KRT14 – Naegeli-Franceschetti-Jadassohn Syndrome

Naegeli-Franceschetti-Jadassohn syndrome (NFJS) is a rare autosomal dominant ectodermal dysplasia characterized by reticulate hyperpigmentation, absence of dermatoglyphics, hypohidrosis, palmoplantar keratoderma and dental anomalies. Heterozygous mutations in the type I keratin gene KRT14 underlie NFJS by disrupting keratin intermediate filament formation and epidermal development ([PMID:26753140]).

Genetic linkage and segregation were first demonstrated in five multiplex families (four NFJS, one dermatopathia pigmentosa reticularis) with combined LOD 8.3 at D17S800, identifying heterozygous nonsense or frameshift variants in KRT14 that segregated with disease ([PMID:16960809]). This finding has been replicated in 33 unrelated NFJS individuals reported across case reports and series, confirming autosomal dominant transmission and high penetrance ([PMID:40093016]).

The variant spectrum in NFJS includes early truncating alleles within the nonhelical head domain of KRT14, for example c.19C>T (p.Gln7Ter) in exon 1, predicted to cause haploinsufficiency through nonsense‐mediated decay ([PMID:16960809]). No recurrent founder alleles have been reported to date.

Clinically, patients present in childhood with reticulate skin hyperpigmentation, absence of fingerprint ridges, reduced sweating (hypohidrosis; HP:0000966), palmoplantar keratoderma (HP:0000982) and dental anomalies (HP:0000164), often with hair and nail changes. The phenotypic overlap with other reticulate pigmentary disorders can delay diagnosis, underscoring the need for molecular confirmation.

Functional studies demonstrate that KRT14 haploinsufficiency increases keratinocyte susceptibility to TNF-α–induced apoptosis, recapitulating the histologic finding of basal cell apoptosis and absence of dermatoglyphics in NFJS patients. In HaCaT keratinocytes, knockdown of KRT14 elevates apoptotic markers upon TNF-α challenge, which is reversible by doxycycline-mediated inhibition of pro-apoptotic signaling ([PMID:18049449]).

Collectively, definitive genetic and experimental evidence establishes haploinsufficiency of KRT14 as the mechanism for NFJS. KRT14 sequencing should be incorporated into diagnostic panels for reticulate pigmentary disorders. Early molecular diagnosis enables tailored management of ectodermal manifestations and informs genetic counseling.

References

• American journal of human genetics • 2006 • Naegeli-Franceschetti-Jadassohn syndrome and dermatopathia pigmentosa reticularis: two allelic ectodermal dysplasias caused by dominant mutations in KRT14 PMID:16960809
• Indian dermatology online journal • 2015 • Naegeli-Franceschetti-Jadassohn syndrome: A rare case. PMID:26753140
• Frontiers in medicine • 2025 • Naegeli-Franceschetti-Jadassohn syndrome: a systematic review of case studies. PMID:40093016
• The Journal of investigative dermatology • 2008 • KRT14 haploinsufficiency results in increased susceptibility of keratinocytes to TNF-alpha-induced apoptosis and causes Naegeli-Franceschetti-Jadassohn syndrome. PMID:18049449

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