Alternative titles; symbols
SNOMEDCT: 254820002; ORPHA: 113;
Cytogenetic location: Xq26 Genomic coordinates (GRCh38): X:129,500,001-138,900,000
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| Xq26 | Bazex-Dupre-Christol syndrome | 301845 | X-linked dominant | 4 |
A number sign (#) is used with this entry because of evidence that Bazex-Dupre-Christol syndrome (BDCS) is caused by small duplications in an intergenic region on chromosome Xq26 harboring noncoding enhancer elements that drive overexpression of the ARHGAP36 gene (300937).
Bazex-Dupre-Christol syndrome (BDCS) is an X-linked dominant disorder characterized by a triad of congenital hypotrichosis, follicular atrophoderma affecting the dorsa of the hands and feet, the face, and extensor surfaces of the elbows or knees, and the development of basal cell neoplasms, including basal cell nevi and basal cell carcinomas from the second decade onward (Yung and Newton-Bishop, 2005).
Rombo syndrome (180730) has similar features, but shows autosomal dominant inheritance.
Bazex et al. (1964, 1966) reported a syndrome comprising hypotrichosis, follicular atrophoderma, and multiple basal cell neoplasms.
Parrish et al. (1972) reported a family of Italian origin in which 11 members spanning 3 generations had hypotrichosis with light-colored hair and facial milia. Examination of the hair showed markedly reduced density of scalp hair and decreased melanization of the hair shaft. Parrish et al. (1972) postulated a defect in the induction phase of hair development during fetal life. There was no male-to-male transmission, but 1 affected man had a normal daughter, arguing against X-linked dominant inheritance. However, Kidd et al. (1996) suspected that the family reported by Parrish et al. (1972) had a variant of Bazex-Dupre-Christol syndrome.
Viksnins and Berlin (1977) described a kindred in which 8 persons in 3 generations had the condition described by Bazex et al. (1964, 1966) in 6 members of a family. Affected persons had lesions suggesting 'multiple ice-pick marks' on the dorsum of the hands and elbows dating from early infancy and basal cell carcinomas that developed on the face between ages 15 and 26 years. Anhidrosis involving the entire face and head was present in 5 of the patients, and generalized hypohidrosis was reported by 3 of them. None of the patients exhibited hypotrichosis. The authors stated that 'follicular atrophoderma,' although a well-established term, was not appropriate because histologic studies did not show atrophy.
Gould and Barker (1978) described affected individuals in 4 generations of a British family. Prominent pitting of the skin on the face and back of the hands was noted, as well as hypotrichosis in 2 patients studied. Hairs had a twisted and flattened appearance on scanning electron microscopy. There was no instance of male-to-male transmission and the only affected male in the family had an unaffected son.
Yung and Newton-Bishop (2005) reported follow-up of the family reported by Gould and Barker (1978). There was a total of 11 affected members spanning 6 generations. The patient was a 3-year-old girl who was the granddaughter of the original proband reported by Gould and Barker (1978). She presented at age 2 years with multiple brown asymptomatic papules over the genital area and medial aspect of the thighs. She had hypotricha since birth, and prominent facial milia and follicular atrophoderma of the cheeks consistent with Bazex-Dupre-Christol syndrome. Skin biopsy from the genital region of the patient showed multiple benign trichoepitheliomas, which arise from cells derived from the hair follicle. The patient's mother had facial milia, follicular atrophoderma of the cheeks and dorsa of the hands, hypotricha since birth, hypohidrosis, and axillary hidradenitis suppurativa. The patient's newborn brother also had features of the syndrome. Yung and Newton-Bishop (2005) noted that trichoepitheliomas and hidradenitis suppurativa had not previously been described in Bazex syndrome.
