Focal Facial Dermal Dysplasia 3, Setleis Type

A number sign (#) is used with this entry because of evidence that focal facial dermal dysplasia-3, Setleis type (FFDD3), is caused by homozygous mutation in the TWIST2 gene (607556) on chromosome 2q37.

Description

The focal dermal dysplasias (FFDDs) are a group of related developmental defects characterized by bitemporal or preauricular skin lesions resembling aplasia cutis congenita. FFFD3 is an autosomal recessive disorder characterized by bitemporal skin lesions with variable facial findings, including thin and puckered periorbital skin, distichiasis and/or absent eyelashes, upslanting palpebral fissures, a flat nasal bridge with a broad nasal tip, large lips, and redundant facial skin (summary by Slavotinek et al., 2013).

FFDD2 (614973) is characterized by the same facial features as FFDD3, but the inheritance is autosomal dominant.

For a classification and a discussion of genetic heterogeneity of FFDD, see FFDD1 (136500).

Clinical Features

Setleis et al. (1963) described 5 children in 3 apparently unrelated Puerto Rican families who had an aged leonine appearance with puckered skin about the eyes, absent eyelashes on both lids or multiple rows on the upper lids and none on the lower lids, eyebrows that slanted sharply upward laterally, and a rubbery feel of the nose and chin. Some of the patients showed bilateral temporal marks superficially like forceps marks and like the lesions seen in focal facial dermal dysplasia.

Rudolph et al. (1974, 1974) described a single patient with what they considered to be the sixth case of this condition.

Marion et al. (1987) reported 2 additional affected children. All affected persons came from Puerto Rico, with 7 of 8 tracing their ancestry to the towns of San Sebastian and Aguadilla. One patient reported by Marion et al. (1987) was the product of a consanguineous mating. Two sets of affected sibs have been described. Marion et al. (1987) noted periorbital puffiness with wrinkling of the skin, flattening of the nasal bridge with a bulbous nasal tip, and increased mobility of the facial skin with markedly redundant facial soft tissue. Growth and development were normal.

Clark et al. (1989) described 3 related children with Setleis syndrome who were not of Puerto Rican descent. Two of them had imperforate anus, a feature not previously reported.

Tsukahara et al. (1995) presented a follow-up on a Japanese patient with Setleis syndrome originally reported by Matsumoto et al. (1991). In addition to characteristic 'coarse' facial appearance, bitemporal 'forceps marks,' skin aplasia, sparse hair, and skin hypo- and hyperpigmentation, at age 8 years he showed previously undescribed manifestations, including an aberrant hair pattern on the forehead, linear skin lesions on the forehead, short palpebral fissures, a small skin tag on the right cheek, cone-shaped teeth, and pectus carinatum. Dermatoglyphic studies showed aberrant distal palmar creases (simian crease variant), 8 arches, and reduced total finger ridge count. When serial photographs were reviewed, his facial characteristics became more obvious with increasing age.

Lee et al. (2015) studied a 21-year-old man who displayed the characteristic features of FFDD3, including bitemporal scar-like lesions, low frontal hairline, whorled hair, upward-slanting eyebrows, thin lateral eyebrows, periorbital puffiness, short palpebral fissures, distichiases of the upper eyelashes, paucity of the lower eyelashes, bulbous nasal tip, nasal septum below the alae, prominent lips, and a horizontal chin furrow. He did not have a pectus deformity or cardiac or genitourinary abnormalities.

Inheritance

Tukel et al. (2010) demonstrated that Setleis syndrome is an autosomal recessive disorder.

Mapping

Tukel et al. (2010) performed homozygosity mapping using genomic DNA from 5 affected individuals and 26 other members of the Puerto Rican family with Setleis syndrome originally reported by Setleis et al. (1963) and found that microsatellites D2S1397 and D2S2968 were homozygous in all affected individuals, mapping the disease locus to chromosome 2q37.3. Haplotype analyses of additional markers in the Puerto Rican family and a consanguineous Arab family with Setleis syndrome, previously reported by Al-Gazali and Al-Talabani (1996), narrowed the disease locus to an approximately 3-Mb interval between D2S2949 and D2S2253.

Cytogenetics

In a 21-year-old man with characteristic features of FFDD3, who was negative for mutation in the TWIST2 gene, Lee et al. (2015) identified heterozygosity for a 3.36-Mb duplication of chromosome 1p36.22-p36.21 (chr1:10,536,144-13,992,333; GRCh37). The duplication was inherited from his clinically unaffected father, indicating lack of penetrance. The authors noted that unlike 3 previously reported unrelated patients with Setleis syndrome and de novo duplication or triplication at chromosome 1p36.22-p36.21 (Weaver et al., 2015), this patient did not exhibit developmental delay or intellectual disability.

Molecular Genetics

Tukel et al. (2010) analyzed the candidate gene TWIST2 (607556) in the Puerto Rican family with Setleis syndrome, originally reported by Setleis et al. (1963), and in the consanguineous Arab family previously reported by Al-Gazali and Al-Talabani (1996), and identified homozygous nonsense mutations that segregated with disease in each family (607556.0001 and 607556.0002, respectively). Sequencing of TWIST2 in 5 additional unrelated probands with Setleis syndrome or focal facial dermal dysplasia did not reveal any disease-causing mutations, demonstrating genetic heterogeneity.

In 2 Mexican-Nahua sibs with the characteristic features of Setleis syndrome, Cervantes-Barragan et al. (2011) identified homozygosity for a 1-bp deletion in the TWIST2 gene (607556.0003). Their parents and 2 sibs were heterozygous for the mutation, and all 4 heterozygotes exhibited distichiasis of the upper eyelids and partial absence of the lower eyelashes. Cervantes-Barragan et al. (2011) concluded that heterozygotes with TWIST2 mutations may have syndromic manifestations.

Animal Model

Tukel et al. (2010) analyzed Twist2 knockout mice on a 129/C57 mixed background and observed a facial phenotype similar to that of Setleis syndrome patients, including thin skin and sparse hair with bilateral pronounced alopecic areas between the ears and the eyes, resembling the bitemporal forceps marks in humans. They also had absent lower eyelashes, narrow snouts, protruding chins, short anterior-posterior head diameters, and low-set dysmorphic ears. Histologically, the bilateral alopecic areas in the Twist2 -/- mice were similar to the defects in Setleis syndrome patients, including hypoplastic dermis and absence of epidermal appendages and subcutaneous fat. The knockout mice also had absent or hypoplastic Meibomian glands, as seen in Setleis syndrome patients.