Dermatopathia Pigmentosa Reticularis 

Updated: Nov 22, 2019
Author: Melba Estrella, MD; Chief Editor: Dirk M Elston, MD 

Overview

Background

Dermatopathia pigmentosa reticularis (DPR) is a very rare disorder with the diagnostic triad of generalized reticulate hyperpigmentation, noncicatricial alopecia, and onychodystrophy. Many other dermatologic findings have been associated with this triad. These findings include adermatoglyphia, hypohidrosis or hyperhidrosis, palmoplantar hyperkeratosis, and acral dorsal nonscarring blisters.[1, 2] The reticulate pigmentation of DPR occurs at birth or during early childhood.

Dereure[3] noted that Naegeli-Franceschetti-Jadassohn syndrome (NFJS) and DPR are two allelic ectodermal dysplasias related to mutations of the dominant gene coding for keratin 14 (KRT14). Other diseases caused by defects in keratin 14 include epidermolysis bullosa and Dowling-Mera disease.[4, 5, 6] Severe keratin 5 and 14 mutations induce down-regulation of junction proteins in keratinocytes,[7] which likely underlies all of these diseases. A number of missense mutations in KRT14 causing a DPR/NFJS phenotype have been reported.[8, 9] DPR resembles NFJS; they share reticulate pigmentation through adulthood, dental abnormalities, and alopecia. DPR and NFJS are considered to be allelic disorders, attributable to mutations on the nonhelical (E1/V1) head domain in the KRT14 gene, with consequent premature termination of protein synthesis.[10, 11]

Pathophysiology

Naegeli-Franceschetti-Jadassohn syndrome (NFJS) and dermatopathia pigmentosa reticularis (DPR) are ectodermal dysplasias inherited in an autosomal dominant fashion.[12] The two disorders are both allelic and caused by dominant mutations in KRT14. Missense mutations can cause either of these diseases.[9] Both can manifest with the absence of dermatoglyphics, reticulate hyperpigmentation of the skin, hypohidrosis, and heat intolerance. Palmoplantar keratoderma, nail dystrophy, and enamel defects are common in NFJS, whereas diffuse alopecia is only seen in DPR.

In some NFJS pedigrees, the reticulate pigmentation fades after puberty and may disappear completely in old age. Hypohidrosis, the main problem for the patients, remains constant. Teeth are always severely affected, leading to early total loss. All patients with NFJS lack dermatoglyphics. Diffuse palmoplantar keratoderma may coexist with punctate keratoses that are sometimes accentuated in the creases or exhibit a linear pattern. Congenital malalignment of the great toenails can occur.[13]

Burger et al[14] examined 9 members of a five-generation Swiss family with overlapping signs of NFJS and DPR. Sanger sequencing of genomic DNA derived from patient lymphocytes revealed a unique 2-bp insertion in exon 1 of KRT14, leading to a frameshift and premature stop codon. They postulate that the identification of this intrafamilial overlap of phenotypes with the same KRT14 frameshift variant challenges the idea that DPR and NFJS are distinct disorders, representing instead a continuous phenotypical spectrum.[14]

p53 can act as a co-repressor to regulate KRT14 expression while epidermal cell differentiation occurs.[15] A half-site occurring on the p53-binding site on the KRT14 promoter involves activation by p63, suggesting that the differing p53-binding site's lengths could determine the gene regulation by different members of the p53 family of proteins.[16]

In 2002 Sprecher et al[17] assessed linkage for 17q in a large Swiss family with NFJS. Band 17q has been postulated to contain the gene for NFJS. They found a considerably narrow NFJS gene region, from 27 cM to 6 cM, flanked by D17S933 and D17S934, with a maximum multipoint logarithm of the odds score of 2.7 at marker locus D17S800. In addition, they studied a small family with DPR and reported that the linkage data they assembled suggested that DPR may map to band 17q. On 17q, the NFJS critical interval spans approximately 5.4 Mb and contains a minimum of 45 distinct genes.[18]

Goh et al[19] noted a patient of Malay ancestry with DPR secondary to a recurrent KRT14 p.R125C mutation. The patient had wiry scalp hair and digital fibromatous thickening in addition to reticulate hyperpigmentation over his trunk and proximal limbs. He also had onychodystrophy without noncicatricial alopecia.

Etiology

Dermatopathia pigmentosa reticularis (DPR) is believed to be a genetic disorder of autosomal dominant inheritance.[12]

Apoptosis may play a key role in its pathogenesis, as evidenced by increased apoptotic activity in the basal cell layer expressing keratin 14.[11]

Epidemiology

Frequency

Since first described in 1958, dermatopathia pigmentosa reticularis (DPR) has been acknowledged as a very rare disorder, with approximately 21 reported cases among the regions of America, Europe, and Asia.[14]

Race

Although most cases of DPR are reported in the European and US literature, no evidence indicates that DPR is associated with any particular race.

Sex

No sex predilection is documented for DPR.

Age

The reticulate pigmentation associated with DPR occurs at birth or during early childhood.

Prognosis

The hyperpigmentation associated with dermatopathia pigmentosa reticularis (DPR) persists throughout life, showing no tendency of spontaneous fading.

Patient Education

Counsel the patient that the reticular hyperpigmentation persists throughout life, showing no tendency of spontaneous fading.

Consider genetic counseling to advise affected patients and their families of the medical implications of the disease and its pattern of inheritance.[20]

Advise patients with dermatopathia pigmentosa reticularis (DPR) to avoid sun exposure, which may trigger blister formation.

 

Presentation

History

The primary clinical feature of dermatopathia pigmentosa reticularis (DPR) is the occurrence of reticulate hyperpigmented macules at birth or in early childhood, usually by age 2 years.