Oley et al. (1992) reported an Australian family of Italian origin in which 9 individuals in 4 generations and 6 sibships had basal cell carcinomas, coarse and sparse scalp hair, sparse body hair, excessive sweating, and multiple milia on face and limbs during childhood. One 32-year-old patient with multiple milia over her face had markedly increased pigmentation of the face, particularly around the eyes. Beginning at the age of 22, she had about 20 basal cell carcinomas removed. Since there was no instance of male-to-male transmission, the pedigree was consistent with either autosomal dominant or X-linked dominant transmission. All 3 daughters of 2 males who had children were affected. Vabres and de Prost (1993) concluded that the family reported by Oley et al. (1992) had Bazex syndrome. They noted that the presence or absence of follicular atrophoderma was not mentioned by Oley et al. (1992) but pointed out that 'this manifestation may be undiagnosed, even by experienced dermatologists, if not carefully sought.'
Herges et al. (1993) reported a mother and 2 sons with BDCS, who were later found to have a small intergenic tandem duplication at chromosome Xq26 (Liu et al., 2022, F7). The mother and her 25-year-old son had a typical presentation, showing all major features of the syndrome, but her 26-year-old son exhibited only follicular atrophoderma and hypotrichosis.
Rapelanoro et al. (1994) reported a 30-month-old boy with coarse, sparse hair and multiple milia on the face, chest, axillae, and pubic region. A sister, aged 16 years, had apparently normal scalp, axillary, and pubic hair, but had had coarse and very sparse scalp hair and multiple milia on the face and limbs in childhood. Most of the milia disappeared at puberty; a few persisted on the forehead. The same manifestations were present in the mother from birth and disappeared at 40 years of age. There were no abnormalities of teeth and nails. Polarizing light microscopy showed an increased diameter of the hair shaft. Family history revealed that the condition affected at least 20 individuals, both males and females, spanning 4 generations. There was no transmission from an unaffected parent, and no male-to-male transmission was observed, consistent with either autosomal or X-linked dominant inheritance.
Lacombe and Taieb (1995) examined 17 members of the family reported by Rapelanoro et al. (1994) and affirmed striking intrafamilial phenotypic variability consistent with Bazex syndrome. In 3 of 8 patients, follicular atrophoderma on the back of the hand was found in addition to hypertrichosis and milia, and 2 patients had been treated for basal cell carcinoma. They concluded that the same family had been reported by Le Coulant et al. (1967). Doubts had been raised at that time concerning the X-linked mode of inheritance of Bazex syndrome because of an instance of male-to-male transmission in the pedigree, but Lacombe and Taieb (1995) found that the suspected affected male was in fact unaffected, thus confirming X-linked dominant inheritance.
Vabres et al. (1995) studied 17 affected and 18 unaffected members of 3 families with BDCS, noting that 4 diagnostic criteria (follicular atrophoderma, hypotrichosis, milia, and basal cell carcinomas) were fulfilled in all 3 families, although no single feature was present in every affected family member. Hypotrichosis and milia were usually present during infancy and childhood, but often improved with age. The authors stated that family 1, with an affected mother, 4 sons, and a granddaughter, was the French family originally reported by Bazex et al. (1966). Family 2 was a large 4-generation French family with 8 affected females and 3 affected males, which had been previously reported by Le Coulant et al. (1967) and Rapelanoro et al. (1994). Family 3 was an Irish American family with an affected mother, son, and daughter; Vabres et al. (1995) stated that some members of the family had previously been described by Viksnins and Berlin (1977).
Kidd et al. (1996) described typical manifestations of Bazex syndrome in 5 members over 3 generations of a Scottish family that was later found to have a small intergenic tandem duplication at chromosome Xq26 (Liu et al., 2022, F1). Kidd et al. (1996) also reviewed 15 previously reported families with approximately 120 affected persons. All of the families had at least 1 affected individual who exhibited follicular atrophoderma, and almost all had at least 1 patient with hypotrichosis and/or milia. Basal cell carcinoma had been diagnosed in three-quarters of the families, and in almost two-thirds at least 1 affected individual experienced hypohidrosis. The authors observed a 'pinched' nose with hypoplastic alae and prominent columella in all 4 Scottish patients examined, and review of published photos of 9 cases showed that 6 of them had similar noses, suggesting that this might be another characteristic manifestation of the disorder.
