David J. Atherton

Mutations in the Gene Encoding Capillary Morphogenesis Protein 2 Cause Juvenile Hyaline Fibromatosis and Infantile Systemic Hyalinosis

Juvenile hyaline fibromatosis (JHF) and infantile systemic hyalinosis (ISH) are autosomal recessive conditions characterized by multiple subcutaneous skin nodules, gingival hypertrophy, joint contractures, and hyaline deposition. We previously mapped the gene for JHF to chromosome 4q21. We now report the identification of 15 different mutations in the gene encoding capillary morphogenesis protein 2 (CMG2) in 17 families with JHF or ISH. CMG2 is a transmembrane protein that is induced during capillary morphogenesis and that binds laminin and collagen IV via a von Willebrand factor type A (vWA) domain. Of interest, CMG2 also functions as a cellular receptor for anthrax toxin. Preliminary genotype-phenotype analyses suggest that abrogation of binding by the vWA domain results in severe disease typical of ISH, whereas in-frame mutations affecting a novel, highly conserved cytoplasmic domain result in a milder phenotype. These data (1) demonstrate that JHF and ISH are allelic conditions and (2) implicate perturbation of basement-membrane matrix assembly as the cause of the characteristic perivascular hyaline deposition seen in these conditions.

An appraisal of acitretin therapy in children with inherited disorders of keratinization

Retinoid therapy represents the treatment of choice for severe inherited disorders of keratinization. This paper reviews our experience of acitretin, compares acitretin with etretinate and defines guidelines for treatment. Forty‐six children have received acitretin since 1992 in our hospital: 29 children had either lamellar ichthyosis (nine), non‐bullous ichthyosiform erythroderma (five), bullous ichthyosiform erythroderma (four), Sjögren‐Larsson syndrome (three) or another rare condition (eight). The other 17 children who had psoriasis (16) and extensive viral warts (one), were excluded. Data on efficacy and tolerability of retinoid therapy were available for all but one patient. The cumulative follow‐up was 472 months for acitretin. The mean (± standard deviation) optimal dosage for acitretin was 0‐47 ± O17mg/kg per day, and this did not significantly differ between disorders. The overall improvement was considerable, with only three patients responding poorly. Mild to moderate mucocutaneous dryness was frequent. Minor abnormalities of liver function tests (four patients) and triglycerides (one patient) never led to changes of therapy. Irreversible side‐effects did not occur. Acitretin therapy for children with inherited keratinization disorders is best started at 0‐5 mg/kg per day. It represents a safe and effective treatment, provided that the minimal effective dose is maintained and that side‐effects are carefully monitored. When switching from etretinate to acitretin, a 20% reduction is recommended if the etretinate dose is over 0‐75 mg/kg per day or if side‐effects are dose limiting. Otherwise the same dose can be used.

A retrospective evaluation of azathioprine in severe childhood atopic eczema, using thiopurine methyltransferase levels to exclude patients at high risk of myelosuppression

Summary Background  Atopic eczema is a chronic inflammatory skin disease, which in most children can be adequately controlled using topical therapy. However, in a small number of children it is necessary to use systemic treatments to gain an acceptable level of disease control.

Keratitis–ichthyosis–deafness syndrome: disease expression and spectrum of connexin 26 (GJB2) mutations in 14 patients

Background  Keratitis–ichthyosis–deafness (KID) syndrome is a rare congenital disorder characterized by the association of skin lesions, hearing loss and vascularizing keratitis. KID syndrome is caused by autosomal dominant mutations in the connexin 26 gene (GJB2).

A review of the pathophysiology, prevention and treatment of irritant diaper dermatitis

SUMMARY Irritant diaper dermatitis (IDD) is a form of contact dermatitis occurring in the diaper area as a consequence of disruption of the barrier function of the skin through prolonged contact with faeces and urine. Despite advances in diaper technology, it is a condition that still occurs regularly in young children. To combat this, barrier preparations can be used to protect the skin by coating the surface of the skin and/or by supplying lipids that can penetrate the intercellular spaces of the stratum corneum. In this review, the pathophysiology of IDD is outlined and its prevention and treatment are discussed, with particular reference to the role of emollients.

Linear and whorled nevoid hypermelanosis

Two cases are presented of congenital linear and whorled hypermelanosis. Hyperpigmented macules in streaky configurations along Blaschkos lines appeared gradually after birth. Histologic examination revealed prominent epidermal melanocytes and irregular basal layer hyperpigmentation with normal melanosomes. This condition must be differentiated from incontinentia pigmenti, early systematized epidermal nevus, extensive hypomelanosis of Ito, and chimerism. Other similar case reports from the literature suggest that incidence is sporadic and may be associated with more serious congenital anomalies. The patterning is the inverse to that found in hypomelanosis of Ito. Developmental somatic mosaicism may be responsible for this patterned hypermelanosis.

Great Ormond Street Hospital for Children Registry for congenital melanocytic naevi: prospective study 1988-2007. Part 1-epidemiology, phenotype and outcomes.

Background  The aetiology of congenital melanocytic naevi (CMNs) is unknown.

Bone changes and their significance in children with ichthyosis on long-term etretinate therapy.

Summary Anxiety about the use of etretinate in children has been provoked by several reports describing skeletal abnormalities during long‐term therapy. However, we have observed no evidence of skeletal toxicity in 42 children treated over an 11‐year period. Radiological screening before and during treatment has failed to reveal abnormalities that would influence our decision to commence or to continue etretinate administration.

Bone mineralization in children with epidermolysis bullosa.

Background  Various factors may have deleterious effects on bone health in patients with epidermolysis bullosa (EB).

Spontaneous remission of congenital leukemia : A case for conservative treatment

A newborn infant with spontaneous remission of congenital leukemia cutis is described and a literature review of this uncommon phenomenon is provided. In view of the unusual and unpredictable behavior of this disease, chemotherapy should be withheld unless there is evidence of an 11q23 translocation or progressive disease. Otherwise, overall survival does not appear to be affected by adopting a conservative approach. Because of occasional late relapses, long-term follow-up is recommended. The biologic basis underlying spontaneous remission of congenital leukemia is unknown; therefore, molecular or molecular cytogenetic analysis of DNA obtained from a skin biopsy is recommended.