Atrichia with papular lesions (APL) is a rare form of irreversible complete loss of hair on the scalp and entire body, and is known to be inherited in an autosomal recessive manner1-4. Clinically, APL is characterized by total hair loss, including scalp, face, axilla, and body hair, during the first few months of life. This is followed by the appearance of multiple follicular papules that consist histopathologically of keratin-filled cysts and are especially prevalent on the face and extensor surfaces of the extremities.

Recently, molecular analysis has been used to diagnose a patient with APL, and studies of numerous APL families have implicated mutations of the hairless (HR) gene in the pathogenesis of this disorder4-6. Several mutations that map to chromosome 8p12 have been identified, and increasing numbers of HR gene mutations are being reported.

Most APL patients have homozygous HR gene mutations, and have been discovered in consanguineous families living within a restricted geographical region, implying that these mutations became fixed owing to a high degree of consanguinity1-3. However, the number of sporadic cases occurring in offspring of unrelated parents has been increasing7-11. Sporadic patients with non-consanguineous parents have been misdiagnosed with alopecia universalis (AU) frequently, as APL and AU are clinically very similar. After unsuccessful treatment for AU, they were subsequently diagnosed as APL by molecular analysis5,12. Thus, the identification and evaluation of HR gene mutations in patients with total hair loss are important for differentiating between APL and AU.

In this study, the HR genes of AU patients who showed little or no response to treatments for restoring hair growth were examined and compared with the HR genes of normal healthy controls, and a novel missense mutation of the HR gene was identified in a Korean boy who finally diagnosed with APL.

Relatively little is known about the mechanism of APL. Although hair follicle development appears to be normal in APL, a defect in the follicular cycling system must induce hair loss because normal hair is present at birth but is subsequently lost during the first few months of life. Panteleyev et al.13 postulated that hair regrowth in APL is disrupted because the lower follicle disintegrates during catagen and the normal juxtaposition of epithelial stem cells in the bulge and mesenchymal cells in the dermal papilla of the hair follicle is not re-established during telogen14. This interferes with mesenchymal-epithelial interactions, which are considered to be necessary for re-entry into anagen, and atrichia is the result14. Consequently, the architecture of hair follicles with short catagen stages, including those of vibrissae, eyelashes, and eyebrows, may not be disrupted sufficiently during catagen, and these hairs may be preserved in APL patients15. Recent studies have suggested that HR protein acts as a nuclear receptor co-repressor in concert with the vitamin D receptor gene and represses the expression of WISE protein, which inhibits Wnt signaling16,17. The follicular cysts seen in APL patients may arise from follicular remnants that survive after the follicle breaks apart during catagen13,18. As the cyst epithelium expresses keratin K17, which normally occurs in the outer root sheath of hair follicles, cysts in APL patients appear to arise from the bulge of the hair follicle13,19. The regression of these follicular papules in older patients has been reported, although the mechanism is unclear4.

Approximately 34 mutations of the HR gene, including the one discovered in this study, have been reported6,10-12,20-22. These include missense, nonsense, deletion, insertion, splice-site, and compound heterozygous mutations10,11,23-25. This study reports a novel G-to-A transition at nucleotide 191 in exon 5, resulting in the replacement of a glycine residue by a glutamate residue. This new missense mutation in the HR gene is called the G64E mutation. This particular mutation has not been reported previously, and this is only the second case report of APL occurring in a Korean family.

Although different mutations of the HR gene have been reported, the clinical manifestations of APL exhibit little variation, and most APL patients have the same degree of clinical severity. There do not appear to be any particular "hot spots" or common locations for mutation in the HR gene or any genotype-phenotype connections in APL patients. Also, there is no information on HR protein levels in affected patients, particularly the actual amount of altered HR protein expressed in the skin. Therefore, to diagnose APL, it is important to sequence all coding regions, including exon-intron junctions, of the entire HR gene.

APL is usually inherited in an autosomal recessive manner. Most reported cases of APL have been discovered in consanguineous families living within a restricted geographical region. However, there are some reports of APL patients with compound heterozygous mutations in small non-consanguineous families7-11. In present study, the novel missense mutation was not inherited as an autosomal recessive, as the patient's mother and maternal grandfather were heterozygous carriers of the G64E mutation, whereas his father had the wild-type HR gene. There are three possible explanations for proband's homozygosity: 1) Proband's father is not his biological father. 2) The father has a large heterozygous deletion in the same region which cannot be recognized by sequencing and which was inherited by the proband. 3) The proband had a spontaneous mutation of the same type as his mother's (G-to-A transition at position 191 in exon 5), which seems to be less likely. It seems that isolated cases of APL may be more common than previously thought, because of a lack of awareness and the misdiagnosis of APL as AU or vitamin-D-dependent rickets, which may present as atrichia in the first few months of life and as follicular cysts in the first few years of life11,17.

On careful examination of this patient, hypopigmented macules and streaks were observed. Hypopigmented streaks on the scalp in APL patients have been reported before6. However, follicular hypopigmented macules over the entire body, especially on both thighs, have not been reported, and may be novel clinical signs of APL. The mechanism and pathogenesis of the hypopigmented streaks or macules in APL is unknown, but it may be that the HR gene mutation could play a role in the development of the follicular hypopigmented macules.

In summary, we report a new case of APL in a nonconsanguineous family that was diagnosed based on clinical findings and molecular data and involved a novel G-to-A transition at nucleotide 191 in exon 5. In addition, a novel clinical sign of APL was observed, namely, follicular hypopigmented macules on the entire body, especially on both thighs. This particular mutation has not been reported previously, and this is only the second case report of APL occurring in a Korean family. These data extend our knowledge of mutations in the HR gene, and suggest that children with presumed AU in non-consanguineous families that do not respond to standard treatment modalities may warrant testing for HR gene mutations to avoid unnecessary treatments.