Inoue et al. (1998) reviewed reports of a total of 125 patients with Bazex syndrome in 20 pedigrees. The disorder was primarily reported in France, and all of the patients were Caucasians. Hypotrichosis and follicular atrophoderma were the most commonly reported features, present in 84% and 83% of the patients, respectively; milia were reported in 76%, hypohidrosis in 54%, and nevoid basal cell carcinoma in 41%.
Torrelo et al. (2006) reported a 2-month-old boy with congenital hypotrichosis and generalized milia, who was later found to have a small intergenic tandem duplication at chromosome Xq26 (Liu et al., 2022, F5). Examination revealed very sparse scalp hair, and eyebrows and body hair were absent. White milia-like papules were present over the entire body, but were more profuse over his head and face. He did not have dysmorphic features, and he sweated normally. Histopathologic analysis of a papule revealed a small epidermal cyst in the upper dermis, with clustered nests of basaloid cells surrounded by a loose peritumoral stroma. Microscopic examination of scalp hairs showed twisted hair shafts with dystrophic cuticles.
Castori et al. (2009) studied an Italian mother and son with BDCS. The 5-year-old boy presented with sparse hair, reduced sweating, ice-pick depressions on the backs of the hands, facial and limb milia, perianal skin hyperpigmentation, and hyperpigmented papules of the axillae and neck. His 30-year-old mother showed similar features but lacked hair involvement; however, she reported total atrichia at birth, with hair appearing in late infancy. Microscopic examination of an axillary hyperpigmented papule from the boy revealed a superficial neoplasm consistent with trichoepithelioma; the authors stated that trichoepitheliomas might be an early sign of BDCS, before the development of basal cell carcinomas. In addition, the authors suggested that given the high frequency of congenital hypotrichosis, hypohidrosis, and dry skin, BDCS could be classified as an ectodermal dysplasia.
Parren et al. (2011) reported a large 6-generation German family with BDCS that was later found to harbor a small intergenic tandem duplication at chromosome Xq26 that segregated with disease (Liu et al., 2022, F1). Nine living affected members over 4 generations were examined. Intrafamilial phenotypic variability was apparent, including a 5-year-old girl who had experienced multiple progressive basal cell carcinomas (BCCs), whereas her affected mother had only manifested a few BCCs, beginning in the third decade of life.
Viksnins and Berlin (1977) suggested X-linked dominant inheritance in Bazex syndrome because no male-to-male transmission had been reported. In their family, all 3 daughters of an affected male, but none of his sons, were affected.
Vabres and de Prost (1993) noted that Pierard et al. (1971) and Gould and Barker (1978) favored X-linked dominant inheritance, and stated that the pedigree pattern described by Oley et al. (1992) was consistent with X-linked dominant inheritance.
The report of Rapelanoro et al. (1994), with follow-up by Lacombe and Taieb (1995), also indicated that Bazex syndrome shows X-linked dominant inheritance.
Using microsatellite markers of the X chromosome in 3 families with Bazex syndrome, including the French family originally reported by Bazex et al. (1964) (family 1), the French family studied by Le Coulant et al. (1967), Rapelanoro et al. (1994), and Lacombe and Taieb (1995) (family 2), and an Irish American family previously described by Viksnins and Berlin (1977) (family 3), Vabres et al. (1995) found evidence for X-linkage and regional assignment to chromosome Xq24-q27. The maximum lod score was 5.26 at theta = 0 with the DXS1192 locus.
