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A Mosaic Pattern of Alopecia in the Oral-Facial-Digital Syndrome Type I (Papillon-Le ´age and Psaume Syndrome) Marı ´a del C. Boente, M.D.,* Norma Primc, M.D.,* Hugo Veliche, M.D.,* S. Rosales, M.D.,* Roque Carrero-Valenzuela, M.D.,² Cesar Saleme, M.D.,and Rau ´ l Asial, M.D.² *Hospital del Nin ˜o Jesu ´s, ²Universidad Nacional de Tucuma´n, and ‡Maternidad, Tucuma ´n, Argentina Abstract: We present an infant girl with oral-facial-digital syndrome type I, who had alopecia following the scalp lines of Blaschko, and we discuss the characteristics of alopecia in this syndrome. The oral-facial-digital syndrome type I (OFD-I) is a rare X-linked dominant disorder limited to females, with lethality in hemizygous males (1–5). This syndrome, characterized by congenital anomalies of the oral, facial, and digital structures, was first recognized by Papillon- Le ´age and Psaume in 1954. Since 1962 the term OFD syndrome has been applied to this constellation of find- ings (6). Similar cases have been reported under a variety of names since 1860; until more than 200 cases have been reported in the literature and reviewed articles sug- gest an incidence of about 1/50,000 to 1/250,000 live births (4,5,7). The most common features of the OFD–I syndrome include a distinctive facies with frontal bossing, nasal alar cartilage hypoplasia with flattening of the nasal tip, broad nasal root, and hypertelorism. Oral findings in- clude lobulated cleft tongue, cleft lip and palate, numer- ous hyperplastic frenulas (lingual, buccal, labial), multi- lobulated tongue with hamartomatous growths, narrow upper lip, and dental anomalies. Hand malformations consist of brachydactyly, syndactyly, clinodactyly, and rarely polydactyly. Mild mental retardation and adult on- set bilateral polycystic kidneys have also been reported (1,2,8–14). Cutaneous abnormalities include numerous milia, especially over the face and pinna, a patterned type of alopecia, and sparse, fine, or coarse, dry lusterless hair (2,3,15). We recently had the opportunity to study a new pa- tient with this syndrome who had polydactyly and severe maldevelopment of oral structures. The goal of this pre- sentation is to further analyze the alopecic changes ob- served in this syndrome. CASE REPORT A 15-day-old infant girl was seen for the evaluation of multiple malformations. She was born at 38 weeks by spontaneous vaginal delivery; birthweight was 3400 g (50%–75%) and cephalic perimeter was 35.5 cm (50%– 75%). Her mother, older sister, maternal grandmother, and a maternal uncle have multiple hamartomatous growths and multiple clefts and frenulas on the tongue. Dysmorphic facial features noted at birth were flat- tening of the nasal tip, broad nasal root, and hypertelor- ism. She had severe oral cavity anomalies including a narrow superior lip and cleft palate. The tongue was barely visible because it had multiple clefts and lobules and was thoroughly adherent with several frenulas to the floor and sides of the mouth (ankyloglossia); on the pha- ryngeal opening the uvula was split and a hamartomatous papilloma could be appreciated (Figs. 1 and 2). Because Address correspondence to Marı ´a del C. Boente, M.D., Pasaje Ber- tre ´s 224, San Miguel de Tucuma ´n, 4000 Tucuma ´n, Argentina. Pediatric Dermatology Vol. 16 No. 5 367–370, 1999 367

A Mosaic Pattern of Alopecia in the Oral-Facial-Digital Syndrome Type I (Papillon-Léage and Psaume Syndrome)

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Page 1: A Mosaic Pattern of Alopecia in the Oral-Facial-Digital Syndrome Type I (Papillon-Léage and Psaume Syndrome)

A Mosaic Pattern of Alopecia in theOral-Facial-Digital Syndrome Type I

(Papillon-Leage and Psaume Syndrome)

Marı a del C. Boente, M.D.,* Norma Primc, M.D.,* Hugo Veliche, M.D.,* S. Rosales, M.D.,*Roque Carrero-Valenzuela, M.D.,† Cesar Saleme, M.D.,‡ and Raul Asial, M.D.†

*Hospital del Nino Jesu´s, †Universidad Nacional de Tucuma´n, and ‡Maternidad, Tucuma´n, Argentina

Abstract: We present an infant girl with oral-facial-digital syndrometype I, who had alopecia following the scalp lines of Blaschko, and wediscuss the characteristics of alopecia in this syndrome.

