Alternative titles; symbols
ORPHA: 2340; DO: 0080754;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| Xp22.12 | Keratosis follicularis spinulosa decalvans, X-linked | 308800 | X-linked recessive | 3 | MBTPS2 | 300294 |
A number sign (#) is used with this entry because of evidence that X-linked keratosis follicularis spinulosa decalvans (KFSDX) is caused by mutation in the MBTPS2 gene (300294).
See also IFAP syndrome (308205), an allelic disorder with an overlapping phenotype.
Keratosis follicularis spinulosa decalvans is an uncommon genodermatosis chiefly characterized by widespread keratosis pilaris, progressive cicatricial alopecia of the scalp, eyebrows, and eyelashes, and an excess of affected males. Photophobia, blepharitis/conjunctivitis, and corneal dystrophy are characteristic ancillary findings. It is most often inherited as an X-linked trait (summary by Castori et al., 2009).
Autosomal dominant inheritance has also been reported (KFSD; 612843).
The term 'cum ophiasi' means 'with ophiasis,' i.e., baldness in 1 or more winding streaks about the head, which comes from the Greek for snake. Decalvans refers to the loss of hair.
Siemens (1925) described 2 families with X-linked inheritance of keratosis follicularis spinulosa decalvans. According to information from Oosterwijk (1992), 1 family was from Bavaria and the other from the Netherlands. Siemens personally investigated 2 members of the Dutch family on the invitation of Lameris, who had reported the cases as ichthyosis follicularis. Two weeks after his visit to Lameris, Siemens encountered the index cases of the Bavarian family. The ophthalmologic features of the Lameris family were reported by Rochat (1906). The family studied by Sendi (1957) was described also by Franceschetti et al. (1956, 1957). The Lameris kindred was studied further by Jonkers (1950) and the pedigree was reproduced by Waardenburg et al. (1961). A further follow-up on the classic family of Siemens (1926) was provided by van Osch et al. (1992). They commented on the finding of high cuticles on the fingernails. Carriers often had dry skin, minimal follicular hyperkeratosis, and mild hyperkeratosis of the calcaneal areas of the soles. Mild corneal dystrophy without photophobia was found in a female carrier.
Herd and Benton (1996) reported the first family with KFSD in the U.K. The proband was a 38-year-old Caucasian man who in infancy suffered from photophobia, recurrent blepharitis and conjunctivitis resulting in deformed eyelashes, entropion, and corneal scarring. He also had abnormal eyebrows. He developed progressive myopia from the age of 9 years, punctate keratitis when age 10, and at the age of 20 a retinal detachment. He came to dermatologic attention because of progressive scalp hair loss at age 26. Examination showed follicular hyperkeratosis and folliculitis of the scalp, resulting in scarring alopecia, and extensive follicular keratotic spinules on the trunk. A first cousin once removed related to the proband through female relatives had been seen at the age of 2 years with flexural eczema. She had at that time sparse scalp hair and eyebrows, with keratosis pilaris on the outer aspect of her upper arms and cheeks. At the age of 3, she developed photophobia but no ophthalmologic abnormality was found. Nonetheless, the development of marked photophobia, widespread follicular hyperkeratosis, and calcaneal hyperkeratosis suggested KFSD. The rest of the pedigree was investigated. The second patient was the only female in the family who was severely affected. Treatment with retinoids led to remission of the inflammation and cessation of the spreading alopecia.
Clinical Variability
Lacarrubba et al. (2007) described an Italian mother and son in whom KFSD was associated with woolly hair. Both had centroparietal alopecia, revealing a smooth and sclerotic scalp, surrounded by curly, thick, heavily pigmented, and unmanageable hair. Alopecia developed at age 23 years in the mother and age 9 years in the son, and the boy also had absent eyelashes. Both patients had diffuse follicular hyperkeratosis, as well as toenail thickening and deflection. The boy also exhibited dental anomalies, including agenesis, inclusions, and malformed (conical) teeth. Neither patient experienced photophobia. The authors stated that this was the first report of woolly hair or dental anomalies in association with KFSD.
The transmission pattern of KFSDX in the families reported by Aten et al. (2010) was consistent with X-linked recessive inheritance.
Oosterwijk et al. (1991, 1992) mapped the KFSD locus to Xp22.2-p21.2 by linkage to RFLP markers. The highest lod score was 5.70 with DXS41 at theta = 0.0. Oosterwijk et al. (1995) studied the same extended Dutch family in which the KFSD locus was mapped to Xp22.2-p21.2 using 5 DNA probes and 14 CA repeat polymorphisms spanning this region. Analysis of recombination events located the gene to the region Xp22.2-p22.13, an area covering approximately 1 Mb.
By analyzing several new markers in the Xp22.2-p22.13 region, Oosterwijk et al. (1997) confirmed the candidate region in a 1-Mb interval in the large Dutch pedigree. In a German family with KFSD, they analyzed 23 markers in Xp22.2-p21.2 and found that the KFSD locus in this family was most likely outside the candidate region. They concluded that in this pedigree there is either another locus on the X chromosome or KFSD is transmitted as an autosomal dominant with variable expression.
