STUDY. The Alopecias Associated With Vitamin D Dependent Rickets Type IIA and With Hairless Gene Mutations

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1 STUDY The Alopecias Associated With Vitamin D Dependent Rickets Type IIA and With Hairless Gene Mutations A Comparative Clinical, Histologic, and Immunohistochemical Study Reuven Bergman, MD; Rinat Schein-Goldshmid, MD; Zeev Hochberg, MD, DSc; Ofer Ben-Izhak, MD; Eli Sprecher, MD, PhD Objective: To establish the unique and common clinical and microscopic characteristics of the alopecias associated with vitamin D dependent rickets (VDDR) type IIA and with hairless gene mutations. Design: A comparative clinical, histologic, and immunohistochemical study of the alopecias in 6 patients with VDDR IIA and 4 patients with atrichia with papular lesions (APL) and/or alopecia universalis congenita (AUC) (hereinafter APL/AUC ). Main Outcome Measures: Clinical data were gathered from medical records, personal interviews, and physical examinations. Histologic and immunohistochemical studies were performed on 6 scalp punch biopsy specimens from each of the 2 studied groups. Results: The alopecias in VDDR IIA and APL/AUC showed similar clinical, histologic, and immunohistochemical features. The clinical ation of the VDDR alopecia resembled either the APL phenotype (ie, with papules and milia) or the AUC phenotype (without papules and milia). The main histologic findings included void infundibula; absence of the lower two thirds of the hair follicles, often replaced by vertically oriented or cysts;, often with small cysts in the middle and lower dermis; and small, medium, and large keratinizing cysts at all levels of the dermis. The larger cysts in the upper dermis stained positively for cytokeratin (CK) 10, which suggests an infundibular derivation, whereas the remaining and cysts in the middle and lower dermis stained positively most frequently for CK17, CK19, and CD34, which suggests an outer root sheath derivation. Conclusions: The alopecias associated with VDDR IIA and with hairless gene mutations show striking clinical and microscopic similarities. Disintegration of the lower two thirds of the hair follicles seems to be the underlying defect, and a common pathogenetic pathway might be involved. Arch Dermatol. 2005;141: Author Affiliations: Departments of Dermatology (Drs Bergman, Schein-Goldshmid, and Sprecher), Pediatrics (Dr Hochberg), and Pathology (Drs Bergman and Ben-Izhak), Rambam Medical Center and the Bruce Rappaport Faculty of Medicine, Technion Institute of Technology, Haifa, Israel. Financial Disclosure: None. RECENT STUDIES HAVE REvealed underlying mutations in the human hairless gene in numerous families affected with 2 allelic disorders: atrichia with papular lesions (APL) (Mendelian Inheritance in Man [MIM] ) and alopecia universalis congenita (AUC) (MIM ) Apart from the absence of hair, the skin is normal in AUC, whereas patients with APL develop papular or milialike growths over most of their skin during the first years of life How impaired function of the hairless protein leads to atrichia is still not fully understood The histopathologic features of alopecia in rhino and hairless mice that carry mutations at the hairless locus 17 have been well documented. 20 The histopathologic characteristics in humans is deduced primarily from case descriptions, some of which were published prior to the discovery of the underlying hairless gene mutations. 1,2,4,5,9,11-14,21-25 Alopecia is also a frequent feature of hereditary vitamin D dependent rickets (VDDR) type IIA (MIM ), a rare autosomal recessive disorder described in several kindreds Similar to families with APL, hair is generally at birth but is then lost within 12 months. Miller et al 29 have recently described a patient with VDDR IIA and reported striking clinical and histologic similarities to APL. Zlotogorski et al 30 also noted clinical similarities to APL in several patients with VDDR IIA, and histologic similarities to APL in 1 patient with VDDR IIA. The study was performed to determine the unique and common features of the alopecias associated with VDDR IIA and with hairless gene muta- 343

