Naegeli-Franceschetti-Jadassohn Syndrome 

Updated: Aug 30, 2018
Author: Rebekah H Clifford, MD; Chief Editor: Dirk M Elston, MD 

Overview

Background

Description

Naegeli-Franceschetti-Jadassohn (NFJ) syndrome is a rare autosomal dominant form of ectodermal dysplasia that affects the skin, sweat glands, nails, and teeth. The incidence is estimated to be 1 case in 2-4 million population. NFJ syndrome is entry 161000 in the Online Mendelian Inheritance in Man database.[1] The syndrome is allelic to dermatopathia pigmentosa reticularis.

In 1927, Naegeli first described the syndrome as familiärer Chromatophoren-Naevus in a Swiss family. In 1954, Franceschetti and Jadassohn further analyzed the syndrome, as did Itin and colleagues in 1993.

NFJ syndrome is a reticulate pigmentary disorder. Other reticulate pigmentary diseases include X-linked reticulate pigmentary disorder, dermatopathia pigmentosa reticularis, Dowling-Degos disease, dyschromatosis, confluent and reticulated papillomatosis of Gougerot and Carteaud, and reticulated acropigmentation of Kitamura.

Differential diagnoses

Franceschetti and Jadassohn distinguished Naegeli syndrome from incontinentia pigmenti (Bloch-Sulzberger syndrome) by the equal frequency of the disorder in males and females and by the presence of palmar and plantar hyperkeratosis, hypohidrosis, and dental abnormalities. In contrast, incontinentia pigmenti is inherited as an X-linked dominant trait.

Dermatopathia pigmentosa reticularis, allelic to NFJ, shares many features and may be a variation of the same genetic defect, but is distinguished by alopecia, reticulate pigmentation that lasts into adulthood, and the lack of dental abnormalities.[2] Dyskeratosis congenita patients can have dental findings, reticulate hyperpigmentation, adermatoglyphia, palmoplantar hyperkeratosis, and nail anomalies similar to NFJ patients. However, these patients may have alopecia, premalignant leukoplakia, poikiloderma, and blood dyscrasias and dyskeratosis congenita is inherited most commonly in an X-linked recessive manner.

The distribution of the reticulate pigmentation in Dowling-Degos, dyschromatosis symmetrica and hereditaria, and reticulate acropigmentation of Kitamura makes these disorders easier to distinguish.[2]

Hereditary bullous acrokeratotic poikiloderma of Weary-Kindler has some striking similarities to NFJ syndrome. However, hypohidrosis is not reported with this entity, and dental abnormalities are only rarely observed.[3]

Pathophysiology

Naegeli-Franceschetti-Jadassohn (NFJ) syndrome may be associated with a number of markers located in the vicinity of the type I keratin gene cluster on band 17q21.

Etiology

Wittock et al studied a single family of British origin, identifying 25 members that are affected by Naegeli-Franceschetti-Jadassohn (NFJ) syndrome and 37 that are unaffected.[4] 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.[4] 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.[2, 4]

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.[2] 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[5] ; frizzled homolog 2, a molecule involved in epithelial cell-signaling pathways[6] ; ADAM-11, a protein implicated in cell-to-cell and cell-to-matrix interactions[7] ; GRB-7, a membrane-bound growth factor receptor of uncertain function[8] ; and the MEOX1 gene.[9]

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.[2, 10, 11, 12]

Letters by Titeux et al and Van Steensel et al call into question the hypothesis of haploinsufficiency causing the dominant effect seen in NFJ syndrome.[13] The authors of Titeux et al 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.

Van Steensel et al describe a 41-year-old woman of Dutch descent with flexural hyperpigmentation, nail dystrophy, and reduced dermatoglyphics, but with normal sweating. She was found to have a heterozygous missense mutation in KRT14. The authors believe this case casts doubt on haploinsufficiency causing NFJ syndrome because missense mutations in keratins are considered to have a dominant negative effect, which was not observed in this case.[14]

Epidemiology

Frequency

United States

Naegeli-Franceschetti-Jadassohn (NFJ) syndrome is rare.

International

The estimated incidence of Naegeli-Franceschetti-Jadassohn (NFJ) syndrome is approximately 1 case in 2-4 million population.

Race

Several families with Naegeli-Franceschetti-Jadassohn (NFJ) syndrome have been reported in Switzerland, Japan, Italy, Greece, and Saudi Arabia. There has also been one case report of a woman of Dutch descent and a case report of a man from India.

Sex

No sexual predilection is recognized for Naegeli-Franceschetti-Jadassohn (NFJ) syndrome.

Age

Because of the inability to sweat, Naegeli-Franceschetti-Jadassohn (NFJ) syndrome is usually diagnosed early in life. The lack of fingerprint lines (ie, dermatoglyphics) can be easily checked.

 

Presentation

History

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.[15] 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.[16] 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.[17]

Physical Examination

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.

Lack of dermatoglyphics in a patient with Naegeli- Lack of dermatoglyphics in a patient with Naegeli-Franceschetti-Jadassohn syndrome.

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.

Reticulated pigmentation on the trunk in a patient Reticulated pigmentation on the trunk in a patient with Naegeli-Franceschetti-Jadassohn syndrome.
Periorbital reticulated pigmentation in a patient Periorbital reticulated pigmentation in a patient with Naegeli-Franceschetti-Jadassohn syndrome.

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.[18, 19, 20]

Spotty palmoplantar hyperkeratosis in Naegeli-Fran Spotty palmoplantar hyperkeratosis in Naegeli-Franceschetti-Jadassohn syndrome.
Defective denture with yellow spots on the enamel Defective denture with yellow spots on the enamel in a patient with Naegeli-Franceschetti-Jadassohn syndrome.

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.[20, 21]

Several slightly different clinical phenotypes and intrafamilial variability are also reported.[20, 22, 23, 24, 21, 14, 25] An additional patient with greater variation from the phenotype was identified in Greece.[26] 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.

Bela et al reported an additional case they believe to be an example of NFJ syndrome with pigmentary dilution of the hair not previously reported. The patient was a 27-year-old man with hypohidrosis and heat intolerance; photophobia; reticulate and mottled pigmentation of the whole body, including the hands, feet, elbows, knees, and tongue; yellow teeth with enamel defects; atrophic skin of the hands and feet; dystrophy of all the nails; mild pigmentary dilution of the hair; and an absence of dermatoglyphics. The patient had molecular analysis for KRT 14 exons 1, 4, and 6 and lacked a mutation. The authors believe the case to be representative of NFJ syndrome and stipulate that further sequencing studies of KRT 14 are needed to diagnose this patient.[27]

 

DDx

 

Workup

Histologic Findings

The histologic findings in Naegeli-Franceschetti-Jadassohn (NFJ) syndrome include slight hyperpigmentation of the basal layer and dermal melanophages. In addition, the variable occurrence of milia is described as part of NFJ syndrome.[26]

 

Treatment

Medical Care

No treatment is effective for Naegeli-Franceschetti-Jadassohn (NFJ) syndrome. As with other ectodermal dysplasias, exposure to heat should be limited and sufficient hydration is recommended. Tooth care to prevent early caries is indicated. Doxycycline has been found to interfere with tumor necrosis factor-alpha (TNF-alpha)–mediated signaling and apoptosis in vitro and may have a role in future treatment.[2]

Activity

Sports-related exercise should be restricted to only nonexhausting activities. In particular, patients with Naegeli-Franceschetti-Jadassohn (NFJ) syndrome can be allowed to swim.