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DISEASE CARD

Disease group Ectodermal displasias
DISEASE NAME NAEGELI-SYNDROME
Synonymous Naegeli-Franceschetti-Jadassohn Syndrome
Estimated prevalence 1/1 000 000 to 1/3 000 000
OMIM 161000
Inheritance Autosomal dominant
Gene (s) KRT14 (148066)

Definition

Naegeli-Franceschetti-Jadassohn (NFJ) syndrome is a rare ectodermal dysplasia that affects the skin, sweat glands, nails, and teeth. NFJ was first described in a family by Naegeli in 1927 and was re-evaluated in the same family by Franceschetti and Jadassohn in 1954.1, 2 NFJ is inherited as an autosomal dominant condition and is caused by mutations in the KRT14 gene (17q11.2-17q21). Males and females are equally affected.3, 4

 

Clinical Description

The most distinctive features of NFJ are absence of dermatoglyhics (no fingerprints), reticular cutaneous hyperpigmentation, hypohidrosis and palmoplantar hyperkeratosis (PPK).5 Hyperpigmentation manifests around the age of two without a preceding inflammatory stage, fades with puberty and usually disappears in the 5-7th decade. Hypohidrosis is a burdensome symptom in NFJ patients, due to diminished sweat gland function, and remains constant throughout adulthood. NFJ patients further show discomfort provoked by heat, moderate diffuse or punctate palmoplantar hyperkeratosis of the palms and soles and nail dystrophy. Congenital misalignment of the great toenails was reported in some patients. Tooth enamel defects with caries end early loss (hypodontia) is common. 6, 7

 

Dermatopathia pigmentosa reticularis (OMIM 125595), also related to heterozygous KRT14 mutations, is associated with noncicatricial alopecia, onychodystrophy and overlapping clinical features to NFJ like reticulate hyperpigmentation, abnormal sweating, PPK and adermatoglyphia. Thus, NJF and DPR are considered to represent a continuous phenotypic spectrum of the same entity.8, 9

 

Pathogenesis

NFJ associated KRT14 mutations affect the non-helical head domain (E1/V1) and are suggested to result in very early termination of translation. Data indicates that those KRT14 mutations affect the ontogenesis of dermatoglyphics and sweat glands. Furthermore, the N-terminal part of keratin molecules confers protection to proapoptotic signals, and patient skin biopsy examination provided evidence for increased TNF-alpha mediated apoptotic activity in the basal cell layer.10, 11

 

Diagnosis

Diagnosis is based on clinical features and can be confirmed by molecular analysis. Histopathologic features comprise mild hyperkeratosis and accumulation of epidermal melanosomes in hyperpigmented skin areas.  

Differential diagnoses include incontinentia pigmenti, dermatopathia pigmentosa reticularis, dyskeratosis congenita, pachyonychia congenita and Dowling-Degos disease. 10

 

Treatment

Treatment is symptomatic. Dry skin may profit from moisturizers, hyperkeratosis can be treated with keratolytics and hyperthermia should be prevented by use of appropriate clothing and physical cooling with e.g. wet dressings or cool water during warm periods. Dental care and oral hygiene is imperative to prevent caries and tooth loss.

 

 

References

1. Naegeli O. Familiärer chromatophorennaevus. Schweiz Med Wochenschr. 1927;57:48.

2. Franceschetti A, Jadassohn W. [On incontinentia pigmenti and differentiation of two syndromes appearing under the same name]. Dermatologica. 1954;108(1):1-28.

3. Whittock NV, Coleman CM, McLean WH, et al. The gene for Naegeli-Franceschetti-Jadassohn syndrome maps to 17q21. J Invest Dermatol. 2000;115(4):694-698.

4. Sprecher E, Itin P, Whittock NV, et al. Refined mapping of Naegeli-Franceschetti- Jadassohn syndrome to a 6 cM interval on chromosome 17q11.2-q21 and investigation of candidate genes. J Invest Dermatol. 2002;119(3):692-698.

5. Sparrow GP, Samman PD, Wells RS. Hyperpigmentation and hypohidrosis. (The Naegeli-Franceschetti-Jadassohn syndrome): report of a family and review of the literature. Clin Exp Dermatol. 1976;1(2):127-140.

6. Itin PH, Lautenschlager S, Meyer R, Mevorah B, Rufli T. Natural history of the Naegeli-Franceschetti-Jadassohn syndrome and further delineation of its clinical manifestations. J Am Acad Dermatol. 1993;28(6):942-950.

7. Itin PH, Burger B. Spontaneous fading of reticular pigmentation in Naegeli-Franceschetti-Jadassohn syndrome. Dermatology. 2010;221(2):135-136.

8. Burger B, Spoerri I. Naegeli-Franceschetti-Jadassohn syndrome and dermatopathia pigmentosa reticularis: intrafamilial overlap of phenotypes in patients with the same KRT14 frameshift variant. 2019;181(4):864-866.

9. Ralser DJ, Kumar S, Borisov O, et al. Identification of a founder mutation in KRT14 associated with Naegeli-Franceschetti-Jadassohn syndrome. 2020;183(4):756-757.

10. Lugassy J, Itin P, Ishida-Yamamoto A, et al. Naegeli-Franceschetti-Jadassohn syndrome and dermatopathia pigmentosa reticularis: two allelic ectodermal dysplasias caused by dominant mutations in KRT14.Am J Genet. 2006;79(4):724-730

11. Lugassy J, McGrath JA, Itin P, et al. KRT14 haploinsufficiency results in increased susceptibility of keratinocytes to TNF-alpha-induced apoptosis and causes Naegeli-Franceschetti-Jadassohn syndrome. J Invest Dermatol. 2008;128(6):1517-1524.