Cyclic ichthyosis with epidermolytic hyperkeratosis: A phenotype conferred by mutations in the 2B domain of keratin K1.

Bullous congenital ichthyosiform erythroderma (BCIE) is characterized by blistering and erythroderma in infancy and by erythroderma and ichthyosis thereafter. Epidermolytic hyperkeratosis is a hallmark feature of light and electron microscopy. Here we report on four individuals from two families with a unique clinical disorder with histological findings of epidermolytic hyperkeratosis. Manifesting erythema and superficial erosions at birth, which improved during the first few months of life, affected individuals later developed palmoplantar hyperkeratosis with patchy erythema and scale elsewhere on the body. Three affected individuals exhibit dramatic episodic flares of annular, polycyclic erythematous plaques with scale, which coalesce to involve most of the body surface. The flares last weeks to months. In the interim periods the skin may be normal, except for palmoplantar hyperkeratosis. Abnormal keratin-filament aggregates were observed in suprabasal keratinocytes from both probands, suggesting that the causative mutation might reside in keratin K1 or keratin K10. In one proband, sequencing of K1 revealed a heterozygous mutation, 1436T-->C, predicting a change of isoleucine to threonine in the highly conserved helix-termination motif. In the second family, a heterozygous mutation, 1435A-->T, was found in K1, predicting an isoleucine-to-phenylalanine substitution in the same codon. Both mutations were excluded in both a control population and all unaffected family members tested. These findings reveal that a clinical phenotype distinct from classic BCIE but with similar histology can result from K1 mutations and that mutations at this codon give rise to a clinically unique condition.

Spontaneous remission of congenital leukemia.

Most patients with congenital leukemia do not survive past infancy despite aggressive chemotherapy. We describe three patients with congenital leukemia who have undergone prolonged periods of spontaneous remission. Our experience suggests that some patients with congenital leukemia may benefit from initial conservative management without chemotherapy. We summarize the clinical presentations of these patients and review the literature.

Incontinentia pigmenti.

This article reviews the clinical features, histopathology, genetics, and differential diagnosis of incontinentia pigmenti. Emphasis is placed on appropriate management strategies for patients with incontinentia pigmenti.

Prevalence of hypopigmented macules in a healthy population.

OBJECTIVE: Although hypopigmented macules are an important manifestation of tuberous sclerosis (TS), the probability of TS in healthy individuals who have hypopigmented macules is unknown. The purpose of this study was to establish the prevalence of hypopigmented macules among a cross section of the general white population. STUDY DESIGN: The skin of 423 white individuals younger than 45 years of age was screened for hypopigmented macules with ambient incandescent and fluorescent light and a Wood lamp. Indirect ophthalmoscopy was performed in patients with unexplained hypopigmentation to screen for retinal manifestations of TS. RESULTS: Twenty individuals (4.7%) had at least one hypopigmented macule. Of these, four had more than one macule. None had more than three. Two (8%) of the 25 hypopigmented macules were identified only with a Wood lamp. Indirect ophthalmoscopy was performed in 13 (65%) of these 20 individuals. None showed the retinal findings of TS. CONCLUSIONS: The prevalence of hypopigmented macules in the general population has been underestimated. The presence of a few hypopigmented macules on the skin of an otherwise healthy individual without a family history of TS need not prompt an evaluation to rule out this disorder.

Reiter syndrome initially misdiagnosed as Kawasaki disease.

A misdiagnosis of Kawasaki disease was made initially for two patients with Reiter syndrome. The first patient had conjunctivitis, urethritis, arthritis, and the characteristic skin finding of keratoderma blennorrhagicum. The second patient had conjunctivitis, uveitis, dysuria, arthritis, and the characteristic musculoskeletal finding of enthesitis. Neither patient responded to intravenous immunoglobulin therapy but both responded to nonsteroidal antiinflammatory medication. The clinical characteristics of Reiter syndrome and Kawasaki disease in children are similar but specific features should allow for their differentiation.

Evidence that the ancestral haplotype in Australian hemochromatosis patients may be associated with a common mutation in the gene.

Hemochromatosis (HC) is a common inherited disorder of iron metabolism for which neither the gene nor biochemical defect have yet been identified. The aim of this study was to look for clinical evidence that the predominant ancestral haplotype in Australian patients is associated with a common mutation in the gene. We compared indices of iron metabolism and storage in three groups of HC patients categorized according to the presence of the ancestral haplotype (i.e., patients with two copies, one copy, and no copies of the ancestral haplotype). We also examined iron indices in two groups of HC heterozygotes (those with the ancestral haplotype and those without) and in age-matched controls. These analyses indicate that (i) HC patients with two copies of the ancestral haplotype show significantly more severe expression of the disorder than those with one copy or those without, (ii) HC heterozygotes have partial clinical expression, which may be influenced by the presence of the ancestral haplotype in females but not in males, and (iii) the high population frequency of the HC gene may be the result of the selective advantage conferred by protecting heterozygotes against iron deficiency.

Familial pityriasis rubra pilaris.

