined the entire 11.5-Mb interval between markers RH62506 and D8S269 containing 20 genes, including the TRPS1 gene, as the candidate interval. Southern blot analysis was suggestive of deletion of TRPS1 in patient SS-1, and no RNA was available for patient BN-1. Quantitative RT-PCR demonstrated significant downregulation of TRPS1 in patient ME-1, suggesting that the inversion breakpoint 7.3 Mb downstream from the TRPS1 gene reduced expression, consistent with a position effect. Fantauzzo et al. (2008) suggested that position effect causing downregulation of TRPS1 expression is the probable cause of hypertrichosis in Ambras syndrome.

Animal Model

Fantauzzo et al. (2008) analyzed koala ('Koa') mice, which represent a mouse model of hypertrichosis and have a semidominant, radiation-induced chromosomal inversion near the mouse ortholog of Trps1, and found that the proximal breakpoint of the Koa inversion is located 791 kb upstream of the Trps1 gene. Quantitative RT-PCR, in situ hybridization, and immunofluorescence analysis revealed that Trps1 expression levels are reduced in Koa mutant mice at the sites of pathology for the phenotype, including muzzle and dorsal skin and cells surrounding the developing vibrissae follicles. Fantauzzo et al. (2008) determined that the Koa inversion created a new Sp1 binding site and translocated additional Sp1 binding sites within a highly conserved stretch spanning the proximal breakpoint, providing a potential mechanism for a position effect.