Alternative titles; symbols
SNOMEDCT: 1010628009; ORPHA: 2222, 79495;
Cytogenetic location: Xq27.1 Genomic coordinates (GRCh38): X:138,900,001-141,200,000
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| Xq27.1 | Hypertrichosis, congenital generalized | 307150 | X-linked dominant | 4 |
A number sign (#) is used with this entry because of evidence that syndromic or nonsyndromic congenital generalized hypertrichosis can be caused by palindrome-mediated interchromosomal insertion at chromosome Xq27.1.
For a general phenotypic description and discussion of genetic heterogeneity of congenital generalized hypertrichosis, see HTC1 (145701).
Macias-Flores et al. (1984) reported a Mexican family with an X-linked dominant form of congenital generalized hypertrichosis. Males were more severely affected than females. Affected females showed asymmetric, somewhat patchy hirsutism consistent with lyonization. Affected persons were observed in 5 generations. The only affected father in this pedigree passed the mutant gene to all 4 daughters but none of his 9 sons. See 145700 and 145701 for the autosomal dominant forms; 135400 for hypertrichosis associated with gingival fibromatosis; and 239850 for an autosomal recessive form of hypertrichosis with skeletal dysplasia. Figuera and Cantu (1994) indicated that the family had grown since the initial report in 1984 and that the pattern of inheritance continued to be in complete concordance with X-linked dominance.
Tadin-Strapps et al. (2003) described a Mexican kindred with X-linked recessive inheritance of a syndrome in which affected males exhibited generalized hypertrichosis, dental anomalies, and deafness, whereas carrier females exhibited only mild hypertrichosis. Dental anomalies became evident around the age of 4 years. These primarily affected the shape of the teeth, which appeared misshapen and mispositioned. Tooth eruption was not delayed and there were no missing teeth. Notably, gingival fibromatosis seen in other forms of hypertrichosis was not present in the affected individuals.
Zhu et al. (2011) ascertained a 5-generation Chinese family in which affected males had severe congenital generalized hypertrichosis associated with scoliosis, whereas all affected females had only mild hypertrichosis, consistent with X-linked inheritance. The proband was a 41-year-old man who also had spina bifida presenting as cervical and sacral meningoceles; none of the other 10 affected individuals had spina bifida.
By linkage studies, Figuera et al. (1995) demonstrated that the X-linked gene in the kindred reported by Macias-Flores et al. (1984) lies within a 22-cM interval between DXS425 and DXS1227 in Xq24-q27.1. They symbolized the gene as CGH. Hall (1995) pointed out that atavisms--the reappearance of ancestral characteristics in individual members of a species--serve to remind us that the genetic and developmental information originally used in the production of such characteristics has not been lost during evolution but lies quiescent within the genome and in the processes of embryonic development. Perhaps the best known examples of atavisms in natural populations are hind limbs in whales and extra toes in horses. Some atavisms, as in the classic example of polydactyly in guinea pigs studied by Castle (1906) and Wright (1934), were brought out by selective breeding, which indicated the polygenic basis of the trait. Experimental manipulations, such as grafting embryonic tissues between embryos of different species and the production of transgenic animals, can also reveal atavisms.
Tadin-Strapps et al. (2003) performed haplotype analysis in a Mexican kindred segregating X-linked recessive generalized hypertrichosis, dental anomalies, and deafness, and found linkage to a 13-cM region on chromosome Xq24-q27.1, the same region as that involved in the family reported by Macias-Flores et al. (1984). The possibility of a relationship between the 2 families was entertained but not established or excluded. In the family reported by Macias-Flores et al. (1984), the authors specifically stated that the teeth were normal and hearing loss, if present, would probably not have been overlooked. One possible explanation for the phenotypic variation is that the differences are due to other genetic factors, such as a modifier gene. Another possibility is that there is a hypertrichosis gene in this region of the X chromosome and that a contiguous microdeletion including a second gene is responsible for the additional phenotypic traits in the family reported by Tadin-Strapps et al. (2003). Finally, one cannot exclude the possibility that the different phenotypes in these families resulted from different mutations in the same gene, which could even behave as a recessive, rather than dominant, trait.
