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Dermatology and clinical genetics joint session

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S. M. Kirke1, C. S. Munro2, A. M. Taylor1.1Department of Dermatology, Royal Victoria Infirmary, Newcastle upon Tyne, UK; 2Department of Dermatology, Southern General Hospital, Glasgow, UK

Proband: A profoundly deaf 9 year old boy of non-consanguineous parents was referred to dermatology outpatients with odd toenails. Examination revealed pitted dystrophy affecting all fingernails and most of toenails. No hyperkeratosis of nails was present. Transgradiens, diffuse, well-demarcated keratoderma involved the feet and was less marked on the hands. Brain stem evoked response audiometry performed at 2 months of age failed to elicit any response at 100 decibels and profound hearing loss was diagnosed. His 39 year old father who was profoundly deaf from birth had a mild palmar/plantar keratoderma while his 36 year old mother, also profoundly deaf, had normal skin. His 12 year old sister had normal hearing and normal skin. This patient’s keratoderma improved with the use of standard topical agents and at 6 years from presentation his skin shows a mild keratoderma on his feet and little detectable abnormality on his hands.

Investigations: Mutation analysis showed the proband to be double heterozygous for two sequence variants of genes coding for connexion 26 (GJB2), 35delG, and a new mutation, 125del AGG. His mother was homozygous for 35delG and his sister heterozygous for it. His father was heterozygous for the 125delAGG mutation.

Discussion: 125delAGG is the fourth reported autosomal dominant mutation of GJB2 that results in hearing impairment and palmoplantar keratoderma. The mutation is predicted to eliminate the amino acid residue E42 in connexion 26. Mutations in GJB2 are the leading cause of autosomal recessive non-syndromic hearing imparment (for example 35delG) whereas dominant mutations in the genes encoding the connexins important for hearing manifest with a spectrum of clinical phenotypes affecting hearing and skin. It is possible that the trans-dominant interference of this new mutation with other epidermal connexins may crucially impair the level or mode of epidermal intercellular signalling causing a disease phenotype.



S. Adalat1, H. M. Goodyear1, D. James2, C. Moss2.1Department of Child Health, Birmingham Heartlands Hospital, Birmingham, UK; 2Dermatology Department, Birmingham Children’s Hospital, Birmingham, UK

Introduction: Kindler syndrome is a rare autosomal recessive skin disorder characterised by skin fragility in infancy. This is followed by photosensitivity and poikiloderma, palmo-plantar hyperkeratosis, gum disease, and an increased risk of skin and mucous membrane malignancies. The disorder has recently been mapped to 20p12.3 and attributed to loss of function mutations in a novel gene, KIND 1.

Case report: MG, son of consanguineous parents of Pakistani origin, presented at birth with blisters over both arms and feet. Postnatally, extensive trauma induced blistering and erosions continued, mainly on the distal limbs. Nails and hair were normal and mucosal surfaces were not involved. The blistering tendency remained severe for the first months of life but had almost resolved after the first year. Now aged 2 years he shows atrophy and reticulate hyperpigmentation of the previously affected skin. He is otherwise well and teeth are erupting normally.

Investigations: A skin biopsy at 3 weeks of age showed duplication of the lamina densa characteristic of Kindler syndrome. DNA analysis confirmed homozygosity for the 676insC mutation in KIND1 found in all affected Pakistani families to date.1

Discussion:KIND1 encodes the protein kindlin-1, found predominantly in basal keratinocytes. Thus far 17 different mutations have been identified, four being recurrent within certain ethnic populations. Kindlin-1 plays a vital role in attaching the actin cytoskeleton to the extracellular matrix (ECM) via focal contacts, to maintain epithelial integrity. Although there is clinical overlap with epidermolysis bullosa, the latter is due to defective attachment of ECM to keratin rather than to actin. Besides its role in cell adhesion, it is postulated that KIND1 is also involved in cell signalling, morphogenesis, differentiation, and cell migration. KIND1 is substantially over expressed in some cancers and is regulated by transforming growth factor beta, which is known to increase motility of tumour cells. However, the exact basis of the increased risk of mucocutaneous malignancies, characteristic of this disorder, has yet to be elucidated. Recognition of Kindler syndrome means that long term complications can be minimised by preventative measures such as photo-protection and meticulous dental care.



