Naegeli-Franceschetti-Jadassohn Syndrome

A number sign (#) is used with this entry because of evidence that the Naegeli-Franceschetti-Jadassohn syndrome (NFJS) is caused by heterozygous mutation in the keratin-14 gene (KRT14; 148066) on chromosome 17q21.

A closely related disorder, dermatopathia pigmentosa reticularis (DPR; 125595), is also caused by heterozygous mutation in the KRT14 gene.

Clinical Features

Naegeli (1927) described the syndrome in a father and 2 daughters. In a restudy of the original family, Franceschetti and Jadassohn (1954) documented autosomal dominant inheritance. The disorder was earlier confused with incontinentia pigmenti (IP; see 308300). Differences from IP include (1) equal frequency in males and females; (2) plantar and palmar hypohidrosis and hyperkeratosis; and (3) uncommon blistering and inflammatory phenomena. The cardinal features are reticular cutaneous pigmentation (starting at about the age of 2 years without a preceding inflammatory stage), discomfort provoked by heat with diminished sweat gland function, poor teeth, and moderate hyperkeratosis of the palms and soles. Males and females are equally affected.

Sparrow et al. (1976) described 7 affected persons in 1 family, with male-to-male transmission. Hypoplasia of the dermatoglyphics was present.

Itin et al. (1993) reexamined the original family with NFJS 65 years after the first description (Naegeli, 1927). The pedigree included 62 members with 14 affected patients; Itin et al. (1993) examined the 10 living patients. They found that the reticulate pigmentation faded after puberty and sometimes disappeared completely in old age. Hypohidrosis, the main problem for the patients, remained constant. Teeth were always severely affected, leading to early total loss. All patients lacked dermatoglyphics. (Adermatoglyphia is a feature of several ectodermal dysplasias (Freire-Maia and Pinheiro, 1984).) Diffuse palmoplantar keratoderma may coexist with punctate keratoses that are sometimes accentuated in the creases or exhibit a linear pattern. Four patients had congenital malalignment of the great toenails, a feature not previously described.

See 246500 for a similar condition possibly inherited as a recessive.

NFJS and dermatopathia pigmentosa reticularis (DPR; 125595) are closely related autosomal dominant ectodermal dysplasia syndromes that clinically share complete absence of dermatoglyphics (fingerprint lines), a reticulate pattern of skin hyperpigmentation, thickening of the palms and soles (palmoplantar keratoderma), abnormal sweating, and other subtle developmental anomalies of the teeth, hair, and skin.

Mapping

Whittock et al. (2000) studied a multigeneration NFJS family of Anglo-Saxon British descent using microsatellite markers. Significant genetic linkage to chromosome 17q was observed using marker D17S1787, with a maximum 2-point lod score of 4.166 at a recombination fraction of theta = 0. Recombination events in the family place the gene in a 26.97-cM interval between markers D17S798 and D17S957, a region known to contain the type I keratin (see 601077) gene cluster and other genes expressed in epithelia. Keratins K15 (148030), K19 (148020), and K20 (608218), plakoglobin (JUP; 173325), and MEOX1 (600147) were excluded as candidates by direct sequencing of genomic PCR products.

Sprecher et al. (2002) studied the large Swiss family with NFJS originally described by Naegeli (1927) and assessed linkage to chromosome 17q, which was proposed to harbor the NFJ syndrome gene. Their results narrowed the NFJS locus region to 6 cM flanked by D17S933 and D17S934 with a maximum multipoint lod score of 2.7 at marker locus D17S800. The critical interval spanned approximately 5.4 Mb and contained a minimum of 45 distinct genes. Sprecher et al. (2002) scrutinized 13 new candidate genes in addition to 5 genes previously examined, established the genomic organization of 10 of these genes, and excluded all of them by mutation analysis. They identified a novel keratin protein (KRT24; 607742) that bears high similarity to the type I keratins and displays a unique expression profile.

Lugassy et al. (2006) studied 4 families with NFJS, including the family originally reported by Naegeli (1927), as well as a family with a closely related disorder, dermatopathia pigmentosa reticularis (DPR; 125595). They confirmed the previously demonstrated linkage of NFJS/DPR to 17q11.2-q21. Combined multipoint analysis generated a maximal lod score of 8.3 at marker D17S800 at a recombination fraction of 0.0. The disease interval was found to harbor 230 genes, including a large cluster of keratin genes.

Molecular Genetics

In 4 families with NFJS, including the family originally reported by Naegeli (1927), as well as in a family with DPR, Lugassy et al. (2006) identified heterozygous nonsense or frameshift mutations in the KRT14 gene that segregated with the disease trait in all 5 families (148066.0015, 148066.0016, and 148066.0019). In contrast with KRT14 mutations affecting the central alpha-helical rod domain of keratin-14, which cause epidermolysis bullosa simplex of several clinical types, NFJS/DPR-associated mutations were found in a region of the gene encoding the nonhelical head (E1/V1) domain and were predicted to result in very early termination of translation. The data suggested that KRT14 plays an important role during ontogenesis of dermatoglyphics and sweat glands. Among other functions, the N-terminal part of keratin molecules confers protection against proapoptotic signals. Ultrastructural examination of patient skin biopsy specimens provided evidence for increased apoptotic activity in the basal cell layer where KRT14 is expressed, suggesting that apoptosis is an important mechanism in the pathogenesis of NFJS/DPR.

History

Family 1 in the study of NFJS by Lugassy et al. (2006) was the large multigenerational Swiss family in which the disorder was originally described by Naegeli in 1927 and had been followed since that time in a number of reports over a period of 80 years (Franceschetti and Jadassohn, 1954; Itin et al., 1993).