In a 5-generation Chinese family with congenital generalized hypertrichosis and scoliosis, Zhu et al. (2011) analyzed 14 polymorphic microsatellite markers from the Xq26.3-q27.3 region and obtained a maximum 2-point lod score of 3.91 (theta = 0.0) for 5 markers, confirming genetic linkage to the same locus as reported previously in the Mexican family studied by Figuera et al. (1995). Recombination events in the Chinese family defined a 5.6-Mb critical interval between markers ZLS3 and ZLS10.
In 4 affected individuals, 2 male and 2 female, from a 5-generation Chinese family with congenital generalized hypertrichosis (CGH) and scoliosis mapping to chromosome Xq26.3-q27.2, Zhu et al. (2011) performed a genomewide high-resolution copy number variation (CNV) scan, followed by genomic sequence sequencing, and identified a direct insertion of a 125,577-bp fragment from within COL23A1 (610043) on chromosome 5q35 into the mutant X chromosome, i.e., der(X)dir ins(X;5)(q27.1;q35.3). The X breakpoints were within and very close to a human-specific short 180-bp palindromic sequence located 82 kb downstream of the SOX3 gene (313430). The insertion was shown to occur concomitantly with a deletion of 1,263 bp between the breakpoints at Xq27.1. Subsequently, in all affected members of the Mexican family with hypertrichosis originally reported by Macias-Flores et al. (1984), Zhu et al. (2011) identified an inverted insertion of a 300,036-bp fragment, encompassing the PRMT10 and TMEM184C (613937) genes and involving parts of ARHGAP10 (609746) and EDNRA (131243) on chromosome 4q31, into the mutant X chromosome, i.e., der(x)inv ins(X;4)(q27.1;q31.23q31.22). The X breakpoints in the Mexican family were at the center of the 180-bp palindromic sequence (chrX: 139,502,951 and 139,502,958, respectively). Xq27.1 insertions were not detected in 215 Chinese, 118 Mexican, and 407 Asian Indian male controls; however, 9 controls did have deletions at Xq27.1, ranging from 173 bp to 9,104 bp, all of which had 1 breakpoint in the center of the palindrome. Zhu et al. (2011) suggested that the palindrome-mediated insertions might have introduced tissue-specific regulatory elements that induce ectopic expression of SOX3 in hair follicles or precursor cells, causing aberrant patterning of hair resulting in hypertrichosis. They postulated that the inserted fragment in the Chinese family might contain additional regulatory elements leading to additional malformations, including scoliosis.
In the large 3-generation Mexican kindred with generalized hypertrichosis, dental anomalies, and deafness, originally reported by Tadin-Strapps et al. (2003), DeStefano et al. (2013) identified a 389-kb interchromosomal insertion in an extragenic palindrome site at Xq27.1 that completely segregated with disease in the family. Whole-genome sequencing revealed that the insertion consisted of a 386-kb duplication of chromosome 6p21.2 and 56 bp of chromosome 3q21.1 in the reverse orientation, separated by 14 bp of unknown origin. Noting that the insertion event in this family and in 2 previously reported families with X-linked CGH (Zhu et al., 2011) all occurred at the same human-specific extragenic palindrome sequence at Xq27.1, DeStefano et al. (2013) suggested that the presence of the insertion rather than its content might be responsible for the excessive hair overgrowth phenotype by disruption of the chromosomal architecture in the region. Analysis of the expression of neighboring genes by quantitative RT-PCR revealed that FGF13 (300070) levels were reduced by approximately 4-fold in patient skin compared to controls, with a clear dosage effect when compared to carriers, whereas mRNA levels of additional neighboring genes were not significantly changed. In patient hair follicles, FGF13 was reduced 18-fold, and RNA sequencing of patient skin confirmed an 8-fold reduction in FGF13 expression. Immunofluorescence of hair follicles showed a decrease in intensity of expression and number of FGF13-positive cells throughout the outer root sheath of affected anagen follicles compared to controls and carriers. In addition, there was a 6.7-fold decrease in FGF13 expression in affected keratinocytes but not fibroblasts, localizing the defect to the keratinocyte compartment. DeStefano et al. (2013) concluded that the insertion has a position effect on FGF13 that alters its spatiotemporal expression in the hair follicle, and suggested that altered FGF13 expression influences important downstream signaling pathways, resulting in the terminal hair overgrowth phenotype of X-linked hypertrichosis.