In the family reported by Herd and Benton (1996), Porteous et al. (1998) demonstrated linkage to the region Xp22.2-p22.13 but were unable to narrow the region described by Oosterwijk et al. (1997).
Gimelli et al. (2002) reported the molecular characterization of an Xp22.12-p21.1 duplication present in a patient with dosage-sensitive sex reversal (DSS; 300018), caused by duplication of the DAX1 gene (300473), who also had KFSD. The duplicated region included both the DAX1 gene and the KFSD interval, in which the SAT1 gene (313020) is located. The SAT1 gene encodes spermidine/spermine N(1)-acetyltransferase, which catalyzes the N(1)-acetylation of spermidine and spermine and, by the successive activity of polyamine oxidase, the spermine can be converted to spermidine and the spermidine to putrescine. Pietila et al. (1997, 2001) found that overexpression of the SAT enzyme in a mouse model resulted in putrescine accumulation and a phenotype with skin and hair abnormalities reminiscent of human KFSD. By analysis of polyamine metabolism in the cells of their patient, Gimelli et al. (2002) found that, as in the mouse model, the levels of metabolites such as putrescine, spermidine, and spermine were consistent with overexpression of the SAT1 gene. They proposed that overexpression of SAT1 and the consequent putrescine accumulation are involved in the KFSD phenotype. However, Aten et al. (2010) stated that the SAT1 gene is not included in the KFSD interval identified by Oosterwijk et al. (1997).
In affected members of the large Dutch family with KFSDX originally reported by Siemens (1926) and followed-up by van Osch et al. (1992), Aten et al. (2010) identified a mutation in the MBTPS2 gene (N508S; 300294.0006). The same mutation was found in an affected family from the U.K. (Herd and Benton, 1996) and in another family from the U.S., although haplotype analysis did not suggest a common ancestor. In vitro functional expression studies in CHO-M19 cells showed that the mutation decreased sterol responsiveness by 50%, indicating loss of proteolytic activity of the MBTPS2 protein. In obligate female carriers, imbalances in allelic expression perfectly matched with skewed levels of X inactivation and with the clinical phenotype. The findings suggested that KFSDX and IFAP syndrome are related along a similar disease spectrum.
Eicher (1974) speculated that the homologous mutation in the mouse may be 'sparse fur' (spf). However, this mouse mutation was later shown to have deficiency of ornithine transcarbamylase (see 311250).
Aten, E., Brasz, L. C., Bornholdt, D., Hooijkaas, I. B., Porteous, M. E., Sybert, V. P., Vermeer, M. H., Vossen, R. H. A. M., van der Wielen, M. J. R., Bakker, E., Breuning, M. H., Grzeschik, K.-H., Oosterwijk, J. C., den Dunnen, J. T. Keratosis follicularis spinulosa decalvans is caused by mutations in MBTPS2. Hum. Mutat. 31: 1125-1133, 2010. [PubMed: 20672378] [Full Text: https://doi.org/10.1002/humu.21335]
Castori, M., Covaciu, C., Paradisi, M., Zambruno, G. Clinical and genetic heterogeneity in keratosis follicularis spinulosa decalvans. Europ. J. Med. Genet. 52: 53-58, 2009. [PubMed: 18984066] [Full Text: https://doi.org/10.1016/j.ejmg.2008.09.005]
Eicher, E. M. Personal Communication. Bar Harbor, Me. 1974.
Franceschetti, A., Jaccottet, M., Jadassohn, W. Manifestations corneennes dans la keratosis follicularis spinulosa decalvans (Siemens). Ophthalmologica 133: 259-263, 1957. [PubMed: 13441248] [Full Text: https://doi.org/10.1159/000303108]
Franceschetti, A., Rossano, R., Jadassohn, W., Paillard, R. Keratosis follicularis spinulosa decalvans (Siemens). Dermatologica 112: 512-514, 1956. [PubMed: 13343918]
Gimelli, G., Giglio, S., Zuffardi, O., Alhonen, L., Suppola, S., Cusano, R., Lo Nigro, C., Gatti, R., Ravazzolo, R., Seri, M. Gene dosage of the spermidine/spermine N(1)-acetyltransferase (SSAT) gene with putrescine accumulation in a patient with a Xp21.1p22.12 duplication and keratosis follicularis spinulosa decalvans (KFSD). Hum. Genet. 111: 235-241, 2002. [PubMed: 12215835] [Full Text: https://doi.org/10.1007/s00439-002-0791-6]
Herd, R. M., Benton, E. C. Keratosis follicularis spinulosa decalvans: report of a new pedigree. Brit. J. Derm. 134: 138-142, 1996. [PubMed: 8745901]
Jonkers, G. H. Hyperkeratosis follicularis and cornea degeneration. Ophthalmologica 120: 365-367, 1950. [PubMed: 14807385] [Full Text: https://doi.org/10.1159/000300909]
Knops, H. J. Siemens' syndrome I (keratosis follicularis spinulosa decalvans). (Abstract) Brit. J. Derm. 100: 611, 1979.