2 Table 1. Histologic and Immunohistochemical Histologic Findings in 6 Cases of Vitamin D Dependent Rickets Type II Alopecia Patient/ Sex/Age, y Mutation Age at Biopsy Histologic Findings* 1/F/15 Y292X 15 y Infundibula devoid of hair of hair follicle missing. Several and 2 small cysts in lower dermis. 2/M/8 Y292X 8 mo Infundibula devoid of hair of hair follicle replaced by with small cysts. 3/F/4 Y292X 4 y Large infundibula devoid of hair shafts. Lower two thirds of hair follicle missing. A large cyst in upper dermis with granular layer in upper half and pale-staining epithelium devoid of granular layer in lower half. 4/F/10 Y292X 10 y Infundibula devoid of hair of hair follicle missing. Two large epidermal cysts in mid- and upper dermis. Several in mid dermis. 5/F/5 Y292X 5 y Infundibula devoid of hair of hair follicle replaced by and small cysts. 6/F/5 Y292X 5 y Infundibula devoid of hair of hair follicle replaced by and small cysts. Immunohistochemical Findings* CK10 CK17 CK19 CD34 of infundibula and upper parts of of infundibula and 1 small cyst in the upper dermis (+) Innermost upper half of large cyst of infundibula and large cysts of infundibula of infundibula of ( cysts not ) of and small cysts of large cyst, more in the lower half of and large cyst of and small cysts of (+) Basal (+) Mostly basal layer cells of (+) Basal layer of lower half of large cyst ( ) Irregular not (+) Basal (+) Basal ( ) (+) Some basal layer cells of (+) Basal layer of lower half of large cyst (+) Basal layer of ( ) ( ) Abbreviations: Plus sign, positive findings; minus sign, negative findings. *Results pertaining to hair follicle related only. tions using comparative, clinical, histologic, and immunohistochemical analysis. METHODS We observed 6 patients with VDDR IIA, 5 female and 1 male ranging in age from 5 to 15 years, and 4 patients with APL and/or AUC (hereinafter APL/AUC ), 1 female and 3 male ranging in age from 4 to 18 years (Table 1 and Table 2). The diagnosis of the APL/AUC cases was confirmed by molecular genetic studies showing mutations in the hairless gene. 7,13,19 The diagnosis of the VDDR IIA cases was confirmed by molecular genetic study showing a point mutation in the vitamin D receptor (VDR) gene. 31 The medical records of each patient were reviewed, and each patient was interviewed and physically examined. The patient s parents were also interviewed. After obtaining informed written consent from each participant, a 4-mm punch biopsy specimen was obtained from their scalps, except for 1 patient with VDDR (patient 2; Table 1), for whom we used a previous biopsy specimen obtained for diagnostic purposes at age 8 months. In 2 patients with APL/AUC from whom new scalp biopsy specimens were obtained (patients 1 and 2; Table 2), we also studied previous specimens obtained for diagnostic purposes 3 years and 1 year earlier, respectively. The routinely processed specimens were completely serially sectioned in a vertical fashion. The first sections were stained with hematoxylin-eosin. The next 4 sections were stained with monoclonal antibodies to cytokeratin (CK) 10, CK17, CK19, and CD34, all available from DAKO A/S, Copenhagen, Denmark, and by using the avidin-biotin immunoperoxidase technique (Histostain-Plus kit; Zymed Laboratories Inc, San Francisco, Calif). All of the remaining serial sections were also stained with hematoxylin-eosin. Positive and negative control immunostainings were performed on 2 normal scalp specimens available from our files. In the normal control scalp specimens, CK10 was expressed 344

3 Table 2. Histologic and Immunohistochemical Findings in 4 Cases of Atrichia With Papular Lesions and/or Alopecia Universalis Congenita Patient/ Sex/Age, y Mutation Age at Biopsy, y Histologic Findings* 1/F/18 D1012N (Biopsy 1) Infundibula devoid of hair of hair follicle missing. In 1 hair follicle, lower two thirds replaced by structure with small cyst; 3 midsized cysts with pale-staining epithelium in mid-dermis and upper dermis; 2 of the cysts ruptured and surrounded by a granulomatous reaction. 18 (Biopsy 2) Infundibula devoid of hair of hair follicle missing. In 3 follicles, lower two thirds replaced by ; in 2 more follicles by small pale-staining cysts; 2 more medium and large cysts with pale-staining epithelium in mid-dermis. 2/M/ delC 7 9 (Biopsy 1) Infundibula devoid of hair of hair follicle missing. In mid-dermis, 1 structure and 3 midsized cysts with pale-staining epithelium. 10 (Biopsy 2) 1 Large cyst with tail in papillary dermis. Pale-staining structure with small cyst in mid-dermis. 3/M/ del and Q478X 13 4 Infundibula devoid of hair of hair follicle missing. Irregular in mid-dermis, and small cysts with pale-staining cytoplasm. 