eMedicine Specialties > Dermatology > Pediatric Diseases

Naegeli-Franceschetti-Jadassohn Syndrome

Author: Theo Rufli, MD, Professor of Dermatology and Venereology, Chair, Department of Dermatology, University Hospital of Basle, Switzerland
Contributor Information and Disclosures

Updated: Dec 2, 2009

Introduction

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. The syndrome is allelic to dermatopathia pigmentosa reticularis.

In 1927, Naegeli first described the syndrome as familiãrer 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.

Hereditary bullous acrokeratotic poikiloderma of Weary-Kindler has some striking similarities to NFJ syndrome. However, hyperhidrosis is not reported with this entity, and dental abnormalities are only rarely observed.¹

Changes in the rete ridges such as those in Dowling-Degos disease and amyloid deposition such as that in macular amyloidosis are not found in NFJ syndrome.^2,3 Changes in hair follicles or apocrine ducts do not occur in NFJ syndrome; this observation excludes Fox-Fordyce disease.⁴

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 (see Causes).

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, and Greece (see Physical).

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.

Clinical

History

• Compared with reticulate hyperpigmentation, which fades, hypohidrosis and palmoplantar keratoderma usually persist in Naegeli-Franceschetti-Jadassohn (NFJ) syndrome.
• In a recent 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 has 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.⁵ 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.⁶ 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.⁷

Physical

• 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-Franceschetti-Jadassohn syndrome.

    [ CLOSE WINDOW ]

    

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

• Patients also have a characteristic reticular pigmentation on their neck, chest, and abdomen, shown below, that begins when they are aged 1-5 years and improves after puberty.
  • 
    

    

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

    [ CLOSE WINDOW ]

    

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

  • In many cases, the pigmentation completely resolves at adolescence.
  • In addition, increased spotlike pigmentation may be present around the mouth and eyes, as in the image below.
  • 
    

    

    Periorbital reticulated pigmentation in a patient with Naegeli-Franceschetti-Jadassohn syndrome.

    [ CLOSE WINDOW ]

    

    Periorbital reticulated pigmentation in a patient with Naegeli-Franceschetti-Jadassohn syndrome.

• Affected individuals have mild palmoplantar keratosis, depicted below, brittle fingernails, and defective dentures with yellow spots on the enamel, shown below.^8,9,10
  • 
    

    

    Spotty palmoplantar hyperkeratosis in Naegeli-Franceschetti-Jadassohn syndrome.

    [ CLOSE WINDOW ]

    

    Spotty palmoplantar hyperkeratosis in Naegeli-Franceschetti-Jadassohn syndrome.

  • 
    

    

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

    [ CLOSE WINDOW ]

    

    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.
• Incomplete forms of variations of NFJ syndrome are reported.^10,11
  • Several slightly different clinical phenotypes and intrafamilial variability are also reported.^12,13,14
  • Malalignment of the great toenails¹⁴ and periungual and mucosal pigmentation are only rarely observed. Characteristically, the pigmentation starts without a preceding inflammatory stage.
• Besides the families in Switzerland, Japan, and Italy,¹³ an additional patient was identified in Greece.^15,16
  • 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.

Causes

In the single family of British origin, 25 members are affected by Naegeli-Franceschetti-Jadassohn (NFJ) syndrome, and 37 are unaffected.¹⁰ Markers located on chromosome arms 1q, 12q, 18q were excluded for links to the disease; this finding indicated that the gene for NFJ syndrome was 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.¹⁷ Hence, the genetic defect in this family is located between the microsatellite markers D17S798 and D17S957, which are separated by approximately 26.97 cM. However, the gene defect is still unknown. Other genes that encode differentiation-specific keratins such as the type I keratins K-15, K-19, and K-20; plakoglobin; and the MEOX1 gene have been excluded.¹⁷

The lack of dermatoglyphics is likely due to a defective protein that is involved in epithelial development and/or epithelial-mesenchymal interactions perhaps less likely due to the structure of the molecule. A number of candidate genes of this type have been mapped to the region critical to NFJ syndrome; these include the granulin gene that encodes a protein involved in epithelium growth and differentiation¹⁸ ; frizzled homolog 2, a molecule involved in epithelial cell-signaling pathways¹⁹ ; ADAM-11, a protein implicated in cell-cell and cell-matrix interactions,²⁰ and GRB-7, a membrane-bound growth factor receptor of uncertain function²¹ ; and the MEOX1 gene.²²

Studies suggest that NFJ syndrome is caused by mutations in KRT14, with haploinsufficiency resulting in keratinocytes being susceptible to apoptosis induced by tumor necrosis-factor-alpha.^16,23,24,25

• Search for CME/CE on This Topic »

• Dermatopathia Pigmentosa Reticularis (Dermatology)