A novel splice-site mutation in the AAGAB gene segregates with hereditary punctate palmoplantar keratoderma and congenital dysplasia of the hip in a large family.

BACKGROUND: Palmoplantar keratoderma punctata (PPKP) is a heterogeneous group of disorders characterized by hyperkeratotic papules occurring over the palms and soles during adolescence. PPKP type 1, also known as PPKP Buschke-Fischer-Brauer type, was recently found to result from mutations in the AAGAB gene, encoding the p34 protein. PPKP type 1 is usually not associated with extracutaneous features. AIM: To investigate a large family in which PPKP1 was present in association with congenital dysplasia of the hip (CDH). METHODS: A combination of direct sequencing of candidate genes and reverse-transcription PCR was used to identify the molecular basis underlying the clinical features displayed by the patients. RESULTS: Direct sequencing showed a novel intronic mutation in AAGAB, which was found to cosegregate with PPKP and CDH throughout the family. The mutation was found to result in aberrant RNA splicing, leading to exon 4 skipping. CONCLUSIONS: This observation suggests either the existence of a CDH-associated gene in the vicinity of AAGAB, or a hitherto unrecognized role for p34 during skeletal development.

Erythrokeratoderma variabilis caused by a recessive mutation in GJB3.

BACKGROUND: Erythrokeratoderma variabilis (EKV) is a rare disorder of cornification usually associated with dominant mutations in the genes GJB3 and GJB4, which code for connexin (Cx)31 and Cx30.3, respectively, and contribute to the formation of functional gap junctions in the epidermis. AIM: To identify the molecular basis of recessive EKV in a consanguineous family of Middle Eastern origin. METHODS: Direct sequencing and site-directed mutagenesis was used to search for the disease-causing mutation and identify its molecular consequences. RESULTS: A novel missense mutation (c.G88A) was found in the human GJB3 gene, resulting in substitution of the amino acid isoleucine for valine at position 30 (p.V30I). Under in vitro conditions, p.V30I prevents Cx31 reaching the cell membrane and taking part in gap-junction formation. CONCLUSIONS: Autosomal recessive inheritance should be considered when providing genetic counselling to consanguineous families at risk for EKV.

Disseminated spiked hyperkeratosis. An unusual discrete nonfollicular keratinization disorder.

An unusual nonfollicular keratinization disorder was observed in a father and his son, and in an unrelated woman. The disorder began during the second decade of life and gradually became more widespread and more pronounced thereafter. The dermatosis is characterized by tiny, rough, keratotic spikes giving the skin a raspy fell on palpation. Microscopically, the lesions showed a thick compact corneum without structural changes in the underlying epidermis except for moderate epidermal cell hyperplasia and some reduction in keratohyalin content.

Migratory ichthyosiform dermatosis with type 2 diabetes mellitus and insulin resistance.

BACKGROUND: In addition to the well-defined hereditary primary ichthyoses, many sporadic or less well-defined keratinization disorders with or without systemic manifestations have been reported. Herein we describe ichthyosiform dermatosis associated with type 2 diabetes mellitus. OBSERVATIONS: The patients were members of a large Arab family with heavy consanguinity. Eighteen members were affected with a variously severe scaly disorder. They showed migratory polycyclic keratotic scaly plaques evolving into diffuse generalized scaling or complete remission. Acanthosis nigricans-like lesions were also noted, and there was an association with type 2 diabetes mellitus. A scarcity of intercorneocyte lamellae and reduction in lamellar body contents were observed. CONCLUSIONS: We could not find a report of a similar dermatosis. Furthermore, an association between ichthyosis and diabetes has not been documented. Therefore, we believe that this may constitute a new entity.

Treatment of retroauricular keratinous cysts.

The excision method for the removal of keratinous cysts was modified and used for the treatment of such cysts in the retroauricular region. In 14 patients, 17 lesions were excised in this fashion with good to excellent results. The reasons for choosing this therapeutic modality and its modifications are discussed. In our opinion, the excision technique described here is the best treatment for keratinous cysts in this common location.

The keratinization disorder in collodion babies evolving into lamellar ichthyosis. Its possible relevance for determining the primary defect in lamellar ichthyosis.