4/M/ delC 7 14 Infundibula devoid of hair shafts; 3 pale-staining and small cysts replacing lower two thirds of hair follicles. Abbreviations: Plus sign, positive findings; minus sign, negative findings. *Results pertaining to hair follicle related only. Immunohistochemical Findings* CK10 CK17 CK19 CD34 cells of infundibula. Mid-dermal cysts not stained. Irregular and ruptured cysts not infundibula infundibula. Epithelial cysts not infundibula and innermost layers of cyst except for tail infundibula infundibula cells of cysts in the mid and upper dermis; not cells of mid-dermal cysts and basal and suprabasal cells of. Epithelial cysts not cyst including the tail and (+) Predominantly suprabasal and small cysts and small cysts ( ) Irregular not ( ) Epithelial cysts not ( ) Irregular and cysts not (+) Few basal cells in tail of large cyst and in structure (+) Basal cells in several segments of some (+) Basal, and occasionally suprabasal (+) Basal layer of mid-dermal cyst. Irregular not (+) Basal layer of mid-dermal large cyst ( ) Irregular and cysts not ( ) Epithelial tail of large cyst not (+) Focal weak staining in few cells of some ( ) Irregular not in the suprabasal the epidermis and in the infundibular portions of the normal hair follicles. Cytokerin 17 was in the suprabasal cells of the outer root sheath (ORS), usually below the infundibulum. Cytokerin 19 was in a few basal cell layer segments and some suprabasal cells of the ORS below the infundibulum. We found that CD34 was expressed more conspicuously in the basal cell layer but also in the suprabasal cell the ORS below the infundibulum. 345

4 RESULTS Our VDDR results are summarized in Table 1 and our APL/AUC findings appear in Table 2. CLINICAL AND MOLECULAR GENETIC FEATURES A reative clinical photograph of a patient with APL is seen in Figure 1. A patient with VDDR IIA is shown in Figure 2. According to the patients parents, most of our patients with VDDR IIA were born with normal hair distribution. All patients lost their hair at age 1 to 3 months. At the time of physical examination (ranging from age 8 months to 15 years), all 6 patients with VDDR had universal alopecia except for remaining eyebrows and eyelashes in 4 patients. Three patients (patients 1, 3, and 4; Table 1) had small milia that were either generalized or restricted to skin areas such as the upper body or the scalp and face. A genetic workup demonstrated the same nonsense mutation (Y292X) in the VDR gene in all 6 patients, who belong to 3 related families. 31 All 4 patients with APL/AUC were born with normal hair distribution but lost their hair between ages 40 days and 4 months. At the time of physical examination (ranging from age 4 to 18 years), all patients had total absence of hair except for occasional eyelashes, and partial eyebrow hair loss in 1 patient. Generalized milia were in 2 patients (patients 2 and 4; Table 2), aged 10 and 14 years, respectively. These patients were siblings previously shown to carry a single-base deletion (3434delC) in the hairless gene. 7 The clinical ation in these 2 patients was compatible with APL. Another patient (patient 1, Table 2), aged 18 years, did not demonstrate any milia or papular rash except for acne lesions on the face and chest since puberty. His clinical ation was compatible with AUC with an underlying homozygous missense mutation (D1012N) in the hairless gene. 19 The fourth patient (patient 3, Table 2), aged 4 years, displayed minute papules on both cheeks. These borderline findings precluded his definitive assignment to an APL or AUC phenotype. This patient was shown to carry 2 heterozygous mutations (Q478X and del) in the hairless gene. 13 HISTOLOGY AND IMMUNOHISTOCHEMISTRY The histologic findings in the VDDR and APL/AUC cases were essentially similar (Tables 1 and 2). In all cases, the normal hair follicles were missing. The only remaining normal portions were the infundibular parts, which had normal-looking sebaceous glands but were devoid of hair shafts (Figure 3 and Figure 4). The lower two thirds of the hair follicles below the level of the sebaceous glands were missing, often replaced by vertically oriented with small cystic dilatations (Figure 3) or by small to medium-sized cysts (Figure 5 and Figure 6). Irregular and small cysts were also found farther down the dermis (Figures 3 and 4). Medium-sized cysts and occasionally large cysts were the predominant finding in the middle and upper dermis of some of the