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Autosomal recessive congenital ichthyosis (ARCI) is a clinically and genetically heterogeneous group of genodermatoses characterized by disorders of cornification. ARCI11 (MIM #602400) includes two syndromes caused by mutations in the ST14 (suppression of tumorigenicity 14) gene: IFAH (autosomal recessive congenital ichthyosis, follicular atrophoderma and hypotrichosis) and ARIH (autosomal recessive ichthyosis and hypotrichosis). All the reported ARCI11 cases so far belonged to consanguineous Turkish or Arab families]. We describe a novel p.Glu519Gln missense mutation in a patient affected by IFAH from a non consanguineous Rumanian family.

Follicular atrophoderma is a rare anomaly observed mainly in the X-dominant form of chondrodysplasia punctata (Conradi-Hunermann-Happle syndrome) and in the X-linked dominant Bazex syndrome. We report on five Emirati sibs (three girls and two boys), 4–18 years old, with normal stature, diffuse congenital ichthyosis, patchy follicular atrophoderma, generalized and diffuse non-scarring hypotrichosis, and marked hypohidrosis. Steroid sulfatase activity, assessed in the two boys, was found to be normal. Electron microscopic studies of ichthyotic skin did not show any specific abnormality. The association of congenital diffuse ichthyosis with follicular atrophoderma and hypotrichosis has not been reported before. The patients were reminiscent of Bazex syndrome; however, ichthyosis is not a component of Bazex syndrome. We conclude that this syndrome of congenital ichthyosis with follicular atrophoderma represents a new autosomal recessive genodermatosis. Am. J. Med. Genet. 75:186–189, 1998. © 1998 Wiley-Liss, Inc.

Bazex-Dupre-Christol syndrome (BDCS) is an X linked dominant disorder of the hair follicle characterised by follicular atrophoderma, multiple basal cell carcinomas, hypotrichosis, milia, and localised hypohidrosis. Follicular atrophoderma (FA) are follicular funnel shaped depressions, "ice pick marks", seen most commonly on the dorsum of the hands. We describe the first known Scottish family with this syndrome, five affected members spanning three generations. They have hypohidrosis confined to the face, coarse hair, dry skin, milia, and follicular atrophoderma. All the adults have a history of multiple basal cell carcinomas. None of them has any skeletal feature suggestive of Gorlin's syndrome. The clinical features, skin histology, and scanning electron microscopic (SEM) examination of the hair are described and illustrated. The features are compared with 15 previous reports of BDCS and four reports in which this is a possible diagnosis are also reviewed. BDCS should be considered as a differential diagnosis in patients with early onset or familial basal cell carcinomas.

A 6-year-old male child presented with progressive hypertrophy and discoloration of all 20 nails. Further evaluation revealed milia in bilateral concha and face, which were present since infancy. Other findings included atrophoderma over bilateral sides of lateral canthi of eyes and absent lower central incisors. Past medical and family history had remarkable findings such as natal teeth and similar nail changes in his elder sister. Similar nail changes, milia and focal plantar keratoderma were present in his father and elder sister. The patient's clinical presentation and history were compatible with pachyonychia congenita subtype 2.

Eight members of a single family all presented the characteristic changes of facial, especially perioral, pigmented follicular atrophoderma, with numerous milia and epidermoid cysts. For this condition. diagnosis at a glance may be possible because of the perioral cutaneous manifestations. Histopathological examination of follicular atrophoderma revealed proliferation of basaloid cells continuous with the epidermis and coarse collagen fibres, with a decreased density of elastic fibres around the basaloid cells. Two of the eight individuals also showed generalized hypohidrosis. The eight affected persons were the proband, her son, mother, uncle, two younger sisters, cousin and nephew: an autosomal dominant mode of transmission was suggested from this family tree. The patients' symptoms resembled those of Bazex-Dupré-Christol syndrome, except for the different distribution of the follicular atrophoderma and the absence of basal cell carcinoma and hypotrichosis. This disease may be an entirely new syndrome characterized by perioral pigmented follicular atrophoderma associated with milia and epidermoid cysts.

Follicular atrophoderma has been associated with a variety of findings. In our patient's family the disease was present in the mother and all of her living children. Scrotal tongue was also found in all but one child. We think that follicular atrophoderma is probably inherited as an autosomal dominant trait.

Follicular atrophoderma has always been associated with other congenital malformations including, Conradi-Hünermann syndrome, Bazex's syndrome and keratosis palmaris et plantaris dissipata. Congenital pseudarthrosis of the tibia has usually been associated with neurofibromatosis. We report a case of follicular atrophoderma in association with congenital pseudarthrosis of the tibia: a previously unreported association with, in our case, a good outcome for the pseudarthrosis.

