Hypertrichosis, Congenital Generalized, With Or Without Gingival Hyperplasia

A number sign (#) is used with this entry because of evidence that congenital generalized hypertrichosis with or without gingival hyperplasia (HTC3) is caused by microdeletion or microduplication on chromosome 17q24.2-q24.3.

There is also evidence that HTC3 is caused by mutation in the ABCA5 gene (612503) on chromosome 17q24. One such patient has been reported.

Description

Extreme hirsutism with gingival fibromatosis follows a dominant pattern of inheritance (Weski, 1920; Garn and Hatch, 1950). There is no necessary relationship between the age of development of the gingival changes and the hypertrichosis. The latter may be present at birth but often appears at puberty (Anderson et al., 1969).

For a discussion of genetic heterogeneity of congenital generalized hypertrichosis, see HTC1 (145701).

Clinical Features

Laurence (1857) described a 'bearded and hairy female' who was being exhibited at the Regent-Gallery, a 23-year-old Mexican woman who was 'clothed with hairs' over her entire body except for the palms and the soles. She was 4 feet, 6 inches in height and 'well-proportioned,' and had regular menses. She had a large tuft of hair extending from the chin and smaller growths of hair on the upper lip and cheeks. Her eyebrows were thick and bushy, and she had short hairs over the remainder of the face and 'remarkably copious' hair on her head; all of the hair was jet-black and fine, with no tendency to curl. She had an unusual facies with flattened and expanded alae of the nose ('so soft as to appear destitute of cartilages') and a large mouth with lips everted by a thickening of the alveolar border of the upper jaw and a warty, hard growth arising from the lower gum. Although the lower teeth and upper molars were intact, the upper front teeth were 'all but deficient.' Her ears were unusually long. She appeared 'intelligent and quick.'

Sokolov (1862) provided a postmortem description of Julia Pastrana, the 'bearded and hairy female' previously described by Laurence (1857), who died of 'metro-peritonitis puerperalis' 5 days after giving birth in Moscow on March 20, 1860. Sokolov (1862) noted that her head was rather large in proportion to her body, with the ears and entire face except for the eyes covered with hair of different lengths. Her beard was 'tolerably thick' with straight, black, bristly hair. She had a broad, flat nose with widely exposed apertures and elastic nostrils, and thick, tightly drawn lips surrounding a 'process' extending from the gum. The lower gum was 'morbidly degenerated and covered with a number of hard, conical, lobe-like, pendulous excrescences;' Sokolov (1862) suggested that this degeneration accounted for the loss of the incisor and canine teeth. Her newborn son, who lived only a few hours, showed a striking facial resemblance to his mother, with a flattened nose and thick lips that arched over his mouth. His right ear was flat, without a helix. His head was covered with thick black hair, extending down his forehead to the eyebrows as well as over the backs of his ears and down his neck, shoulders, and back. Microscopic examination of the mother's hair showed collection of the black pigment into a compact mass with no evidence of the central canal in some areas; in other areas, however, especially near the roots, the canal was plainly visible. Sokolov (1862) also detailed the embalming process he used to mummify the bodies of Julia Pastrana and her son.

Witkop (1971) reported 52 cases of gingival fibromatosis with hypertrichosis, and noted an association with epilepsy and mental retardation. Witkop (1971) stated that when hypertrichosis is present, signs of the disease are nearly always reported as appearing at birth or within the first year of life. Vogel (1977) noted that the anticonvulsant drug dilantin produces a phenocopy of the gingival fibromatosis. Horning et al. (1985) described a case of gingival fibromatosis with hypertrichosis.

Bondeson and Miles (1993) provided a historical account of Julia Pastrana (1834-1860), whose mummified body along with that of her son continued to be exhibited for more than a century after their deaths. Microscopic examination of head and beard hair samples from her mummy confirmed that the hairs were normal terminal scalp and face hair, i.e., representing hypertrichosis terminalis rather than hypertrichosis lanuginosa congenita (145700) as had been earlier presumed. Bondeson and Miles (1993) suggested that her severe gingival hyperplasia probably gradually buried such teeth as had erupted, making suspect any observations regarding her dentition. A radiograph of her skull showed normal skull thickness and a pituitary fossa of normal size; panoramic radiographs of her dentition revealed that, with the possible exception of the left lateral incisor, she had a complete permanent (secondary) dentition.

Irvine et al. (1996) reported a 3-generation Irish family with 4 affected members who had an acromegaloid facial appearance and generalized hypertrichosis terminalis without gingival hyperplasia. The phenotype segregated as an autosomal dominant, affecting both males and females and showing male-to-male transmission.

Canun et al. (2003) described a woman with universal congenital hypertrichosis terminalis associated with gingival hyperplasia and a coarse face resembling that of the patient described by Bondeson and Miles (1993).

Mangino et al. (2003) described an Italian family in which hereditary gingival fibromatosis was associated with hypertrichosis. Affected males showed bushy eyebrows with synophrys, which was less evident in females. Marked hypertrichosis was present in 2 males. No patients had hearing loss or epilepsy, and all had normal intelligence.

