Updated Review of Genetic Reticulate Pigmentary Disorders

J. Zhang; M. Li; Z. Yao


The British Journal of Dermatology. 2017;177(4):945-959. 

In This Article

Epidermolysis Bullosa Simplex With Mottled Pigmentation and Naegeli–Franceschetti–Jadassohn Syndrome/Dermatopathia Pigmentosa Reticularis

Epidermolysis bullosa simplex with mottled pigmentation (EBS-MP; OMIM 131960) is a rare subtype of EBS characterized by blistering, mottled pigmentation of the trunk and limbs, punctate hyperkeratosis of the palms and soles, and onychodystrophy. Mutations in the KRT5 or KRT14 genes were shown to be responsible for this bullous and pigmentary disorder.[53,54] It has been suggested that haploinsufficiency of KRT5 may affect keratinocyte organization and adhesion, as well as melanosome uptake by keratinocytes and longevity of melanin granules in basal layer cells,[5] thus accounting for the formation of bullae in EBS and the co-occurrence of pigmentary abnormalities in DDD. The mutation p.Pro25Leu in the head domain can cause EBS-MP, whereas 1649delG in the end of the tail domain of KRT5 can result in two distinct phenotypes with or without mottled pigmentation.[9] This finding indicates the complexity of the structure and function of KRT5 and shows that the head domain has a closer relationship to melanosome trafficking and distribution. One study using microarray analysis suggested that skin pigmentation in the patient with EBS-MP may be dependent on higher expression of tyrosinase.[55]

Dermatopathia pigmentosa reticularis (DPR; OMIM 125595), caused by a mutation in the KRT14 gene, is characterized by a triad of reticulate pigmentation, noncicatricial alopecia of the scalp/eyebrows/axillae and onychodystrophy.[56] The pigmentation can be either generalized or limited to the flexure.[57,58] Naegeli–Franceschetti–Jadassohn syndrome (NFJS; OMIM 161000) clinically resembles DPR and is a rare autosomal dominant form of ectodermal dysplasia that manifests as absence of dermatoglyphics, reticulate hyperpigmentation, palmoplantar keratoderma, dental abnormalities and abnormal sweating. DPR is distinguished from NFJS by the reticulate pigmentation lasting until adulthood, as well as alopecia, and the lack of dental abnormalities.[56] NFJS and DPR are allelic disorders. The majority of the causative mutations were found to be null variants located at the head domain of KRT14 (e.g. c.17delG, p.Cys18* and p.Gln7*),[56] suggesting a similar mechanism to that involving the head domain of KRT5 in EBS-MP. Lugassy's group revealed one aspect of the pathogenesis of NFJS: early nonsense- or frameshift changes at the head domain of KRT14 results in keratin 14 haploinsufficiency, which caused increased susceptibility of keratinocytes to tumour necrosis factor-α-induced apoptosis.[59]

A recurrent p.Arg125Cys mutation in KRT14 has been reported to cause a DPR phenotype with nonscarring blisters on the limbs upon minor trauma, which overlaps with EBS-MP.[57] Moreover, a recurrent p.Pro25Leu mutation in KRT5 was recently reported to be found in a patient with EBS-MP with noncicatricial alopecia, which overlaps with DPR.[60] These findings suggest that NFJS, DPR and EBS-MP, previously believed to be independent disorders, likely belong to a spectrum of diseases with a certain degree of phenotypic diversity (Table S5; see Supporting Information).

Differential Diagnosis

Kindler syndrome (OMIM 173650) is distinguished from EBS-MP by progressive poikiloderma and diffuse cutaneous atrophy; reticulate hyperpigmentation in NFJS can differentiate it from other ectodermal dysplasia syndromes.

Clinical Management

Treatment is supportive. The phenotypes of this spectrum clearly affect the quality of life of the affected individual; thus, genetic counselling should be recommended for those families with an intense desire for future pregnancies.