We describe a new case of Bazex, Dupré and Christol (BDC) syndrome in a family (family B...) where the disease affects four generations. Moreover, we report the clinical and genealogical evolution of the first family (family A...), described in 1966 by Bazex. A review of the literature has enabled us to collect the various symptoms of BDC syndrome, to discuss the relationship of this syndrome with basal cell naevomatosis and X-linked dominant chondrodysplasia punctata, and to discuss the kind of heredity. In family B..., two patients were examined. A one-month-old girl, with hypotrichosis and pseudo pili torti, and her 29-year-old father, with hypotrichosis and dorsal follicular atrophoderma of the hands. In this family, the paternal grand mother, one of her sisters, and the great grand father were also affected, but no basal cell carcinomas were found. In family A..., five patients were followed up. Four brothers, adult men aged 43 to 55 years initially presented only dorsal follicular atrophoderma the hands and face, hypotrichosis and numerous basal cell carcinomas of the face, especially in palpebral, temporal, nasal and forehead sites. Surgery was required and gave better results than radiotherapy, which left sites of sclerosis. Their mother was also affected and had been treated for numerous basal cell carcinomas of the face. The other members of the same generation (two women, two men) were unaffected. But the uncle and the grand father had the disease and at the last generation, a girl, child of one of the brothers affected, presented follicular atrophoderma and hypotrichosis.(ABSTRACT TRUNCATED AT 250 WORDS)

The Bazex-Dupré-Christol syndrome (BDC syndrome) was first described in 1964. Only 14 affected families and 47 patients with this very rare dominant genodermatosis have been reported so far. The three main features of BDC syndrome are (1) follicular atrophoderma, especially on the dorsum of hands and feet, (2) multiple basal cell carcinomas of the face, occurring mainly during the second decade of life, reflecting the clinical relevance of BDC syndrome and (3) congenital generalized hypotrichosis, sometimes with pili torti and trichorrhexis nodosa. The expressivity of the main features varies. Common associated symptoms are milia, calcifying epithelial tumours and hypohidrosis. We present three members of one family with BDC syndrome, a mother and her two sons. In the mother and one son the clinical picture is very typical with all major features, whereas in the other son only follicular atrophoderma and hypotrichosis are present.

四肢伸側に毛孔性皮膚萎縮を持つ中年男子に基底細胞癌が多発した。他の5人兄弟には皮疹をみなかつたが, 母親にも同様の毛孔性皮膚萎縮をみたことよりBazex症候群が疑われた。毛孔性皮膚萎縮は幼児期より前腕, 下腿の伸側ではつきりしており, ほとんどに体毛を伴つたが一部では脱落していた。基底細胞癌は42才時より顔面に初発し, 以後, 頭頸部や限界線照射の既往がある躯幹にも多発した。以上の臨床所見と, 頭髪, 発汗の異常はみられなかつたことを考えあわせ不完全型のBazex症候群と考えた。なお患者は22才時, 尋常性乾癬のため躯幹に限界線照射を受けたが, 両部にも多数の基底細胞癌が出現したことより, Bazex症候群患者には放射線治療は禁忌と考えた。

In 1943 Miescher (1) reported peculiar atrophic changes of the skin of body and scalp in a 7 year old Swiss girl. There were spots of atrophic alopecia on the scalp, and on the extremities and trunk irregular zones in which dimple-like depressions were found at the place of follicular orifices. The child was very small and had thoracic kyphoscoliosis, lumbar lordosis, luxation of the right hip, a considerably shortened right leg, and a moderately shortened left arm. Five years earlier, Burckhardt (2) has described the skeletal condition of the same child, then 2 years old, as chondrodystrophia foetalis calcarea. In the English speaking countries this disease is called chondrodystrophia calcificans congenita, chondro-osseous dystrophy with punctate epiphyseal dysplasia, or similar variations.