The oral-facial-digital syndrome type I (OFD-I) is arare X-linked dominant disorder limited to females, withlethality in hemizygous males (1–5). This syndrome,characterized by congenital anomalies of the oral, facial,and digital structures, was first recognized by Papillon-Leage and Psaume in 1954. Since 1962 the term OFDsyndrome has been applied to this constellation of find-ings (6). Similar cases have been reported under a varietyof names since 1860; until more than 200 cases havebeen reported in the literature and reviewed articles sug-gest an incidence of about 1/50,000 to 1/250,000 livebirths (4,5,7).

The most common features of the OFD–I syndromeinclude a distinctive facies with frontal bossing, nasalalar cartilage hypoplasia with flattening of the nasal tip,broad nasal root, and hypertelorism. Oral findings in-clude lobulated cleft tongue, cleft lip and palate, numer-ous hyperplastic frenulas (lingual, buccal, labial), multi-lobulated tongue with hamartomatous growths, narrowupper lip, and dental anomalies. Hand malformationsconsist of brachydactyly, syndactyly, clinodactyly, andrarely polydactyly. Mild mental retardation and adult on-set bilateral polycystic kidneys have also been reported(1,2,8–14). Cutaneous abnormalities include numerousmilia, especially over the face and pinna, a patterned type

of alopecia, and sparse, fine, or coarse, dry lusterless hair(2,3,15).

We recently had the opportunity to study a new pa-tient with this syndrome who had polydactyly and severemaldevelopment of oral structures. The goal of this pre-sentation is to further analyze the alopecic changes ob-served in this syndrome.

CASE REPORT

A 15-day-old infant girl was seen for the evaluation ofmultiple malformations. She was born at 38 weeks byspontaneous vaginal delivery; birthweight was 3400 g(50%–75%) and cephalic perimeter was 35.5 cm (50%–75%). Her mother, older sister, maternal grandmother,and a maternal uncle have multiple hamartomatousgrowths and multiple clefts and frenulas on the tongue.

Dysmorphic facial features noted at birth were flat-tening of the nasal tip, broad nasal root, and hypertelor-ism. She had severe oral cavity anomalies including anarrow superior lip and cleft palate. The tongue wasbarely visible because it had multiple clefts and lobulesand was thoroughly adherent with several frenulas to thefloor and sides of the mouth (ankyloglossia); on the pha-ryngeal opening the uvula was split and a hamartomatouspapilloma could be appreciated (Figs. 1 and 2). Because

Address correspondence to Marı´a del C. Boente, M.D., Pasaje Ber-tres 224, San Miguel de Tucuma´n, 4000 Tucuma´n, Argentina.

Pediatric Dermatology Vol. 16 No. 5 367–370, 1999

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of these multiple anomalies a nasogastric feeding tubewas attached for alimentation. Her right hand has pre-axial polydactyly of the thumb with 1–2 syndactyly. Theterminal phalanx of the opposing finger was broad andshort, its nail partially bifid. On the feet a preaxial poly-dactyly was present over the inner surface of the left foot(Fig. 3); excision was performed and a supernumerarydigit was confirmed histologically.

Examination of the skin showed small, pearly white,

milialike cysts on the face and auricular surface (Fig. 1).The scalp showed alopecic areas arranged in spiralstreaks following a linear pattern beginning on the fron-tal area, covering the lateral side of the scalp, and ex-tending to the crown of the head (Figs. 4 and 5). In theseareas dark dots corresponding to broken hairs could beseen; the hair on the rest of the scalp was coarse, luster-less, and brittle. On microscopic examination the hairwas of varying diameter, with an increased number ofunmedullated hairs, but no specific abnormality could bedetected. The follicular openings were widely spaced inboth areas. Cerebral echography and CT disclosed agen-esis of the corpus callosum.