The hyperpigmentation persists throughout life, showing no tendency of spontaneous fading. The reticulate network of hyperpigmented macules occurs particularly on the trunk, neck, and proximal areas of the limbs.

Physical Examination

Most reported cases of dermatopathia pigmentosa reticularis (DPR) have demonstrated a clinical triad of reticulate hyperpigmentation, mild nonscarring alopecia, and mild onychodystrophy. Al-Hamdi et al[21] reported a case of DPR with late onset of both alopecia and onychodystrophy, proposing that the reticulate hyperpigmentation may be the only feature present before puberty. Other associated features may include the following:

  • Punctate or diffuse palmoplantar hyperkeratosis

  • Darkly pigmented nipples

  • Nonscarring blisters on the dorsa of hands and feet following minor trauma or sun exposure

  • Hyperhidrosis or hypohidrosis

  • Adermatoglyphia (loss of dermal ridges on fingers and toes)

  • Thin eyebrows and sparse pubic and axillary hair

It is possible that Naegeli-Franceschetti-Jadassohn syndrome (NFJS), poikiloderma Clericuzio type, and dyskeratosis congenita can overlap, with a presentation of prenatal and postnatal growth restriction, developmental delay, microcephaly, and pigmentation pathology.[22]

Complications

No serious complications are known for dermatopathia pigmentosa reticularis (DPR). A few cases of DPR showing extracutaneous manifestations have been addressed in the literature as probable coincidences rather than complications.

Early-onset gastric carcinoma in a male with DPR was noted by Tunca et al in 2008.[23]

Goh et al[19] reported a case of DPR caused by a recurrent KRT14 mutation in which the patient had digital fibromatosis and wiry scalp hair.[19]

Very few cases of DPR have been described to present with corneal opacity and superficial punctate spots, but only one case has been reported presenting bilateral Salzmann’s nodular degeneration of the cornea.[2, 20]

 

DDx

Diagnostic Considerations

The diagnosis of dermatopathia pigmentosa reticularis (DPR) is based on the presence of the clinical triad and a typical histopathologic picture; however, the following hyperpigmentation disorders should be considered and excluded:

  • Acromelanosis progressiva

  • Hereditary symmetric dyschromatosis of Dohi

  • Reticular acropigmentation of Kitamura

  • Heterochromia extremitarium

  • Reticulate pigmented dermatosis of the flexures (Dowling-Degos disease)

  • Congenital diffuse mottling of the skin

  • Hereditary universal dyschromatosis

  • Dyskeratosis congenita syndrome

  • Franceschetti-Jadassohn or Naegeli syndrome

Points of differentiation

Each of the following demonstrate a distinctive distribution of pigmentation with diffuse frecklelike or reticulate hyperpigmentation on the dorsa of the hands and feet, the extremities, or the flexural areas (axillae, groin): acromelanosis progressiva, hereditary symmetric dyschromatosis of Dohi, reticular acropigmentation of Kitamura, heterochromia extremitarium, and reticulate pigmented dermatosis of the flexures.

Differentiation from congenital diffuse mottling of the skin can be made histopathologically by demonstrating clubbing of the rete ridges and hyperpigmentation of the basal layer without pigmentary incontinence.

Hereditary universal dyschromatosis is associated with hyperpigmented and hypopigmented macules of irregular shape and size, as well as small stature and high-tone deafness.

Dyskeratosis congenita syndrome is an X-linked condition and occurs most commonly in males, usually in males older than 5 years. In addition to reticulate hyperpigmentation, nail dystrophy, and hyperkeratosis and atrophy of the palms and soles, patients with dyskeratosis congenita also have leukokeratosis of mucosal surfaces and blood dyscrasias.

Franceschetti-Jadassohn (Naegeli) syndrome is an autosomal dominant condition with gray-brown reticulate pigmentation of the trunk and neck that fades after adolescence. Dental anomalies and a bleeding tendency are frequently observed in these patients.

Franceschetti-Jadassohn (Naegeli) syndrome and DPR share complete absence of dermatoglyphics; a reticulate pattern of hyperpigmentation; palmoplantar keratoderma; abnormal sweating; and anomalies of the teeth, hair, and skin.[24]

Differential Diagnoses

 

Workup

Laboratory Studies

Dermatopathia pigmentosa reticularis (DPR) does not warrant laboratory studies beyond genetic testing because of the lack of consistent report of abnormal results.

Al-Hamdi[21] et al reported an isolated case of DPR with elevated serum cortisol and hepatomegaly.

Procedures

Excisional or punch cutaneous biopsy of the reticular pigmentation may be helpful when making the diagnosis of dermatopathia pigmentosa reticularis (DPR).

Histologic Findings

The typical histopathologic picture of dermatopathia pigmentosa reticularis (DPR) shows hyperpigmentation of the basal layer with cytoplasmic vacuolization and the presence of melanophages within the reticular dermis.[2, 21] That is, an interface dermatitis can be present.

 

Treatment

Medical Care

No specific treatment exists for dermatopathia pigmentosa reticularis (DPR). Symptomatic management of palmoplantar hyperkeratosis and other secondary changes can be addressed with topical steroids, keratolytics, and emollients.[11] Nonscarring blisters are generally transient and self-healing. Cold compresses may suffice.

Activity

Advise patients with dermatopathia pigmentosa reticularis (DPR) to avoid sun exposure, which may trigger blister formation.

Prevention

Advise patients with dermatopathia pigmentosa reticularis (DPR) to avoid sun exposure and minor trauma, which may trigger blister formation.