Keratosis Follicularis Spinulosa Decalvans, X-Linked

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.

Description

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.

Clinical Features

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.

Inheritance

Most affected families with KFSD show X-linked inheritance (Aten et al., 2010).

Mapping

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).

Cytogenetics

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).

Molecular Genetics

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.

History

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).