S. M. Taibjee1, I. L. C. Chapple2, N. Thakker3, C. Moss1.1Department of Dermatology, Birmingham Children’s Hospital, Birmingham, UK; 2Birmingham Dental Hospital, Birmingham, UK; 3Unit of Medical Genetics, St Mary’s Hospital, Manchester, UK

Introduction: Papillon-Lefèvre syndrome (PLS) is an autosomal recessive condition characterised by palmoplantar keratoderma and severe prepubertal periodontitis. Haim-Munk syndrome (HMS), first described in immigrant Jews from Cochin, India, shows additional features of pyogenic skin infections, arachnodactyly, acro-osteolysis, and onychogryphosis. Both PLS and HMS are caused by mutations in the cathepsin C (CTSC) gene (11q14.1–14.3). We report a patient with overlapping features who presented paediatrically with apparent immunodeficiency.

Case Report: A 4 year old boy with consanguinous parents of Pakistani origin presented with recurrent staphylococcal abscesses from 4 months of age. Periodontitis was noted at 2 years 9 months, with recession and mobility of his anterior deciduous incisors. He also suffers from uniform thickening and cracking of his palms and soles, extending round to the sides of his fingers. His hands appear otherwise normal. His father and two paternal aunts are similarly affected, his father edentulous by 18 years of age.

Investigations: Immunological investigations, including serum immunoglobulins, T and B cell markers, luminometry, and specific antibody responses were all normal, other than an isolated suboptimal antibody response to Haemophilus influenzae B. Mutation analysis in CTSC confirmed a homozygous R272P mutation in the proband and his father, his mother being heterozygous.

Management: The periodontal management strategy has aimed to eliminate periodontal pathogens from the child and both parents using non-surgical periodontal therapy and adjunctive metronidazole and amoxycillin. The skin has been treated with emollients and topical antiseptics. A trial of systemic retinoids is being considered.

Summary: Our patient shows features of PLS, with additional susceptibility to skin infections usually associated with HMS. The idea that these two conditions represent different ends of the same disease spectrum is supported by identification of the Q286R mutation in both HMS1 and PLS.2 The R272P mutation found here has also been reported in families with PLS lacking susceptibility to skin infections.3 Associated polymorphisms in disease modifying loci may underpin this heterogeneity. CTSC mutations may cause recurrent skin abscesses in infants.





V. C. Diba1, H. Fassihi2, V. Wessagowit2, C. Jones2, J. A. McGrath2, N. P. Burrows1.1Department of Dermatology, Addenbrookes Hospital, Cambridge, UK; 2St John’s Institute of Dermatology, St Thomas’ Hospital, London, UK

Background: A male infant was born at 34 weeks gestation with a weight of 2189 kg. Twenty four hours after birth, blisters were noticed on his feet which did not clear with antibiotics. The blisters appeared particularly at sites of trauma. On examination he had bullae on his hands and feet, some of which were starting to crust over. Blood cultures were negative, as were skin and viral swabs. Blisters continued to develop until he was 4 months old. The child’s father had had a history of blistering of his hands and feet at birth which had resolved within weeks but examination was normal. The infant’s grandfather also had a similar history of blistering at birth which also spontaneously resolved. The infant had an older brother age 2 who was not affected.

Investigations: A provisional diagnosis of transient bullous dermolysis of the newborn (TBDN) was made. Indirect immunofluorescence microscopy, using a monoclonal anti-type VII collagen antibody (LH 7:2) demonstrated punctuate and granular labelling within the epidermis of the child’s skin. There was also reduced staining for type VII collagen at the dermal-epidermal junction supporting a diagnosis of TBDN. Samples from the father and paternal grandfather showed linear staining at the dermal–epidermal junction of similar intensity to normal control skin. There was also focal intra epidermal deposits of type VII collagen within the basal keratinocyte layer although this was less prominent than in the child’s skin. A causative mutation (G1522E) of COL7A1 gene was identified in all three individuals.

Summary: TBDN is a recently described neonatal blistering disorder of the skin presenting with bullae at birth, usually at the extremities and at sites of trauma.1 These blisters usually disappear within a few months to 1 year of age without leaving dystrophic scars.2 Electron microscopy reveals subepidermal blisters, reduced or abnormal anchoring fibrils at the dermo-epidermal junction, and electron dense inclusions in keratinocytes. TBDN is considered a subtype of dystrophic epidermolysis bullosa caused by mutations in the COL7A1 gene which encodes collagen VII, the major structural protein of anchoring fibrils in the skin.3 The presence of monoclonal antibodies revealing intra-epidermal type VII collagen on indirect immunofluorescence is typical in TBDN though it may be seen in some forms of dystrophic epidermolysis bullosa. TBDN is distinguished by its benign self limiting nature.2




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