In 8 families with BDCS, including 5 previously reported families (Parren et al., 2011, F1; Kidd et al., 1996, F4; Torrelo et al., 2006, F5; Herges et al., 1993, F7; and Bal et al., 2017, F8), Liu et al. (2022) identified small overlapping intergenic noncoding tandem duplications at chromosome Xq26.1, flanked by the ARHGAP36 (300937) and IGSF1 (300137) genes. Whole-exome and -genome sequencing in families F1, F2, and F3 excluded putative disease-causing variants within the Xq26.1 locus previously linked to BDCS; however, aCGH in families F1, F2, F3, and F7 revealed small intergenic gains of varying sizes at Xq26.1, and qPCR in the 4 other families (F4, F5, F6, and F8) was also consistent with gains at this locus. The smallest shared overlapping region was an 18-kb gain (chrX: 131,207,776-131,226,336; GRCh38). Chromosome conformation analysis (Hi-C) showed that the duplications did not affect the topologically associated domain (TAD), but Liu et al. (2022) found potential enhancers within the minimum duplicated region. The duplications segregated with disease in 6 families and were shown to have arisen de novo in 2 patients; no gains were identified in 215 unrelated European controls. Immunofluorescence showed that IGSF1 was absent from the actively proliferating hair matrix, but ARHGAP36 was present in both anagen and telogen. In addition, there was a marked increase in ARHGAP36-positive cells around the epithelial stem cell compartment in a patient telogen hair follicle, and a trichoepithelioma and basal cell carcinoma from a BDCS patient also showed strong ARHGAP36 staining. Liu et al. (2022) concluded that noncoding Xq26.1 duplications cause BDCS, most likely through dysregulation of ARHGAP36.
In 6 families with BDCS mapping to Xq25-q26.2, including 3 families (A, B, and C) previously reported by Vabres et al. (1995), Bal et al. (2017) identified variation in and around the ACTRT1 gene (300487) that segregated with disease: in families C and D, it was a 1-bp insertion within the gene, whereas in the remaining families, noncoding variants were found, designated 'A2' in family A, 'B2' in family B, and 'CNE12' in families E and F. However, Liu et al. (2022) modeled maximum tolerated allele counts for the 1-bp duplication and found that the observed minor allele frequency in population control data was approximately 10,000 times higher than expected. In addition, other putative loss-of-function variants had been reported in ACTRT1 in both male and female individuals without BDCS, and in 7 of 8 BDCS families studied by Liu et al. (2022), no rare coding variants in ACTRT1 were identified; the remaining family (F8) was family D of Bal et al. (2017), in which the 1-bp insertion was found, as expected. Although Bal et al. (2017) reported expression of ARPT1 in epidermal layers and skin appendages involved in BDCS, immunofluorescence staining by Liu et al. (2022) showed that ACTRT1 was absent from the disease-relevant portions of control hair follicles (stem cell bulge region); and both authors found absence of ACTRT1 or ARPT1 in basal cell carcinoma tissue from BDCS patients. Liu et al. (2022) concluded that ACTRT1 loss-of-function variants were unlikely to cause BDCS.
Exclusion Studies
In a 2-month-old boy with congenital hypotrichosis and generalized milia (see papular atrichia, 209500), Torrelo et al. (2006) sequenced the candidate gene HR (602302) but did not find any pathogenic mutations.
In a large 6-generation German family with BDCS mapping to an 11.4-Mb interval on chromosome Xq25-27.1, Parren et al. (2011) screened the coding regions and adjacent splice sites of 12 candidate genes, including ACTRT1, but did not find any pathogenic mutations.