Two collodion baby girls with disorder evolving into lamellar ichthyosis were followed by light and electron microscopy. Light microscopically, the neonatal colloidion skin was characterized by a thick compact stratum corneum which was PAS positive in its upper two thirds, by a thin stratum granulosum and by a non-acanthotic stratum spinosum with normal mitotic activity. Electron microscopically, the upper stratum corneum appeared pathological, whereas the lower part was normal except for some minor parakeratosis. The main alterations in the underlying stratum granulosum were diminished tonofibrils and keratohyalin. Biopsy specimens taken at the age of 2 weeks were typical for lamellar ichthyosis and showed hyperkeratosis with focal parakeratosis, a thickened stratum granulosum in which the cellular content of keratohyalin and tonofibrils was moderately diminished, and acanthosis with increased mitotic activity. It appears that the ultrastructural changes of the stratum granulosum, seen in lamellar ichthyosis, are already present in the collodion skin of the newborn, at a time when the epidermis does not yet show an increase in mitotic activity.

The prevalence of accentuated palmoplantar markings and keratosis pilaris in atopic dermatitis, autosomal dominant ichthyosis and control dermatological patients.

The prevalence of keratosis pilaris and accentuated palmoplantar marking was evaluated in 61 patients with atopic dermatitis, 35 patients with dominant ichthyosis vulgaris and 247 other dermatological cases taken as controls. Our data showed that (1) these features are of no diagnostic significance for atopic dermatitis and (2) they are significantly more frequent in patients with ichthyosis vulgaris without associated eczema than in those with atopic dermatitis. Consequently, they should be considered as part of the phenotype of ichthyosis vulgaris rather than attributed to a concomitant atopic dermatitis as suggested by some. These findings should be taken into account when evaluating atopic dermatitis or ichthyosis. To assess the frequency of scaling under winter weather conditions, 155 control subjects were also examined for evidence of visible desquamation and 25.8% showed slight but definite scaling.

The Nägeli-Franceschetti-Jadassohn syndrome: A hereditary ectodermal defect leading to colloid-amyloid formation in the dermis.

Light- and electron-microscopical examination of 4 skin biopsies from 2 members of the initially described family with Nägeli-Franceschetti-Jadassohn syndrome revealed that the already reported pigment incontinence is accompanied by varying amounts of colloid-amyloid bodies located in the superficial dermis. Occasionally, such bodies could also be seen around sweat glands in the reticular dermis. These findings indicate that cutaneous colloid-amyloid formation could be a pathogenic factor in the phenotypic expression of this autosomal dominant syndrome.

Ichthyosis vulgaris showing features of the autosomal dominant and X-linked recessive variants in the same family.

A family in which the mother and six of her sons present an ichthyosis of the vulgaris type has been analysed clinically, histologically and electron microscopically. Phenotypically the ichthyosis in the mother is purely of the dominant type, while that in all the affected sons shows, to varying degrees, features of both the dominant and X-linked recessive variants. The findings are interpreted as reasonably good evidence that the mother has transmitted to all her affected sons both the autosomal dominant and the X-linked recessive genes for ichthyosis. Although genetically this is a most unusual situation, it corresponds best to our findings.

[Rare melanocytes and nevus-cell nevi]. / Seltenere Melanozyten- und Naevuszellnaevi

This review considers the following melanocytic and nevocytic nevi: nevus spilus, cellular blue nevus, benign juvenile melanoma, mongolian spot and nevus of Ota. Clinical aspects, histopathology and prognosis are outlined, based on data from the recent literature.

Dermal melanocytosis. Report of an unusual case.

A 32-year-old Portugese woman presented with a bluish spot on the right hand. It had appeared at the age of 11 years. The histologic examination revealed typical dermal melanocytes. Although clinically this lesion was typical of an aberrant and persistent Mongolian spot, it exhibited, both histologically and ultrastructurally, also some features of the common blue nevus. Dermal melanocytosis of the macular type, as observed in our patient, is very rare.

Peeling skin syndrome: a clinical, ultrastructural and biochemical study.

A case of 'peeling skin syndrome' is reported. We have demonstrated a hitherto unreported keratohyalin abnormality and a four-fold increase of cellular retinoic acid binding protein, in one of two biopsies from an erythematous, scaling lesion.

Minor clinical features of atopic dermatitis. Evaluation of their diagnostic significance.