BACKGROUND: Familial pityriasis rubra pilaris is a rare autosomal dominant skin disorder. Four individuals from one family are described who demonstrate clinical features compatible with a diagnosis of familial pityriasis rubra pilaris. Results of light and electron microscopic, immunocytochemical, and biochemical analysis of skin biopsy specimens from three of these four individuals are presented. OBSERVATIONS: All affected individuals demonstrated erythematous scaly skin with follicular prominence and islands of sparing. Inheritance was consistent with an autosomal dominant trait. Light and electron microscopic findings were compatible with those reported in sporadic cases of pityriasis rubra pilaris. Immunocytochemistry showed suprabasal staining with monoclonal antibody AE1. Immunoblot analysis revealed abnormal keratins with K6/16 expression, the possibility of an abnormal K14 or K16, and a 45-kd acidic keratin not normally expressed in epidermis. Because similar biochemical analyses have not been reported previously in other cases of pityriasis rubra pilaris (familial or sporadic), comparisons cannot be made. CONCLUSIONS: The observations suggest that the cutaneous abnormality in this family extends beyond clinical and morphological alterations to abnormalities in biochemical markers of epidermal differentiation.

Genetic skin diseases.

Recent advances in molecular genetics have led to major breakthroughs in the understanding of two heterogeneous groups of inherited skin diseases, epidermolysis bullosa and the ichthyoses. Mutations in keratins K5 or K14 are found in epidermolysis bullosa simplex. The gravis (Herlitz) variety of junctional epidermolysis bullosa is characterized by defects in the anchoring filament protein kalinin. Both dominant and recessive forms of dystrophic epidermolysis bullosa appear to be due to mutations in the type VII collagen gene. Biochemical studies in patients with ichthyosis vulgaris reveal that the proteins profilaggrin and filaggrin are reduced or absent. Recessive X-linked ichthyosis is characterized by a deficiency of the enzyme steroid sulfatase. A type of lamellar ichthyosis may be explained on the basis of abnormal cornified cell envelope formation, and bullous congenital ichthyosiform erythroderma (epidermolytic hyperkeratosis) is caused by mutations in keratins K1 or K10.

Congenital monocytic leukemia: report of a case with cutaneous involvement, and review of the literature.

Congenital leukemia is a rare disease that can become manifest soon after birth. Cutaneous involvement consists of red, brown, or purple papules and nodules, and confluent areas of purpura. The diagnosis is established by the presence of leukemic cells in biopsy specimens of bone marrow and involved skin, and by immunocytochemical characterization of these cells. We report a case of congenital monocytic leukemia with a normal karyotype, whose disease underwent temporary spontaneous regression.

Cardiovascular effects of chronic intraventricular administration of angiotensin II in dogs.

Intracerebroventricular administration of angiotensin II (AII), 1 microgram twice a day to mongrel dogs plus saline as the drinking fluid for 4 weeks produced a significant sustained elevation in systolic and diastolic blood pressures. The hypertensive state appeared to be due to an increase in total peripheral resistance. Fluid intake and urine output were elevated and there was a significant increase in body weight at the end of week 2, 3 and 4. Serum Na+ levels were significantly decreased and serum Ca++ levels significantly increased in the hypertensive animals. These studies indicate that increasing AII levels in the cerebrospinal fluid for a prolonged period of time produces a sustained hypertensive state only if the daily intake of sodium is increased and that the alterations in vascular resistance may be due to changes in the Na+ - Ca++ fluxes.

Differential cardiovascular changes as a function of stimulation electrode site in rabbit hypothalamus.

Twenty chronically prepared, unanesthetized rabbits received both high-frequency (200 pulse/sec), short pulse-train (1.0 sec) and relatively low-frequency (25 pulse-sec), long pulse-train (10 sec) electrical stimulation of the hypothalamus. High-frequency, short pulse-train stimulation elicited a pressor response and bradycardia at all 27 electrode sites. In contrast, three other cardiovascular response patterns were obtained following low-frequency, long pulse-train stimulation. These latter patterns reflected a medial-lateral organization of autonomic function within the hypothalamus. Whereas all 15 lateral hypothalamic placements yielded depressor responses, 7 of 12 medial hypothalamic placements yielded pressor responses and tachycardia. Cardiovascular changes following administration of selective autonomic blocking agents (e.g., phentolamine, propranolol, methylatropine) suggest that high-frequency, short pulse-train stimulation elicited a pressor response followed by a reflexive bradycardia essentially mediated by an increase in vagal restraint. In contrast, the heart rate changes observed to low-frequency, long pulse-train stimulation all appear to have been importantly influenced by changes at the heart in beta-adrenergic activity.

Antiarrhythmic activity of four pteridine compounds in ouabain intoxication.

The antiarrhythmic effects of 4 pteridine analogues, 2 of which are potassium-sparing diuretics, triamterene (2, 4, 7-triamino-6-phenylpteridine) and [2-phenyl-4, 7 diaminopteridine-6-(N-diethylaminoethyl) carboxamide] and 2 of which have no diuretic effects [2-phenyl-4, 7-diaminopteridine-6-(N-2-hydroxyethyl) carboxamide], on ouabain-induced ventricular tachycardia in intact pentobarbital-anesthetized dogs were investigated. Ouabain was given as a continuous infusion 2 mug/kg/min intravenously until 5 min after the onset of a sustained ventricular tachycardia. It was found that both 6-(N-dimethylaminopropyl) and 6-(N-diethylaminoethyl) carboxamide derivates of the pteridine had a significant protective effect against ouabain-induced ventricular tachycardia in dogs that had been pretreated with a dose of 5 mg/kg intravenously. At this dose the 2 pteridine compounds with diuretic activity exhibited a transient antiarrhythmic effect in abolishing the ouabain-induced ventricular tachycardia while those without diuretic properties failed to suppress the ventricular tachycardia.