P.M. Steijlen

HID and KID syndromes are associated with the same connexin 26 mutation

Summary Background Keratitis–ichthyosis–deafness (KID) syndrome is a debilitating ectodermal dysplasia that predisposes patients to develop squamous cell carcinomas in addition to leading to profound sensory deafness and erythrokeratoderma. We recently demonstrated that KID can be caused by a specific missense mutation in connexin 26 (GJB2). Another syndrome, called hystrix‐like ichthyosis–deafnesss (HID) syndrome, strongly resembles the KID syndrome. These disorders are distinguished mainly on the basis of electron microscopic findings. We hypothesized that KID and HID syndromes may be genetically related.

The pathogenesis of hemangiomas: a review.

Learning Objectives: After reading this article, the participant should be able to: 1. Differentiate between hemangiomas and vascular malformations. 2. Describe arguments for the trophoblast origin of hemangiomas. 3. Give arguments for the angioblast theory for the origin of hemangiomas. 4. Identify key genes involved in the origin of hemangiomas. Background: Hemangiomas of infancy are common endothelial tumors. They differ from vascular malformations in their tissue architecture and biological properties. To date, there is no universally accepted theory that explains the pathogenesis and pathophysiology of hemangiomas. Methods: Theories from the medical literature from 1981 to 2004 were gathered, categorized, and reviewed. Results: Current research is mostly on the cellular and genetic levels. The most authoritative theories focus on angioblast origins, trophoblast origins, mutations in cytokine regulatory pathways, and field defects as the cause of the deranged angiogenesis of hemangiomas. Conclusions: To date, no single theory can easily explain all the characteristics of hemangiomas, such as predilection for the female sex, usual occurrence after birth, spontaneous involution, abnormal tissue architecture, and distribution within a developmental field. Hemangiomas are probably the final common expression of several pathophysiological mechanisms taking effect alone or in combination.

A 2‐bp deletion in the GJA1 gene is associated with oculo‐dento‐digital dysplasia with palmoplantar keratoderma

Oculo‐dento‐digital dysplasia (ODDD, OMIM no. 164210) is a pleiotropic disorder characterized mainly by ocular anomalies, varying degrees of finger and toe syndactyly, and enamel defects. It is caused by missense mutations in the gene coding for the gap junction protein connexin 43 or GJA1. Other types of mutations have so far not been reported. Here we describe a Dutch kindred with ODDD showing a new symptom, palmoplantar keratoderma, and associated with a novel 2‐bp deletion mutation of GJA1. The dinucleotide deletion 780_781delTG is located in the cytoplasmic C‐terminal loop and leads to a frameshift. This is predicted to lead to the production of a slightly truncated protein with 46 incorrect amino acids in the C‐terminal cytoplasmic loop (C260fsX307). This novel mutation may explain the presence of skin symptoms.

A missense mutation in the type II hair keratin hHb3 is associated with monilethrix

Monilethrix (MIM #158 000) is an autosomal dominant hair disorder that can cause scarring alopecia in affected individuals.1 Nail changes and keratosis pilaris of the skin of neck and arms have also been described. The hallmark hair abnormality in monilethrix is a beading of the hair shaft caused by periodic narrowing with the nodes separated by about 0.7 mm. The cause of the beading is unknown. The expression of monilethrix is variable.2 In mild cases, dystrophic hairs may be found only on the occiput, but severely affected individuals may suffer complete alopecia. Most cases described so far are associated with mutations in the type II (basic) trichocyte keratin genes hHb1 and hHb6 .2,3,4,5,6,7,8,9,10,11,12,13,14 Both genes have a mutational hotspot in the region coding for the helix termination motif. Most mutations seem to affect the same residues—glutamic acids at positions 413 and 402.3,6,10,15 Mutations affecting the helix initiation motif have also been found.7 From the phenotype, it is apparent that hHb1 and hHb6 are major hair cortex keratins. A third type II trichocyte keratin, hHb3, is expressed in much the same pattern as hHb1.16 From this, it may be expected that mutations of hHb3 may cause monilethrix as well. However, mutations in this gene have so far not been described. We analysed three patients suffering from monilethrix for the presence of mutations in hHb1 , hHb3 , and hHb6 . In one patient, we found a heterozygous missense mutation in hHb3 causing the substitution of a glutamic acid by a lysine at position 407 in the helix termination motif (E407K). This mutation corresponds to the E402K substitution in hHb1 and hHb6, clearly defining this particular residue as a trichocyte keratin …