other cases (Figures 5, 6, 7, and 8). The middle dermal cysts had a laminated corneal layer in their innermost parts without an underlying granular cell layer (Figure 5). In 1 of the cases, a large cyst had a granular cell layer in its upper half and palerappearing cells devoid of a granular cell layer in its lower half (Figures 7 and 8). The immunohistochemical stainings were performed with 4 monoclonal antibodies, each used on a single section of each specimen. Infundibula were usually in these sections, but some of the other in the hematoxylin-eosin analysis were occasionally absent in the single serial immunohistochemistry sections. This has been noted in the footnotes in Tables 1 and 2. The immunohistochemical staining patterns in patients with VDDR and APL/AUC were also essentially similar (Figures 9, 10, and 11). Cytokeratin 10 was expressed in the suprabasal the residual infundibula of all cases (Figure 9). All of the large cysts in the upper dermis stained positively for CK10. In 1 of the large cysts, only the upper half of the cyst, which had a granular cell layer, stained positively for CK10 (Figure 7). This entire cyst stained positively for CK17, and the basal layer of the lower half, which did not have a granular cell layer, stained positively for CD34 and CK19 (Figure 8). In another case, the entire large cyst in the upper dermis stained positively for CK10 except for a lower tail, which stained positively for CK19. Most of the small and midsized cysts stained negatively for CK10. Also, CK10 was not detected in the except in 1 case in which it was expressed only in their uppermost vertical portions. Cytokeratin 17 was always expressed in the suprabasal cells of the vertically oriented and deep-seated and the small cysts (Figure 11). Positive staining for CK17 was also detected in midsized and large cysts. The residual infundibula were not stained except occasionally in their lowermost parts (Figure 11). The staining for CK19 was usually positive in the basal cell layer and occasionally in some suprabasal cells of the vertically oriented and deep-seated (Figure 10). In about half of the cases in which were, CD34 was expressed in the basal cells of these. Staining was also detected in the basal cell layer of a medium-sized cyst and in the lower part of a large cyst in the middle dermis (Figure 8). COMMENT Most histologic studies of patients with APL regard the presence of keratinous cysts in the dermis as the dominant feature. 1,6,8,11,12,14,15,22 These dermal cysts may reach the size of milia and occasionally demonstrate granularlayer cells in their innermost layers. 1,22 Misciali et al 25 described additional tubular devoid of hair shafts extending from the epidermis to the deep dermis and characterized by the presence of clear cells resembling the lower portion of the ORS. Ill-defined aggregates in the lower dermis have been reported 346

5 A B C Figure 1. Alopecia associated with hairless gene mutations resulting in atrichia with papular lesions. Note the total absence of scalp hair with papules (A), milia on the ears and face (B-C), but a few eyelashes remain (C). in a patient with APL. 13 Serial sectioning of the entire specimen from this patient was included in the study (patient 3; Table 2) and revealed additional small cysts with pale-staining cytoplasm. Complete serial sectioning of all of our VDDR IIA and APL/AUC cases in which keratinous cysts were the dominant feature often demonstrated small in the middle dermis as well. In a recent VDDR IIA case study, researchers found an absence of normal hair follicles along with the presence of 347

6 Figure 2. Vitamin D dependent rickets type IIA alopecia. Note the total absence of hair on the forehead and scalp except for the eyebrows, which show partial loss. Numerous milia and milialike lesions are also. Figure 5. Alopecia associated with hairless gene mutations. The lower two thirds of the normal hair follicle is missing and replaced by small and medium-sized keratinizing cysts devoid of an inner granular cell layer (hematoxylin-eosin, original magnification 40). Figure 3. Vitamin D dependent rickets type IIA alopecia. The infundibula are devoid of hair shafts but have normal-looking sebaceous glands. The lower two thirds of the hair follicles are missing, replaced by vertically oriented (closed arrowheads). Irregular are also in the deeper dermis (open arrowheads), one of which (left) also has a small cyst (hematoxylin-eosin, original magnification 40). Figure 6. Alopecia associated with hairless gene mutations. A large, keratinizing, infundibular type of cyst (open arrowhead) is in the papillary dermis. On the left side, a small cyst with an tail (closed arrowhead) is situated below the remaining infundibulum, which suggests that it may have been derived from the lower two thirds of the hair follicle (hematoxylin-eosin, original magnification 40). Figure 4. Alopecia associated with hairless gene mutations. The infundibula are devoid of hair shafts, and the remaining normal parts of the hair follicles are missing. Small cysts (closed arrowhead) and (open arrowheads) are in the middle and lower dermis (hematoxylin-eosin, original magnification 40). follicular remnants and multiple middle dermal cysts lined with ORS-like epithelium in the dermis. 29 A few abnormal follicles reed by the remaining parts of their upper portions and a large keratinizing cyst were observed in another VDDR IIA case. 30 These findings were similar to those of APL. 29,30 In the study, we found a striking histologic similarity between the alopecias in VDDR IIA and APL/AUC cases. The main histologic findings included empty infundibula; absence of the lower two thirds of the hair follicles, often replaced by vertically oriented or cysts; often with small cysts in the middle and lower dermis; and small, medium-sized, and large keratinizing cysts at all levels of the dermis. Histologic resemblance was also noted between hairless mice and VDR knockout mice, especially in relation to the formation of dermal cysts. 32 Recent experiments have demonstrated that the VDR is most likely involved directly in hair-growth signaling and that forceful induction of catagen by hair plucking results in failure of new anagen hair formation in VDR-deficient mice. 33 It has been suggested, on the basis of experimental findings in mice with hairless gene mutations, that the entire ORS except the infundibulum and bulge disintegrates toward the end of the first hair cycle. 17,34 The remaining putative bulge cells proliferate to produce long, downward-oriented outgrowths and dermal cysts. Additional cysts are formed by the epi- 348

7 Figure 7. Vitamin D dependent rickets alopecia. A large keratinizing cyst is in the middle dermis. Immunostaining demonstrates cytokeratin 10 in the innermost the upper portion of the cyst (arrowhead) and in the suprabasal the overlying epidermis (immunoperoxidase, original magnification 40). thelial remnants of the ORS and by the utricles, which are equivalent to the infundibular portion of the human hair follicle. 17,34 The results of the study seem to extend this proposed scenario in hairless mice 34 to humans with alopecias associated with VDDR IIA and hairless gene mutations. The upper dermal large keratinous cysts in our study often contained a granular cell layer and stained positively for CK10, which is expressed by the normal infundibulum. 35 Therefore, these cysts may have derived from the remaining infundibula, which are equivalent to the utricles in the mouse. The missing lower two thirds of the normal hair follicle was often replaced by vertically oriented with occasional small cystic dilatations or by small to mediumsized cysts usually without a granular cell layer. These stained positively for CK17, which is expressed in the normal ORS, 36 and mostly negatively for CK10. The vertically oriented (or downgrowths) also stained positively for CK19, predominantly in their basal cell layer. CD34 was expressed in the basal cell layer of a few middle dermal cysts and in some of the vertically oriented. Both CK19 and CD34 are normally expressed in follicular germinative cells (or stem cells) and in more differentiated daughter cells. 36,37 CD34 is also expressed in the suprabasal cells of the normal ORS, and its presence in these cells denotes trichilemmal keratinization. 