Sun et al. (2009) examined 16 affected individuals from 3 Han Chinese families segregating autosomal dominant congenital generalized hypertrichosis. All had universal overgrowth of terminal hair and coarse facies; hair overgrowth on the back and limbs was particularly remarkable. All affected individuals showed bushy and dark eyebrows, a broad flat nose (in adults) or a bulbous soft nose (in children), large ears with thick, long, and hairy lobes, and thickened lips. About half of affected individuals had a relatively large head. Except for widely spaced teeth seen in affected adults from 1 family, there were no dental abnormalities in affected individuals, and all had normal gingival growth and mental development. Sun et al. (2009) also studied a 31-year-old Chinese man with extreme HTC, coarse face, and gingival hyperplasia; the authors noted that his phenotype closely resembled that of Julia Pastrana. The Chinese man was recorded as one of the world's hairiest men, with 96% of his body covered in long, thick jet-black terminal hair; he also had a large head, abnormal dental occlusion with delayed tooth eruption, and had undergone surgical treatment for a deformed nose.

Fantauzzo et al. (2012) described a father and son who exhibited generalized hypertrichosis with mild gingival hyperplasia. The hypertrichosis was striking, and most prominent on the face, ears, and upper trunk. Both patients displayed bushy eyebrows with synophrys and elongated eyelashes, as well as downslanted palpebral fissures and epicanthic folds. Facial and body hair was often coarse, straight, and black. The parents reported that their son developed progressive hypertrichosis shortly after birth. Both affected individuals also had bulbous nasal tip, thick nasal wings, long prominent philtrum with a deep groove, and mild thoracic kyphoscoliosis. There was no lip swelling or eversion, and endocrine and metabolic assessments were unremarkable for both patients.

DeStefano et al. (2014) studied an 11-year-old Yemeni girl, born of first-cousin parents, who had congenital generalized hypertrichosis, severe gingival hyperplasia, and epilepsy. She had severe hypertrichosis and low anterior hairline that merged with the eyebrows, as well as excessive body hair on the back and extremities, upper lip, genitalia, and axillary regions. Hair overgrowth progressed on her face, trunk, eyebrows, and eyelashes, and her scalp hair as well as body hair was long and coarse. Histologic analysis of a forearm biopsy demonstrated that the hairs were of the terminal type, since they were medullated and pigmented, and penetrated deep into the dermis. Patient hair follicles were thicker than those of controls, and anagen hairs were present in the patient's biopsy, whereas none were detected in control skin biopsies. In addition, patient hair shafts were significantly longer than those of controls. Gingival hyperplasia became evident at 18 months of age and progressed to the extent that it interfered with tooth eruption and feeding; the patient required multiple surgeries beginning at 3 years of age to remove excessive gum growth. Periodic endocrine and metabolic evaluations always showed normal results. DeStefano et al. (2014) also studied a female infant from Mexico who presented at 3 months of age with universal hypertrichosis that was accentuated on the extremities, back, chest, and face; palms, soles, and distal phalanges were spared. In addition, she had unusual facial features, including widely set eyes and a nose with a bulbous tip and broad base. Her parents reported that the excessive body hair was shed during the first months of life but then grew back with increased length. Histologic analysis of patient hair follicles revealed the presence of large anagen hair follicles deep within the dermis. Her parents and sibs were unaffected, and there was no history of hypertrichosis in the family.

Mapping

Mangino et al. (2003) performed linkage analysis in an Italian family with gingival fibromatosis and hypertrichosis and excluded linkage to previously mapped gingival fibromatosis loci on chromosomes 2p21 (GINGF1; 135300) and 5q13-q22 (GINGF2; 605544). Mangino et al. (2003) suggested that this family provided evidence that hereditary gingival fibromatosis with hypertrichosis is independent of isolated gingival hyperplasia.

Sun et al. (2009) conducted a genomewide scan in a 4-generation Han Chinese family segregating autosomal dominant congenital generalized hypertrichosis, and obtained a maximum multipoint lod score of 2.37 on chromosome 17q24.2-q24.3. Microsatellite typing yielded a maximum 2-point lod score of 3.91 (theta = 0.0) between markers D17S2182 and D17S1786; haplotype analysis in 2 recombinants narrowed the critical region to a 4-Mb interval between D17S795 and D17S1351 containing 9 genes. All affected individuals from the 3 Han Chinese families with HTC showed a null allele for markers D17S2182 and D17S1786, suggesting the possibility of a recurrent genomic microdeletion.

In the Irish family with congenital generalized hypertrichosis, coarse facies, and normal gingivae, originally reported by Irvine et al. (1996), Sun et al. (2009) did not find linkage to chromosome 17q24.2-q24.3, suggesting genetic heterogeneity in autosomal dominant HTC with coarse facies.

