NAEGELI–FRANCESCHETTI–JADASSOHN SYNDROME
Key features
Autosomal dominant disorder due to heterozygous mutations in the keratin 14 gene
Reticulated hyperpigmentation beginning by 2 years of age and often fading during adolescence
Ectodermal dysplasia with hypohidrosis and heat intolerance as well as dental anomalies, including early loss of teeth
Palmoplantar keratoderma, with absent or hypoplastic dermatoglyphics
Introduction
NFJ syndrome is a rare autosomal dominant genodermatosis that is characterized by reticulated hyperpigmentation as well as ectodermal dysplasia (primarily dental anomalies and hypohidrosis) and hypoplastic dermatoglyphics.
History
First described by Naegeli in 1927, NFJ was initially confused with incontinentia pigmenti. In 1954, Franceschetti and Jadassohn re-examined the original family and noted the autosomal dominant pattern of inheritance.
Epidemiology
Affected families have been primarily of Swiss and British descent.
Pathogenesis
NFJ syndrome is caused by truncating mutations in the non-helical head domain of the keratin 14 gene (KRT14) that result in haploinsufficiency (see Fig. 56.5). This leads to increased susceptibility of keratinocytes to tumor necrosis factor (TNF)-induced apoptosis, which explains the hyperpigmentation secondary to pigment incontinence observed in affected individuals. It also points to a role for the N-terminal portion of keratin 14 in regulating apoptosis during morphogenesis of cutaneous appendages.
Clinical Features
Brown or gray–brown reticulated hyperpigmentation develops by the age of 2 years, without a preceding inflammatory stage. The pigmentary changes are most often observed on the abdomen and periocular and perioral regions, with variable involvement of the neck, trunk, proximal extremities, axillae, and groin. The hyperpigmentation often fades after puberty and may eventually disappear. Some infants have bullae on their feet during the newborn period. Decreased sweat gland function with lifelong heat intolerance is a problem for many patients. Other cutaneous manifestations include absent or hypoplastic dermatoglyphics, palmoplantar keratoderma (diffuse or punctate), and onychodystrophy (onycholysis, subungual hyperkeratosis, and congenital malalignment of the great toenails). Dental anomalies are common and include abnormally shaped teeth, supernumerary teeth, and yellow spotted tooth enamel. Early total loss of teeth may occur.
Pathology
Histologically, the hyperpigmented skin demonstrates pigment incontinence, i.e. melanophages in the upper dermis.
Differential Diagnosis
The lack of leukoplakia, bone marrow failure, or an increased risk of malignancies in patients with NFJ syndrome differentiates it from DKC. Although NFJ syndrome lacks the prominent alopecia and more persistent hyperpigmentation that characterize DPR, there is significant overlap between these allelic disorders. X-linked reticulate pigmentary disorder often presents with hypohidrosis and dental anomalies as well as reticulate hyperpigmentation, but additional systemic manifestations as well as the inheritance pattern distinguish it from NFJ. Reticulated hyperpigmentation and palmoplantar keratoderma may develop in patients with epidermolysis bullosa simplex due to mutations in keratin 5 or 14, but blistering is more prominent. In addition, patients with Kindler epidermolysis bullosa may have absent or hypoplastic dermatoglyphics, but they develop poikiloderma rather than reticulated hyperpigmentation (see Ch. 32). Obviously, hypohidrosis, onychodystrophy, dental anomalies, and hypoplastic or absent dermatoglyphics can be seen in other forms of ectodermal dysplasia (see Ch. 63).
Treatment
Treatment is supportive. Genetic counseling should be offered to affected individuals and families.