Castle, W. E. The origin of a polydactylous race of guinea-pigs. Publ. Carnegie Inst. Wash. 49: 17-29, 1906.
DeStefano, G. M., Fantauzzo, K. A., Petukhova, L., Kurban, M., Tadin-Strapps, M., Levy, B., Warburton, D., Cirulli, E. T., Han, Y., Sun, X., Shen, Y., Shirazi, M., Jobanputra, V., Cepeda-Valdes, R., Salas-Alanis, J. C., Christiano, A. M. Position effect on FGF13 associated with X-linked congenital generalized hypertrichosis. Proc. Nat. Acad. Sci. 110: 7790-7795, 2013. [PubMed: 23603273] [Full Text: https://doi.org/10.1073/pnas.1216412110]
Figuera, L. E., Cantu, J. M. Ambral (sic) syndrome and congenital generalized hypertrichosis. (Letter) Clin. Genet. 46: 384 only, 1994. [PubMed: 7889653] [Full Text: https://doi.org/10.1111/j.1399-0004.1994.tb04186.x]
Figuera, L. E., Pandolfo, M., Dunne, P. W., Cantu, J. M., Patel, P. I. Mapping of the congenital generalized hypertrichosis locus to chromosome Xq24-q27.1. Nature Genet. 10: 202-207, 1995. [PubMed: 7663516] [Full Text: https://doi.org/10.1038/ng0695-202]
Hall, B. K. Atavisms and atavistic mutations. Nature Genet. 10: 126-127, 1995. [PubMed: 7663504] [Full Text: https://doi.org/10.1038/ng0695-126]
Macias-Flores, M. A., Garcia-Cruz, D., Rivera, H., Escobar-Lujan, M., Melendrez-Vega, A., Rivas-Campos, D., Rodriguez-Collazo, F., Moreno-Arellano, I., Cantu, J. M. A new form of hypertrichosis inherited as an X-linked dominant trait. Hum. Genet. 66: 66-70, 1984. [PubMed: 6698556] [Full Text: https://doi.org/10.1007/BF00275189]
Tadin-Strapps, M., Salas-Alanis, J. C., Moreno, L., Warburton, D., Martinez-Mir, A., Christiano, A. M. Congenital universal hypertrichosis with deafness and dental anomalies inherited as an X-linked trait. Clin. Genet. 63: 418-422, 2003. [PubMed: 12752576] [Full Text: https://doi.org/10.1034/j.1399-0004.2003.00069.x]
Wright, S. The results of crosses between inbred strains of guinea pigs, differing in number of digits. Genetics 19: 537-551, 1934. [PubMed: 17246736] [Full Text: https://doi.org/10.1093/genetics/19.6.537]
Zhu, H., Shang, D., Sun, M., Choi, S., Liu, Q., Hao, J., Figuera, L. E., Zhang, F., Choy, K. W., Ao, Y., Liu, Y., Zhang, X.-L., Yue, F., Wang, M.-R., Jin, L., Patel, P. I., Jing, T., Zhang, X. X-linked congenital hypertrichosis syndrome is associated with interchromosomal insertions mediated by a human-specific palindrome near SOX3. Am. J. Hum. Genet. 88: 819-826, 2011. [PubMed: 21636067] [Full Text: https://doi.org/10.1016/j.ajhg.2011.05.004]