The Gene for Hypotrichosis of Marie Unna Maps between D8S258 and D8S298: Exclusion of the hr Gene by cDNA and Genomic Sequencing

Hypotrichosis of Marie Unna (MU) is an autosomal dominant hair-loss disorder with onset in childhood. A genomewide search for the gene was performed in a large Dutch family using 400 fluorescent microsatellite markers. Linkage was detected with marker D8S258, and analysis of this family and a further British kindred with additional markers in the region gave a combined maximum two-point LOD score of 13.42, with D8S560. Informative recombinants placed the MU gene in a 2.4-cM interval between markers D8S258 and D8S298. Recently, recessive mutations in the hr gene were reported in families with congenital atrichia, and this gene was previously mapped close to the MU interval. By radiation-hybrid mapping, we placed the hr gene close to D8S298 but were unable to exclude it from the MU interval. This, with the existence of the semidominant murine hr allele, prompted us to perform mutation analysis for this gene. Full-length sequencing of hr cDNA obtained from an affected individual showed no mutations. Similarly, screening of all exons of the hr gene amplified from the genomic DNA of an affected individual revealed no mutations. Analysis of expressed sequences and positional cloning of the MU locus is underway.

Oral liarozole vs. acitretin in the treatment of ichthyosis: a phase II/III multicentre, double-blind, randomized, active-controlled study

Background  Liarozole, a retinoic acid metabolism blocking agent, has been granted orphan drug status for congenital ichthyosis by the European Commission and the U.S. Food and Drug Administration.

New syndrome of hypotrichosis, striate palmoplantar keratoderma, acro-osteolysis and periodontitis not due to mutations in cathepsin C

We report a mother and daughter with a syndrome of hypotrichosis, striate palmoplantar keratoderma, onychogryphosis, periodontitis, acro‐osteolysis and psoriasis‐like skin lesions. The syndrome resembles Papillon–Lefèvre syndrome (PLS), characterized by palmoplantar keratoderma, periodontitis and psoriasis‐like skin lesions, and particularly Haim–Munk syndrome, an allelic variant of PLS with acro‐osteolysis. Both are caused by mutations in the cathepsin C gene (CTSC). Our patients differ in the unique nature of the palmar keratoderma and hypotrichosis. We have sequenced CTSC in the mother without finding mutations in either coding or non‐coding parts of the gene. We propose that our patients suffer from a new syndrome possibly caused by mutations in a gene that has a functional or structural relation with CTSC.

Novel EBP gene mutations in Conradi-Hünermann-Happle syndrome

Summary Background  Conradi–Hünermann–Happle syndrome [X‐linked dominant chondrodysplasia punctata type 2 (CDPX2); MIM no. 302960] is an X‐linked dominant disorder of cholesterol metabolism that causes a wide spectrum of skeletal abnormalities and linear ichthyosiform skin lesions. Mosaicism is probably responsible for the variability of the phenotype.

Myhre syndrome in a female with previously undescribed symptoms: Further delineation of the phenotype

Myhre syndrome is a rare connective tissue disease characterized by nonprogressive stiffness of the large joints, short stature with a peculiar build, and a distinctive facial phenotype. Developmental delay is common. Three female patients have so far been described. Here, we report on a 16‐year‐old female with Myhre syndrome. She has vertebral defects, hypertrophic scar formation, and a stiff skin in addition to the features that have previously been reported in association with Myhre syndrome.

A new type of erythrokeratoderma.

We describe a Dutch man suffering from a previously undescribed erythrokeratoderma associated with palmoplantar keratoderma and circular constrictions of the fingers. No mutations were identified in the genes encoding loricrin, connexin 26, 30, 30.3, 31 and 31.1, and ARS/complex B. There are some similarities between the disorder described here and other palmoplantar keratodermas and erythrokeratodermas, but assignment to a particular disease category is not possible. Hence we propose that we have delineated a novel type of keratoderma.