Background Bazex–Dupré–Christol syndrome (BDCS; MIM301845) is a rare X-linked dominant genodermatosis characterized by follicular atrophoderma, congenital hypotrichosis and multiple basal cell carcinomas (BCCs). Previous studies have linked BDCS to an 11·4-Mb interval on chromosome Xq25-q27.1. However, the genetic mechanism of BDCS remains an open question. Objectives To investigate the genetic aetiology and molecular mechanisms underlying BDCS. Methods We ascertained multiple individuals from eight unrelated families affected with BDCS (F1–F8). Whole-exome (F1 and F2) and genome sequencing (F3) were performed to identify putative disease-causing variants within the linkage region. Array comparative genomic hybridization and quantitative polymerase chain reaction (PCR) were used to explore copy number variations, followed by long-range gap PCR and Sanger sequencing to amplify the duplication junctions and to define the head–tail junctions. Hi-C was performed on dermal fibroblasts from two affected individuals with BDCS and one control. Public datasets and tools were used to identify regulatory elements and transcription factor binding sites within the minimal duplicated region. Immunofluorescence was performed in hair follicles, BCCs and trichoepitheliomas from patients with BDCS and sporadic BCCs. The ACTRT1 variant c.547dup (p.Met183Asnfs*17), previously proposed to cause BDCS, was evaluated with t allele frequency calculator. Results In eight families with BDCS, we identified overlapping 18–135-kb duplications (six inherited and two de novo) at Xq26.1, flanked by ARHGAP36 and IGSF1. Hi-C showed that the duplications did not affect the topologically associated domain, but may alter the interactions between flanking genes and putative enhancers located in the minimal duplicated region. We detected ARHGAP36 expression near the control hair follicular stem cell compartment, and found increased ARHGAP36 levels in hair follicles in telogen, in BCCs and in trichoepitheliomas from patients with BDCS. ARHGAP36 was also detected in sporadic BCCs from individuals without BDCS. Our modelling showed the predicted maximum tolerated minor allele frequency of ACTRT1 variants in control populations to be orders of magnitude higher than expected for a high-penetrant ultra-rare disorder, suggesting loss of function of ACTRT1 variants to be an unlikely cause for BDCS. Conclusions Noncoding Xq26.1 duplications cause BDCS. The BDCS duplications most likely lead to dysregulation of ARHGAP36. ARHGAP36 is a potential therapeutic target for both inherited and sporadic BCCs. What is already known about this topic? Bazex–Dupré–Christol syndrome (BDCS) is a rare X-linked basal cell carcinoma susceptibility syndrome linked to an 11·4-Mb interval on chromosome Xq25-q27.1.Loss-of-function variants in ACTRT1 and its regulatory elements were suggested to cause BDCS. What does this study add? BDCS is caused by small tandem noncoding intergenic duplications at chromosome Xq26.1.The Xq26.1 BDCS duplications likely dysregulate ARHGAP36, the flanking centromeric gene.ACTRT1 loss-of-function variants are unlikely to cause BDCS. What is the translational message? This study provides the basis for accurate genetic testing for BDCS, which will aid precise diagnosis and appropriate surveillance and clinical management.ARHGAP36 may be a novel therapeutic target for all forms of sporadic basal cell carcinomas.

A dominant inheritance leading to development of nevoid basal cell epitheliomas on the face and follicular atrophoderma on the extremities constitute the two constant manifestations of Bazex syndrome. A patient with both manifestations on the trunk who fulfilled all the criteria for a diagnosis of nevoid basal cell epitheliomas is described. Histopathology of the basal ceil cancer corresponded to that of the fibroepithelial tumor, thus differing from the more common nodular and trichoepitheliomatous persentations. Difficulty in associating the atrophoderrna with a hair follicle (histologically) arises because the latter ceases to exist as a functional unit.

Five patients from a single family are reported who have an inherited condition of which the main features are follicular atrophoderma, abnormalities of scalp hair and multiple basal cell carcinomas. Thes abnormalities are consistent with the syndrome described by Bazex et al. (1964). The pattern of inheritance of this condition is discussed.

• Seven members of one family had a rare, inherited syndrome of follicular atrophoderma, basal cell carcinomas, and localized anhidrosis. Associated findings in some subjects were generalized hypohidrosis and "eczema" involving the face shortly after birth. This syndrome shows dominant inheritance, possibly x-linked. Follicular atrophoderma is an important skin manifestation, as it has been associated in all reported cases with other systemic or cutaneous abnormalities. ( Arch Dermatol 113:948-951, 1977)

• Follicular atrophoderma apparently does not occur alone but is associated with other abnormalities. It is present in three groups: (1) If it is associated with chondrodystrophia calcificans congenita, it occurs only in girls and is due either to an X-chromosomal gene causing the changes in the heterozygote (ie, in the female sex) and prenatal death in the hemizygous state (ie, in the male sex), or to an autosomal dominant gene with expression almost wholly limited to the female sex; (2) If it is associated with Bazex's syndrome, it occurs in male and female persons in successive generations and is due either to an autosomal dominant gene or to an X-linked dominant gene; and (3) If it occurs in association with keratosis palmoplantaris dissipata, keratosis follicularis, and hyperhidrosis palmoplantaris, it may be due to a recessive gene or a mutation. (Arch Dermatol114:1479-1483, 1978)

A dominant inheritance leading to development of nevoid basal cell epitheliomas on the face and follicular atrophoderma on the extremities constitute the two constant manifestations of Bazex syndrome. A patient with both manifestations on the trunk who fulfilled all the criteria for a diagnosis of nevoid basal cell epitheliomas is described. Histopathology of the basal cell cancer corresponded to that of the fibroepithelial tumor, thus differing from the more common nodular and trichoepitheliomatous presentations. Difficulty in associating the atrophoderma with a hair follicle (histologically) arises because the latter ceases to exist as a functional unit.