37 The restriction of CD34 expression to the basal cell layer in the vertically oriented and middle dermal cysts may indicate a lack of trichilemmal keratinization in these. These staining patterns are compatible with an ORS derivation, and since CK19 and CD34 are not expressed only by bulge cells, 36,37 the suggested bulge-cell derivation of Figure 8. Immunostaining of the biopsy specimen pictured in Figure 7. In basal layer of the lower part of the cyst, CD34 is expressed (closed arrowhead). A granular cell layer is in the innermost the upper part of the cyst (open arrowhead), which also stained positively for cytokeratin 10 (Figure 7). Therefore, this cyst may have derived partly from the lower portion of the infundibulum and partly from the upper portion of the isthmus (immunoperoxidase, original magnification 100). Figure 9. Immunostaining a deeper section of the biopsy specimen shown in Figure 3. Cytokeratin 10 is expressed in the remaining infundibula but not in the situated in the lower dermis (closed circle) (immunoperoxidase, original magnification 40). these vertically oriented 29,34 cannot be confirmed in the study. Similar staining patterns in the lower dermal cysts and the deep suggest an ORS derivation as well. The study and previous reports indicate that although patients with AUC and some with VDDR IIA lack papules or milialike lesions clinically, cysts 349

8 REFERENCES Figure 10. Immunostaining of the biopsy specimen shown in Figure 3. Cytokeratin 19 is expressed, mostly in the basal cells and in some of the suprabasal cells of the situated in the lower dermis (rhomboid marks) and in the adjacent sweat glands and ducts (immunoperoxidase, original magnification 100). Figure 11. Immunostaining a deeper section of the biopsy specimen shown in Figure 4. Cytokeratin 17 is expressed in the suprabasal cell the situated in the lower dermis (closed circles). The epidermis and remaining infundibula stain negatively except for an occasional positive staining in the lower infundibular epithelium (right) (immunoperoxidase, original magnification 40). may be histologically 9,19 (Tables 1 and 2). Vitamin D dependent rickets type IIA and APL/AUC are considered to be different genetic diseases, and both APL and AUC result from hairless gene mutations. 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9 resistance to 1,25-dihydroxyvitamin D. Clin Endocrinol (Oxf ). 1986;25: Miller J, Djabali K, Chen T, et al. Atrichia caused by mutations in the vitamin D receptor gene is a phenocopy of generalized atrichia caused by mutations in the hairless gene. J Invest Dermatol. 2001;117: Zlotogorski A, Hochberg Z, Mirmirami P, et al. Clinical and pathologic correlations in genetically distinct forms of atrichia. Arch Dermatol. 2003;139: Ritchie HH, Hughes MR, Thompson ET, et al. An ochre mutation in the vitamin D receptor gene causes hereditary 1,25-dihydroxyvitamin D 3 resistant rickets in three families. Proc Natl Acad Sci U S A. 1989;86: Xie Z, Komuves L, Yu Q-C, et al. Lack of vitamin D receptor is associated with reduced epidermal differentiation and hair follicle growth. J Invest Dermatol. 2002; 118: Kong J, Li XJ, Gavin D, Jiang Y, Li YC. Targeted expression of human vitamin D receptor in the skin promotes the initiation of the postnatal hair follicle cycle and rescues the alopecia in vitamin D receptor null mice. J Invest Dermatol. 2002; 118: Panteleyev AA, Paus R, Ahmad W, Sundberg JP, Christiano AM. Molecular and functional aspects of the hairless (HR) gene in laboratory rodents and humans. Exp Dermatol. 1998;7: Yamamoto O, Hamada T, Doi Y, Sasaguri Y, Hahimoto H. Immunohistochemical and ultrastructural observations of desmoplastic trichoepithelioma with a special reference to a morphological comparison with normal apocrine acrosyringium. J Cutan Pathol. 2002;29: Misago N, Narisawa Y. Tricholemmal carcinoma in continuity with trichoblastoma within nevus sebaceous. Am J Dermatopathol. 2002;24: Haas N, Audring H, Sterry W. Carcinoma arising in proliferating trichilemmal cyst expresses fetal and trichilemmal hair phenotype. Am J Dermatopathol. 2002; 24: ARCHIVES Web Quiz Winner C ongratulations to the winner of our December quiz, Firouzeh Niakosari, MD, McMaster University, Hamilton, Ontario. The correct answer to our December challenge was annular atrophic lichen planus. For a complete discussion of this case, see the Off-Center Fold section in the January ARCHIVES (Popkin DL, Greene RE, Fung JF. Widespread annular eruption in a black man. Arch Dermatol. 2005;141:93-98). Be sure to visit the Archives of Dermatology Web site ( to try your hand at the Interactive Quiz. We invite visitors to make a diagnosis based on selected information from a case report or other feature scheduled to be published in the following month s print edition of the ARCHIVES. The first visitor to our Web editors with the correct answer will be recognized in the print journal and on our Web site and will also receive a free copy of The Art of JAMA II. 351