Bal, E., Park, H.-S., Belaid-Choucair, Z., Kayserili, H., Naville, M., Madrange, M., Chiticariu, E., Hadj-Rabia, S., Cagnard, N., Kuonen, F., Bachmann, D., Huber, M., and 25 others. Mutations in ACTRT1 and its enhancer RNA elements lead to aberrant activation of Hedgehog signaling in inherited and sporadic basal cell carcinomas. Nature Med. 23: 1226-1233, 2017. [PubMed: 28869610] [Full Text: https://doi.org/10.1038/nm.4368]
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Bazex, A., Dupre, A., Christol, B. Atrophodermic folliculaire, proliferations baso-cellulaires et hypotrichose. Ann. Derm. Syph. 93: 241-254, 1966. [PubMed: 5963641]
Castori, M., Castiglia, D., Passarelli, F., Paradisi, M. Bazex-Dupre-Christol syndrome: an ectodermal dysplasia with skin appendage neoplasms. Europ. J. Med. Genet. 52: 250-255, 2009. [PubMed: 19138767] [Full Text: https://doi.org/10.1016/j.ejmg.2008.12.003]
Goldsmith, L. A., Baden, H. P. The analysis of genetically determined hair defects. Birth Defects Orig. Art. Ser. VII(2): 86-90, 1971. [PubMed: 5173316]
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Liu, Y., Banka, S., Huang, Y., Hardman-Smart, J., Pye, D., Torrelo, A., Beaman, G. M., Kazanietz, M. G., Baker, M. J., Ferrazzano, C., Shi, C., Orozco, G., and 20 others. Germline intergenic duplications at Xq26.1 underlie Bazex-Dupre-Christol basal cell carcinoma susceptibility syndrome. Brit. J. Derm. 187: 948-961, 2022. [PubMed: 35986704] [Full Text: https://doi.org/10.1111/bjd.21842]
Oley, C. A., Sharpe, H., Chenevix-Trench, G. Basal cell carcinomas, coarse sparse hair, and milia. Am. J. Med. Genet. 43: 799-804, 1992. [PubMed: 1642265] [Full Text: https://doi.org/10.1002/ajmg.1320430509]
Parren, L. J. M. T., Abuzahra, F., Wagenvoort, T., Koene, F., Van Steensel, M. A. M., Steijlen, P. M., Van Geel, M., Frank, J. Linkage refinement of Bazex-Dupre-Christol syndrome to an 11.4-Mb interval on chromosome Xq25-27.1. Brit. J. Derm. 165: 201-203, 2011. [PubMed: 21219295] [Full Text: https://doi.org/10.1111/j.1365-2133.2011.10219.x]
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Pierard, J., Dhondt, F., Geerts, M. L., Kriekemans, J. Atrophodermie folliculaire, proliferations baso-cellulaires et hypotrichose. Arch. Belg. Derm. Syph. 27: 55-68, 1971. [PubMed: 5126848]
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Torrelo, A., Sprecher, E., Mediero, I. G., Bergman, R., Zambrano, A. What syndrome is this? Pediat. Derm. 23: 286-290, 2006. [PubMed: 16780482] [Full Text: https://doi.org/10.1111/j.1525-1470.2006.00237.x]
Vabres, P., de Prost, Y. Bazex-Dupre-Christol syndrome: a possible diagnosis for basal cell carcinomas, coarse sparse hair, and milia. (Letter) Am. J. Med. Genet. 45: 786 only, 1993. [PubMed: 8456866] [Full Text: https://doi.org/10.1002/ajmg.1320450628]
Vabres, P., Lacombe, D., Rabinowitz, L. G., Aubert, G., Anderson, C. E., Taieb, A., Bonafe, J.-L., Hors-Cayla, M.-C. The gene for Bazex-Dupre-Christol syndrome maps to chromosome Xq. J. Invest. Derm. 105: 87-91, 1995. [PubMed: 7615983] [Full Text: https://doi.org/10.1111/1523-1747.ep12313359]
Viksnins, P., Berlin, A. Follicular atrophoderma and basal cell carcinomas: the Bazex syndrome. Arch. Derm. 113: 948-951, 1977. [PubMed: 879818]
Yung, A., Newton-Bishop, J. A. A case of Bazex-Dupre-Christol syndrome associated with multiple genital trichoepitheliomas. (Letter) Brit. J. Derm. 153: 682-684, 2005. [PubMed: 16120174] [Full Text: https://doi.org/10.1111/j.1365-2133.2005.06819.x]