Cytogenetics

In a Mexican female infant with generalized hypertrichosis, DeStefano et al. (2014) performed karyotype and FISH analysis that revealed heterozygosity for an apparently balanced de novo translocation between chromosomes 3q12 and 17q25. Karyotype analysis of parents and sibs showed no abnormalities. FISH analysis using BAC clones revealed a cryptic deletion at the breakpoint of chromosome 17. Fine mapping defined an 849.4-kb cryptic breakpoint deletion on chromosome 3p12.2 that did not contain any annotated genes, as well as a 1.3-Mb deletion on chromosome 17q24.2-17q24.3 that encompassed 7 genes: ABCA5 (612503), ABCA6 (612504), ABCA8 (612505), ABCA9 (612507), and ABCA10 (612508), as well as MAP2K6 (601254) and KCNJ16 (605722). The 1.3-Mb deletion was confirmed by quantitative PCR; cloning of the breakpoints did not reveal any evidence for gene disruption. Sequencing all ABCA5 exons and the area approximately 2 kb upstream of the gene revealed no mutations in the second allele. Analysis of RNA from patient keratinocytes and fibroblasts by quantitative RT-PCR showed a 3.7- and 2.4-fold decrease in ABCA5 transcript levels, respectively, and immunoblot analysis demonstrated a striking decrease in levels of glycosylated ABCA5 protein compared to controls. Immunofluorescence staining of patient hair follicles showed dramatically reduced ABCA5 throughout the outer and inner root sheath compared to controls. In addition, there was a 2.5-fold decrease in SOX9 (608160) expression in patient keratinocytes compared to controls, indicating a position effect on the downstream gene. DeStefano et al. (2014) suggested that loss of 1 genomic copy of ABCA5 and its surrounding regulatory elements severely disrupts expression from the other allele and significantly reduces expression levels, resulting in haploinsufficiency of ABCA5. They also suggested that decreased SOX9 expression contributes to the excessive hair overgrowth phenotype of congenital generalized hypertrichosis.

Molecular Genetics

Sun et al. (2009) performed copy number variation (CNV) analysis in 1 affected individual from each of 3 Han Chinese families with congenital generalized hypertrichosis without gingival hyperplasia. They detected genomic microdeletions on chromosome 17q24.2-q24.3 of different sizes and with different breakpoints in all 3 familial cases; all 3 microdeletions were confirmed by quantitative PCR assay and segregated completely with disease in each family. In a 31-year-old man with HTC and gingival hyperplasia, Sun et al. (2009) performed high-resolution CNV screening and identified a de novo 1.4-Mb genomic microduplication on chromosome 17q24.2-q24.3, validated by quantitative PCR assay, that was not present in his unaffected parents. The minimal overlapping genomic region in the 3 families and sporadic patient contains 4 genes, ABCA5 (612503), ABCA6 (612504), ABCA10 (612508), and MAP2K6 (601254). RT-PCR analysis demonstrated mRNA expression of all 4 genes in normal hair follicles. Although Sun et al. (2009) did not detect CNV of this genomic region in 434 unrelated Han Chinese controls, they noted that in a previous large-scale survey of CNVs in the Han Chinese population, Lin et al. (2008) had found that 4 of 300 individuals carried a 203-kb deletion encompassing the 3 ABCA genes; thus Sun et al. (2009) suggested that MAP2K6 was the leading candidate gene from the overlapping region in their patients.

In a father and son with generalized hypertrichosis and mild gingival hyperplasia, Fantauzzo et al. (2012) identified a series of 4 microduplications, measuring 391 kb, 66 kb, 1.2 Mb, and 35 kb, respectively, within a 2.4-Mb region on chromosome 17q24.2-q24.3 located 975 kb upstream of the SOX9 gene (608160). The authors noted that the duplicated region encompassed the 1.4-Mb duplication reported by Sun et al. (2009) in a sporadic case of congenital generalized hypertrichosis. Quantitative PCR using DNA from the affected son revealed that he had a 2.24- and a 1.54-fold increase in relative copy number of 2 different amplicons, respectively, within the duplication region compared to a control individual. FISH analysis demonstrated that the 1.2-Mb duplication was inverted. Immunofluorescence analysis of a biopsy from the son's posterior neck showed a striking decrease in SOX9 protein expression throughout the follicle epithelium, primarily in the proliferative epithelial cells at the base, compared to a control. On histologic examination, patient follicles were more highly pigmented and larger in diameter, particularly in the medulla layer in the center of the hair shaft, compared to control follicles. Fantauzzo et al. (2012) concluded that these findings were consistent with a position effect of the 2.4-Mb duplication on SOX9 expression.

In an 11-year-old Yemeni girl, born of first-cousin parents, who had generalized hypertrichosis and severe gingival hyperplasia as well as epilepsy, DeStefano et al. (2014) performed whole-exome sequencing and identified homozygosity for a splice site mutation in the ABCA5 gene (612503.0001) that segregated with disease in the family. She was also homozygous for a missense mutation in the DGKZ gene (601441), which the authors suggested might contribute to the pathogenesis of her seizures. RT-PCR of RNA from patient skin showed complete absence of wildtype ABCA5 transcript, and immunoblot analysis showed that the glycosylated form of the protein was absent from patient fibroblasts, suggesting loss of function of both the full- and half-transporters encoded by ABCA5 in congenital generalized hypertrichosis. Analysis of patient and control keratinocytes by quantitative RT-PCR showed no significant difference in SOX9 expression.