A series of surgeries was done in order to repair themultiple oral anomalies. Developmental stimulation iscurrently being performed, and a phoniatrician is teach-ing her how to eat without the nasogastric tube.

DISCUSSION

A cutaneous dysplasia has been found in patients withOFD–I syndrome (2), with a diminished number of se-baceous glands, alopecia, and keratinous milialike cysts.Although the milia as well as the sebaceous dysplasia donot follow any particular pattern of distribution, it isinteresting to note that, although all the hair is affectedwith some dysplastic changes, more severely affectedhairs show a patterned distribution following the Blas-chko lines on the scalp as delineated by Happle (3). Thespiral pattern seen in our patient as well as in Happle’sapparently reflects functional X chromosomal mosa-icism, as this type of linear alopecia has likewise beenobserved in X-linked dominant ichthyosis (15).

A striking feature in the OFD–I syndrome is the highphenotypic variability in heterozygous females, varyingfrom mild signs, such as minimal dental or lingual alter-ations in our patient’s female relatives, to the full pictureof the syndrome as seen in this girl. This variation indegrees of expression can be explained by the Lyon ef-fect of X-inactivation (16): one of the X chromosomespresent in the cells of female mammals is functionallyinactivated at an early stage of embryonic development;this inactivation occurs randomly. The inactivated X canbe either the maternal or paternal one in different cells ofthe same individual. The inactivated X chromosome re-mains the same in all daughter cells of a given cell line.Affected females, who are heterozygous for the OFD-Igene, represent an OFD-I mosaicism and therefore couldcarry varying percentages of cells with an active mutantgene, explaining the high phenotypic variability seen inthis syndrome. Since hemizygous males have only one Xchromosome, all of their cells will carry the active OFDgene, causing lethality (1,3,15–17).

Figure 1. Dysmorphic facial features: flattened nasal tip,broad nasal root, and hypertelorism. Narrow superior lip,recessed chin. Note small pearly cysts on nasal root, up-per lid, and cheeks.

Figure 2. Severe oral cavity anomalies; note cleft palateand split uvula.

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X-linked genes affecting the development as well asthe function of the skin structures give rise to a mosaicpattern of cutaneous lesions. This pattern of distributionis not simply patchy but follows Blaschko lines (3). Thisholds true in the patterned alopecia seen in OFD-I, aswell as in some cases of X-linked dominant ichthyosis(3,15). In another X-linked disorder, focal dermal hypo-plasia (Goltz–Gorlin syndrome), a cribriform as well aspatterned alopecia has been observed. Sparse, thin, andbrittle hair has been described (18). Besides the cutane-ous lesions (focal areas of thinning of the skin with linearpigmentation and telangiectasia), which represent thehallmark of the syndrome, skeletal defects are oftenfound. Longitudinal striation of the long bones, crossing

the epiphysis (osteopathia striata), is a frequent and char-acteristic finding. The combination of split hand withsyndactyly and absence of rays, the so-called lobster-claw deformity, has come to be recognized as a strikingfeature of this disorder and helps in the differential di-agnosis (19).

This hypothesis cannot explain the other anomalies inthe pilosebaceous development observed in this syn-drome (2), for instance, the milialike cysts, the dimin-ished number of sebaceous glands, as well as the abnor-malities observed in other areas of the scalp, such as thedecreased number of hair follicles per scalp area, and thepresence of fine or coarse but brittle, dry, lusterless hairs.These other features do not follow the lines of Blaschko,

Figure 4. Alopecic area with linear pattern over the pari-etal area of the scalp. Broken hairs, with diminished num-bers per square centimeter could be seen.

Figure 5. On the crown of the head, alopecic areas followthe spiral pattern of the scalp Blaschko lines.

Figure 3. (A) Polysyndactyly. Preaxial polydactyly of the right thumb associated with syndactyly between the first andsecond digits. Radial deviation of the second finger could be seen. The right thumb is broad and short, with partialduplication of the nail. (B) Pedunculated postaxial polydactyly is observed on the left foot.

Boente et al: Mosaic Pattern Alopecia in OFDS-I369

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and therefore could be explained by a different geneticmechanism that deserves further investigation.

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