The diagnostic significance of 8 previously proposed minor features of atopic dermatitis (AD) was evaluated. The minor features studied were: nipple eczema, cheilitis, Dennie-Morgan infraorbital fold, pityriasis alba, anterior neck folds, wool intolerance, white dermographism and infraauricular fissuring. The incidence of these features was appreciated in 105 patients with typical AD (median age 8.5 years) and compared to that in 113 control subjects (median age 16 years). The ages of all studied individuals ranged from 7 months to 24 years. Two of these signs, anterior neck folds and the Dennie-Morgan infraorbital fold as defined by us, were shown to be of no diagnostic significance. The other 6 features were confirmed to be valuable diagnostic clues in AD.

Sweat studies under conditions of moderate heat stress in two patients with the Nägeli-Franceschetti-Jadassohn syndrome.

The sweating response of 2 patients with the Nägeli-Franceschetti-Jadassohn syndrome was measured by direct calorimetry. During the experiment, under conditions of moderate heat stress, the 2 patients felt comfortable and showed a normal thermoregulatory response. This tended to corroborate the patients' history which did not reveal a clear-cut heat intolerance. However, the starch-iodine test on the right flexor forearm revealed a marked reduction in activated sweat gland density while the patients were still under experimental conditions. Probably this was not the only region with a reduced number of functioning glands. Still, the patients' overall performance through the experiment indicated that their total number of functioning glands was able to produce a sweat output sufficient to prevent disturbances in thermoregulation. To our knowledge, this is the first study of the thermoregulatory capacity of patients suffering from a hereditary dermatosis in which hypohidrosis is part of the clinical picture.

Meleda disease: report of two cases investigated by electron microscopy.

We report 2 cases of clinically typical Meleda disease in a family from Herzegovina. Electron microscopy did not reveal major ultrastructural anomalies of keratinization; however, the transition from stratum granulosum to stratum corneum appeared to occur less abruptly than normally by a stepwise process suggesting a slowing down of terminal cornification.

Linkage studies in a family with X-linked recessive ichthyosis employing a cloned DNA sequence from the distal short arm of the X chromosome.

Recently linkage has been described between the Duchenne muscular dystrophy (DMD) gene and a cloned DNA sequence, RC8, that detects restriction fragment length polymorphism and is derived from the distal short arm of the X chromosome. Positive lod scores between RC8 and Xg prompted us to examine the linkage relationship of RC8 to the steroid sulfatase-X-linked recessive ichthyosis (XRI) locus which is situated 15 cM proximal from Xg in the subtelomeric region of Xp. Unexpectedly, at least two crossovers were found among nine informative meioses of an informative family, suggesting that RC8 and XRI may be about 25 cM apart. This implies that the genetic distance between the Xg locus and the DMD locus may exceed 50 cM.

Clinical significance of markedly elevated serum creatine kinase levels in patients with acne on isotretinoin.

Muscle-related complaints and high creatine kinase (CK) blood levels have been reported in 16-51% of patients with acne treated with isotretinoin. It has been suggested that this retinoid and exercise have a synergistic effect on muscle. The presence of marked hyperCKemia during the treatment raises concern about rhabdomyolysis. The objective of this report was to evaluate the incidence, course and clinical significance of severe hyperCKemia in isotretinoin therapy for acne. Out of 442 patients on isotretinoin, we reviewed 7 patients (1.58%) with CK values above 5,000 IU/l. Only two of them had myalgia. Physical activity or intramuscular injection prior to blood testing was reported in 6 patients. CK values returned to normal within 2 weeks and all subjects except 2, completed treatment. In conclusion, marked hyperCKemia with or without muscle-related complaints in isotretinoin-treated patients with acne is a benign phenomenon.

Autosomal dominant ichthyosis and X-linked ichthyosis. Comparison of their clinical and histological phenotypes.

The clinical and histologic distinction between X-linked recessive and autosomal dominant ichthyosis was studied by evaluating 12 classical differential parameters in 85 patients. Thirty-three of them had X-linked and 52 autosomal dominant ichthyosis. Eight of these parameters were generally helpful in the differential diagnosis: age of onset, severity of involvement, scale size, chapping of hands and feet, atopic background, influence of warm weather, corneal opacities and state of the granular layer. Involvement of skin folds, keratosis pilaris, increased palmo-plantar markings and improvement with age were unreliable. In the literature, age of onset and corneal opacities were additionally found unreliable; the histology was of limited value in two reports. Therefore, we concluded that the herein evaluated differential criteria seem to be valid mainly when considering groups of patients. For the individual case, an error in diagnosis, particularly in X-linked ichthyosis, is not rare when relying solely on these criteria. When in doubt, determination of steroid sulphatase activity is mandatory.