Lacarrubba, F., Dall'Oglio, F., Rossi, A., Schwartz, R. A., Micali, G. Familial keratosis follicularis spinulosa decalvans associated with woolly hair. Int. J. Derm. 46: 840-843, 2007. [PubMed: 17651168] [Full Text: https://doi.org/10.1111/j.1365-4632.2007.03162.x]
Lameris, H. J. Ichthyosis follicularia. Ned. Tijdschr. Geneeskd. 2: 1524, 1905.
Oosterwijk, J. C., Nelen, M., van Zandvoort, P. M., van Osch, L. D. M., Oranje, A. P., Wittebol-Post, D., van Oost, B. A. Confirmation of X-linked inheritance and provisional mapping of the keratosis follicularis spinulosa decalvans gene on Xp in a large Dutch family. Ophthalmic Paediat. Genet. 13: 27-30, 1992. [PubMed: 1350668] [Full Text: https://doi.org/10.3109/13816819209070050]
Oosterwijk, J. C., Nelen, M., van Zandvoort, P. M., van Osch, L. D. M., Oranje, A. P., Wittebol-Post, D., van Oost, B. A. Linkage analysis of keratosis follicularis spinulosa decalvans, and regional assignment to human chromosome Xp21.2-p22.2. Am. J. Hum. Genet. 50: 801-807, 1992. [PubMed: 1550124]
Oosterwijk, J. C., Richard, G., van der Wielen, M. J. R., van de Vosse, E., Harth, W., Sandkuijl, L. A., Bakker, E., van Ommen, G.-J. B. Molecular genetic analysis of two families with keratosis follicularis spinulosa decalvans: refinement of gene localization and evidence for genetic heterogeneity. Hum. Genet. 100: 520-524, 1997. [PubMed: 9341865] [Full Text: https://doi.org/10.1007/s004390050546]
Oosterwijk, J. C., van der Wielen, M. J. R., van de Vosse, E., Voorhoeve, E., Bakker, E. Refinement of the localisation of the X linked keratosis follicularis spinulosa decalvans (KFSD) gene in Xp22.13-p22.2. J. Med. Genet. 32: 736-739, 1995. [PubMed: 8544196] [Full Text: https://doi.org/10.1136/jmg.32.9.736]
Oosterwijk, J. C., van Zandvoort, P., Nelen, M., van Oost, B. Linkage analysis and regional assignment of keratosis follicularis spinulosa decalvans to Xp22.2-p21.2. (Abstract) Cytogenet. Cell Genet. 58: 2078, 1991. Note: Also Am. J. Hum. Genet. 49 (suppl.): 353, 1991.
Oosterwijk, J. C. Personal Communication. Leiden, The Netherlands 7/2/1992.
Pietila, M., Alhonen, L., Halmekyto, M., Kanter, P., Janne, J., Porter, C. W. Activation of polyamine catabolism profoundly alters tissue polyamine pools and affects hair growth and female fertility in transgenic mice overexpressing spermidine/spermine N(1)-acetyltransferase. J. Biol. Chem. 272: 18746-18751, 1997. [PubMed: 9228047] [Full Text: https://doi.org/10.1074/jbc.272.30.18746]
Pietila, M., Parkkinen, J. J., Alhonen, L., Janne, J. Relation of skin polyamines to the hairless phenotype in transgenic mice overexpressing spermidine/spermine N(1)-acetyltransferase. J. Invest. Derm. 116: 801-805, 2001. [PubMed: 11348473] [Full Text: https://doi.org/10.1046/j.1523-1747.2001.01330.x]
Porteous, M. E. M., Strain, L., Logie, L. J., Herd, R. M., Benton, E. C. Keratosis follicularis spinulosa decalvans: confirmation of linkage to Xp22.13-p22.2. J. Med. Genet. 35: 336-337, 1998. [PubMed: 9598732] [Full Text: https://doi.org/10.1136/jmg.35.4.336]
Rochat, G. F. Familiaire cornea degeneratie. Ned. Tijdschr. Geneeskd. 42: 515-518, 1906.
Sendi, H. Quelques cas de keratosis follicularis spinulosa decalvans (Siemens). Thesis: Geneva (pub.) 1957.
Siemens, (NI). Keratosis follicularis spinulosa decalvans. Arch. Derm. Syph. 151: 384-386, 1926.
Siemens, H. W. Ueber einen in der menschlichen Pathologie noch nicht beobachteten Vererbungsmodus: dominant geschlechtsgebundene Vererbung. Arch. Rass. Ges. Biol. 17: 47-61, 1925.
Thelen, J. Arzt auf vorgeschobenem posten (ein Fall aus der Praxis des Landarztes). Muench. Med. Wschr. 87: 594, 1940.
van Osch, L. D. M., Oranje, A. P., Keukens, F. M., van Voorst Vader, P. C., Veldman, E. Keratosis follicularis spinulosa decalvans: a family study of seven male cases and six female carriers. J. Med. Genet. 29: 36-40, 1992. [PubMed: 1552542] [Full Text: https://doi.org/10.1136/jmg.29.1.36]
Waardenburg, P. J., Franceschetti, A., Klein, D. Genetics and Ophthalmology. Vol. 1. Oxford: Blackwell (pub.) 1961.