Disorders of Keratinization

Objectives: To determine linkage in a pedigree with palmoplantar keratoderma (PPK) associated with squamous cell carcinoma of the esophagus. Design: A large American pedigree was studied and the clinical phenotype was described. Linkage analysis was performed using genomic DNA from key individuals. Setting: A community-based family study. Patients: The family pedigree was expanded from a single index case. Main Outcome Measures: To demonstrate linkage and the relative risk of squamous cell carcinoma of the esophagus in this pedigree. Results: Focal PPK was inherited as an autosomal dominant with variable expression, but signs were not limited to the palmoplantar epidermis. The generalized nature of this pattern of PPK was highlighted by the perifollicular papules and oral hyperkeratosis. Affected individuals (125 individuals) in 7 generations were identified, with 17 affected individuals having associated cancer. Seven of the 8 squamous cell carcinomas of the esophagus occurred in smokers. Other tumors were seen in nonsmokers, but these were not significantly increased. The combined male-female expected incidence of squamous cell carcinoma of the mouth and esophagus was 0.21; observed, 8 (relative risk of 38; P D17S1603. Conclusion: The distinctive clinical phenotype in this family suggests a new classification for PPKs, in particular a reappraisal of the phenotype as a focal PPK. A very similar phenotype is found in patients with keratin K16 gene mutations. (Arch Dermatol. 1996;132:640-651)

Linkage of an American pedigree with palmoplantar keratoderma and malignancy (palmoplantar ectodermal dysplasia type III) to 17q24. Literature survey and proposed updated classification of the keratodermas.

Mal de Meleda (MDM) or keratosis palmoplantaris transgrediens of Siemens is an autosomal recessive skin disorder characterized by diffuse palmoplantar keratoderma (PPK) and transgressive keratosis with an onset in early infancy. There is no associated involvement of other organs; however, a spectrum of clinical presentations with optional and variable features has been described. Mutations in the ARS (component B)-81/s gene (LY6LS) on chromosome 8q24-qter, which encodes SLURP-1, have recently been identified in patients with MDM. Here, we have analyzed four MDM families for mutations in SLURP-1. In a large Palestinian pedigree with multiple consanguinity, patients are homozygous for a new mutation that substitutes an arginine for a conserved glycine residue at position 86. A different mutation in Turkish patients results in the same amino acid exchange. Some remarkable similarities are seen in the clinical picture of patients from both families. Patients of an Emirati Bedouin family have a homozygous alteration of the translation initiation codon. In a German family with no known consanguinity, we have shown pseudodominant inheritance. Three affected children and their affected mother are homozygous for the missense mutation W15R. Our findings indicate that the MDM type of transgressive PPK is caused by SLURP-1 mutations in patients from various origins and demonstrate allelic heterogeneity for mutations in SLURP-1.

Mal de Meleda (MDM) caused by mutations in the gene for SLURP-1 in patients from Germany, Turkey, Palestine, and the United Arab Emirates.

The United Arab Emirates inhabitants are ethnically diverse, with ancestries from Arabia, Persia, Baluchistan, and Africa. However, the majority of the current five million inhabitants are expatriates from the Asian subcontinent, Middle Eastern, African, and European countries. Consanguineous marriages within most UAE subpopulations are still the norm, leading to the formation of isolates and higher frequencies of recessive conditions. The UAE is ranked sixth in terms of prevalence of birth defects, with more than 270 genetic disorders reported in the national population. The UAE has high frequencies of blood disorders including thalassemias, sickle cell disease, and G6PD. In addition, certain genetic conditions are relatively common including cystic fibrosis, Joubert, and Meckel syndromes. Furthermore, numerous rare congenital malformations and metabolic disorders have been reported. We review the single gene disorders that have been studied at the molecular level in the UAE (which currently stand at 76) and compile the mutations found. Several novel (p.S2439fs) mutations have been reported including c.7317delA in NF1, c.5C>T (p.A2V) in DKC1, c.1766T>A (p.I589N) in TP63, and c.2117G>T (p.R706L) in VLDLR. We hope that this review will form the basis to establish a UAE mutations database and serve as a model for the collection of mutations of a country. Hum Mutat 31:505–520, 2010. © 2010 Wiley-Liss, Inc.

https://www.onlinelibrary.wiley.com/doi/pdf/10.1002/humu.21232

Mutations of a country: a mutation review of single gene disorders in the United Arab Emirates (UAE).

Esophageal Squamous Cell Dysplasia and Delayed Differentiation With Deletion of Krüppel-Like Factor 4 in Murine Esophagus

Mal de Meleda (keratoderma palmoplantaris transgrediens) is a rare autosomal recessive form of palmoplantar keratoderma characterized by hyperkeratosis of the palms and soles which appears soon after birth and progressively (progrediens) involves other areas (transgrediens) of the body skin. We report the case of a patient with mal de Meleda with three unusual facultative features, i.e. prominent knuckle pads, peculiar finger-nail anomalies and pseudo-ainhum on both fifth fingers. Four other members of the family are also affected by mal de Meleda.

Qayed Ki

Papers

Mal de Meleda: recessive transgressive palmoplantar keratoderma with three unusual facultative features.