Naegeli-Franceschetti-Jadassohn Syndrome Clinical Presentation

Compared with reticulate hyperpigmentation, which fades, hypohidrosis and palmoplantar keratoderma usually persist in Naegeli-Franceschetti-Jadassohn (NFJ) syndrome. In a reexamination of the original family, the natural history of the syndrome was described. The pedigree now documents findings in 6 generations including 62 members with 14 persons affected by NFJ syndrome.

Further data have been accumulated from the original family with NFJ syndrome. Mevorah et al examined 2 patients and documented a mild reduction in the number of functional sweat glands when they were exposed to moderate heat stress.^[3] However, the patients remained comfortable and had normal thermal regulation. In addition, Frenk et al performed an electron microscopic study of skin samples from 2 members in the original family.^[4] Pigment incontinence was accompanied by varying amounts of colloid-amyloid bodies in the papillar dermis and occasionally around sweat glands in the reticular dermis. This finding is also described in incontinentia pigmenti.^[5]

The main syndrome of Naegeli-Franceschetti-Jadassohn (NFJ) syndrome, an ectodermal dysplasia, is heat intolerance worsened by reduced sweating, with a potential to cause collapse, flushing, and dizziness after even mild exercise. Clinically, patients lack dermatoglyphics, or fingerprint lines, as shown below.

Patients also have a characteristic reticular pigmentation, without a preceding inflammatory stage, on their neck, chest, and abdomen, that begins when they are aged 1-5 years and improves after puberty. In many cases, the pigmentation completely resolves at adolescence. In addition, increased spotlike pigmentation may be present around the mouth and eyes. Note the images below.

Affected individuals have mild palmoplantar keratosis, depicted below, brittle fingernails, and defective tooth enamel with a rough surface and yellow spots (shown below). Many patients may develop complete loss of adult teeth.^{[6, 7, 8]}

To date, all patients reported had normal intelligence and were usually in good health. Malalignment of the great toenails, bullae, and periungual and mucosal pigmentation are only rarely observed.^{[8, 9]}

Several slightly different clinical phenotypes and intrafamilial variability are also reported.^{[8, 10, 11, 12, 9]} Besides the families in Switzerland, Japan, and Italy,^[12] an additional patient was identified in Greece.^{[13, 14]} In this patient's family, the reticular hyperpigmentation was accentuated on the flexural areas of the arms and legs; neck; axillae; and cruroinguinal, antecubital, and popliteal regions, where extensive milia formation was observed. The formation of milia had not been reported in the other patients. In the father and grandfather of this patient, the generalized reticular hyperpigmentation was reported to have faded in adulthood. The hyperpigmented macules varied in color (brown to black), pattern, and distribution. Some of the macules were frecklelike or angulated, and they tended to form a reticulate pattern. Others had a mottled pattern or formed streaks and whorls.

Wittock et al studied a single family of British origin, and 25 members are affected by Naegeli-Franceschetti-Jadassohn (NFJ) syndrome and 37 are unaffected.^[15] Markers located on arms 1q, 12q, and 18q were excluded for links to the disease; this finding indicates that the gene for NFJ syndrome is not located in the epidermal differentiation complex, the type II keratin cluster, or the desmosomal cadherin cluster, respectively.

In contrast, a highly significant linkage was detected with a number of markers located in the vicinity of the type I keratin gene cluster on band 17q21, with maximum 2-lod scores of 4.16 and 3.717 for the markers D17S1787 and D17S1886, respectively.^[15] The genetic defect appears to be a region of the gene encoding the KRT14 nonhelical head (E1/V1) domain located between the microsatellite markers D17S798 and D17S957, which are separated by approximately 26.97 cM. A nonsense mutation in a corresponding region of KRT5 has been found in Dowling-Degos disease and a missense mutation in the V1 domain of KRT5 has been described in patients with epidermolysis bullosa with mottled pigmentation. These observations support a mutation in a basal keratin gene as causing both blistering and pigmentary disorders.^{[1, 15]}

While abnormal keratin filament structure and function can explain hypohidrosis and epithelial differentiation abnormalities, the absence of dermatoglyphics is not well understood. Proliferation of KRT14 -expressing basal cells leads to development of dermatoglyphics during the first trimester of gestation. KRT14 is therefore considered a candidate gene.^[1] Other candidate genes have been mapped to the region critical to NFJ syndrome; these include the granulin gene that encodes a protein involved in epithelium growth and differentiation^[16] ; frizzled homolog 2, a molecule involved in epithelial cell-signaling pathways^[17] ; ADAM-11, a protein implicated in cell-to-cell and cell-to-matrix interactions^[18] ; GRB-7, a membrane-bound growth factor receptor of uncertain function^[19] ; and the MEOX1 gene.^[20]

Studies suggest that NFJ syndrome is caused by frameshift or nonsense mutations in KRT14, leading to early termination of translation- or nonsense-mediated degradation of mRNA (50% or less), with resulting haploinsufficiency. Type I keratins have been shown to protect keratinocytes by blocking tumor necrosis factor-alpha (TNF-alpha) proapoptotic signals, likely through interaction with TNF receptor type 1 (TNFR1)–associated death domain protein (TRADD). Specifically, decreased KRT14 has been shown to lead to increased TNF-alpha–induced apoptosis of keratinocytes.^{[14, 21, 22, 1]}

A recent letter by Titeux et al calls into question the hypothesis of haploinsufficiency causing the dominant effect seen in NFJ syndrome.^[23] The authors studied a patient with a null mutation of KRT14 with clinical manifestations of epidermolysis bullosa simplex but with absent dermatoglyphs. The authors stipulate that the patient’s offspring are heterozygous carriers of the KRT14 null mutation and would therefore have some manifestations of NFJ syndrome, according to the haploinsufficiency hypothesis. However, the 2 healthy children displayed no pigmentation abnormalities, had normal dermatoglyphs, and had no other cutaneous findings of NFJ syndrome. The authors offer the following alternative explanations to haploinsufficiency:

• The synthesis of short serine-rich peptides arising from the K14 head domain could impair its assembly.
• There may be alteration of a putative noncoding RNA (ncRNA) arising from the 5′ terminus of KRT14.