Naegeli-Franceschetti-Jadassohn Syndrome

Are You Confident of the Diagnosis?

What you should be alert for in the history

Patients with Naegeli-Franceschetti-Jadasson (NFJ) syndrome often report marked heat intolerance because of partial or total absence of sweat glands. In addition, the patients observe marked mottled pigmentation that starts to fade with age. A further complaint is thickening of skin on palms and soles. Early caries is an often mentioned problem. In general several members in the family are affected. Blistering in the first years of life may occur. Patients have a normal life span. The most dnagerous problem is hypohidrosis with possible hyperthemia.

Characteristic findings on physical examination

Characteristic findings on physical examination include absent dermal ridges (dermatoglyphics), hypohidrosis, and reticulate pigmentation predominantly on the abdomen, neck, face, and large flexures (Figure 1, Figure 2). After progression during childhood, hyperpigmentations fade with age and can disappear completely. Diffuse palmoplantar keratoderma with punctate keratoses may coexist (Figure 3). Enamel defects with early caries and premature loss of dentition are often seen. Nonscarring alopecia is more common than in controls (Figure 4).

Figure 1.

Figure 2.

Figure 3.

Figure 4.

Expected results of diagnostic studies

Histology shows pigment incontinence and absent or reduced sweat glands and electron microscopy documents keratin filament retraction and increased apoptosis of keratinocytes. Ink prints show missing dermatoglyphs. Sweat testing confirms hypohidrosis. Genetic tests confirm a mutation in keratin 14.

Diagnosis confirmation

Diagnosis is confirmed by an autosomal dominant inheritance pattern within the pedigree and the genetic testing. The clinical symptom complex of reticulate pigmentation with hypohidrosis, enamel defects, keratoderma and hypotrichosis makes the diagnosis highly probable. Dermatopathia reticularis pigmentosa is an allelic disease of NFJ syndrome which shows marked clinical overlap. Differentiating factors are that the pigmentation in dermatopathia reticularis pigmentosa does not fade over time and has no enamel effects.

Who is at Risk for Developing this Disease?

NFJ syndrome is extremely rare and only few families have been reported in the literature. The disease belongs to the large spectrum of ectodermal dysplasias. A large family has been reported from Switzerland.

What is the Cause of the Disease?

Etiology

NFJ syndrome is an autosomal dominant inherited disease and belongs to the ectodermal dysplasias. A germline mutation in keratin 14 gene, KRT14, is the cause of the disease. The gene is located on the long arm of chromosome 17.

Pathophysiology

This mutation leads to developmental alterations within the ectodermal structures and is responsible for a higher susceptibility of keratinocytes to TNF-alfa induced apoptosis .

Systemic Implications and Complications

Patients with NFJ syndrome have a marked heat intolerance and can collapse under physical work or in hot temperatures. Enamel defects lead to early caries and teeth loss. Consequent dental hygiene and regular controls by the dentist is necessary. Hypotrichosis is often a cosmetic problem for affected patients and nail abnormalities, such as congenital malalignment, can produce painful toes. Palmoplantar keratoderma can produce painful fissures and become secondarily infected. Topical keratolytics are able to prevent those complications. Adermatoglyphia can lead to problems at immigration as no finger prints can be made.

Treatment Options

– Heat stroke prevention with physical cooling during hot temperatures and physical activity

– Keratoderma is treated by topical keratolytics, such as salicylic vaseline 10-20% or urea preparations

– Regular dental hygiene and control by the dentist at regular intervals, every 3-6 months

– Laser therapy (IPL or Nd:YAG) of marked reticulate pigmentation on exposed sites such as the face

– In severe cases of keratoderma, systemic retinoids are possible. Acitretin is the retinoid of choice. Topical retinoids are not effective.

Optimal Therapeutic Approach for this Disease

Education about the disease and the need for preventing overheating and how to provide optimal dental care is crucial. Greasing of palms and soles with keratolytics should be performed daily. As the disease is genetic, the treatment must be long-term. Give the patients a letter of confirmation that they have a disease that makes fingerprints impossible to help them at immigration. Families should be sent to a genetist for evaluation and counseling. There is no genetic test to differentiate NFJ syndrome from dermatopathia reticularis pigmentosa.

Patient Management

Patients should be informed about the dominant inheritance pattern and the risk for the next generation.

Within the first years of life the patients should be kept in a controlled environment with the aim being to monitor the degree of heat intolerance and dentition and to instruct the parents continuously. Follow up every 3-6 months during the first years of life. Later evaluation on a yearly basis is sufficient. No aggressive treatment of the mottled hyperpigmentation should be performed, as complete fading has been documented repeatedly.

Unusual Clinical Scenarios to Consider in Patient Management

Help the patients to find a profession that is compatible with the hypohidrosis. Systemic retinoids can be tried in special cases but blistering as a side effect could be a possible complication in this keratin 14 disease, as epidermolysis bullosa simplex is caused by mutations in keratin 5 or 14.

What is the Evidence?

Itin, P, 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. vol. 28. 1993. pp. 942-50. (In-depth clinical description of the disease.)

Sprecher, E, Itin, P, Whittock, NV, McGrath, JA, Meyer, R, DiGiovanna, JJ. “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. vol. 119. 2002. pp. 692-8. (The genetic mapping has been performed with the help of two large families with NFJ syndrome.)

Lugassy, J, Itin, P, Shida-Yamamoto, A, Holland, K, Huson, S, Geiger, D. “Naegeli-Franceschetti-Jadassohn syndrome and dermatopathia pigmentosa reticularis: two allelic ectodermal dysplasias caused by dominant mutations in KRT14”. Am J Hum Genet. vol. 79. 2006. pp. 724-30. (In this work, the responsible gene for the disease has been described and it was shown that NFJ syndrome is allelic with dermatopathia reticularis pigmentosa.)

Lugassy, J, McGrath, JA, Itin, P, Shemer, R, Verbov, J, Murphy, HR. “KRT14 haploinsufficiency results in increased susceptibility of keratinocytes to TNF-alfa-induced apoptosis and causes Naegeli-Franceschetti-Jadassohn syndrome”. J Invest Dermatol. vol. 128. 2008. pp. 1517-24. (In this work, it has been documented that cells of NFJ syndrome are more prone to apoptosis by TNF-alfa and that this effect can be diminised with doxycycline.)

Itin, PH, Burger, B. “Spontaneous fading of reticular pigmentation in Naegeli-Franceschetti-Jadassohn syndrome”. Dermatology. vol. 221. pp. 135-6. (In NFJ syndrome, it is typical that after decades the reticulate pigmentation fades. This is well documented in an affected person documented 25 years after photographic documentation of the pigmentation. The natural fading was complete.)

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