eMedicine Specialties > Dermatology > Pediatric Diseases

Naegeli-Franceschetti-Jadassohn Syndrome

Author: Ulrich Hengge, MD, MBA, Professor, Department of Dermatology, Heinrich-Heine-University Düsseldorf, Germany
Coauthor(s): Theo Rufli, MD, Professor of Dermatology and Venereology, Chair, Department of Dermatology, University Hospital of Basle, Switzerland; Peter Itin, MD, Associate Professor, Dermatology University Clinic, Switzerland
Contributor Information and Disclosures

Updated: Jan 25, 2007

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 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.

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 (Larregue, 1981).

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 (Rebora, 1984; Tidman, 1987). Changes in hair follicles or apocrine ducts do not occur in NFJ syndrome; this observation excludes Fox-Fordyce disease (Arnold, 2000).

Pathophysiology

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

NFJ syndrome is rare.

International

The estimated incidence is approximately 1 case in 2-4 million population.

Race

Several families with this condition have been reported in Switzerland, Japan, Italy, and Greece (see Physical).

Sex

No sexual predilection is recognized.

Age

Because of the inability to sweat, the disease 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 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 (Mevorah, 1993). 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 (Frenk, 1993). 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 (Zillikens, 1991).

Physical

• The main syndrome of this 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 (see Image 1).
• Patients also have a characteristic reticular pigmentation on their neck, chest, and abdomen (see Image 2) 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 (see Image 3).
• Affected individuals have mild palmoplantar keratosis (see Image 4), brittle fingernails, and defective dentures with yellow spots on the enamel (see Image 5) (Naegeli, 1927; Franceschetti, 1954; Sparrow, 1976).
• To date, all patients reported had normal intelligence and were usually in good health.
• Incomplete forms of variations of NFJ syndrome are reported (Kitamura, 1955; Sparrow, 1976).
  • Several slightly different clinical phenotypes and intrafamilial variability are also reported (Levi, 1971; Papini, 1978; Itin, 1993).
  • Malalignment of the great toenails (Itin, 1993) 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 (Papini, 1978), an additional patient was identified in Greece (Tzermias, 1995; Whiting, 1971).
  • 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 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 (Whittock, 2000). 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 (Whittock, 2000).

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 differentiation (Bhandari, 1992); frizzled homolog 2, a molecule involved in epithelial cell-signaling pathways (Zhao, 1995); ADAM-11, a protein implicated in cell-cell and cell-matrix interactions (Emi, 1993), and GRB-7, a membrane-bound growth factor receptor of uncertain function (Margolis, 1992); and the MEOX1 gene (Froehlich, 1999).

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