CHAPTER 2 PAEDIATRICS AND GENETICS THE ROLE OF INHERITANCE AND THE CARE OF CHILDREN Paediatrics and Genetics 21 Dry skin – the sort that itches, peels, flakes or cracks in cold weather – is extremely common. As many as one in ten of the population – five to ten million people – suffer from it at some stage. The cosmetics industry, with its emollient creams and lotions, is founded on it. Some people have a more serious condition known as ichthyosis in which the skin is dry, thickened and scaly. Ichthyosis is derived from the Ichthyosis Ichthyosis Vulgaris Lichen Sclerosus Chromosome Mutation Greek, meaning “fish scales”, a reference to the characteristic appearance of the skin. The commonest type, accounting for 95 per cent of cases, is ichthyosis vulgaris which affects an estimated 800,000 people in Britain. It is mostly mild and in many cases mistaken for normal dry skin but rare types of ichthyosis can be severe and even life threatening. Ichthyosis is a genetic skin disease, passed down the generations. There are an estimated 5,000 genetic diseases in all, of which around one third One in ten people – five to ten million – suffer from dry skin but some have a more serious conditions. Ichthyosis Vulgaris (left) affects around 800,000 people in Britain and Lichen Sclerosis (right) affects 200,000 involve the skin. The best hope for patients suffering from these diseases is to identify the gene sclerosus , which affects one in 300 people. The 3 1 3 1 3 2 2 2 2 1 2 2 2 1 2 . 3 2 1 2 4 3 2 4 2 5 1 4 1 1 5 (or genes) that is the culprit and to develop a breakthrough in understanding led to new . q q q 4 1 3 3 6 2 3 2 2 3 3 6 1 1 q 1 p p p q 3 q q p p p 3 1 1 1 1 p 1 1 1 1 1 1 p 1 therapy based on that. approaches to treating both diseases. 1 2 3 1 2 2 1 3 2 3 2 2 3 2 2 3 . 1 1 4 1 2 3 2 4 2 . 4 1 3 1 1 1 . q p p 3 2 3 That is the task of the Paediatrics and Genetics Professor McGrath and colleagues have since 6 2 2 3 2 2 2 3 6 1 q 1 1 p p 3 q q q q p p 4 3 1 1 1 p q 1 1 1 1 1 1 p 1 1 department headed by Professor John McGrath . He discovered several single gene mutations that are 1 The gene that causes lipoid proteinosis: ECM1 is a gene hunter with a collection of scalps on his the cause of other skin diseases and opened the belt. To take one example, he and his team way for the development of new and more effective Today, the St John’s clinic is designated as a investigated lipoid proteinosis , a rare condition therapies. national centre for the treatment of highly affecting one in 300,000 people which causes At the same time the clinical service of paediatric specialised paediatric skin disease. Last year, under scarring and infiltration (thickening and hardening dermatology offered at St John’s has expanded consultant dermatologist Jemima Mellerio , it saw of the skin) and found the gene that caused it, rapidly since the mid-2000s. Prior to 2007, there 2,000 patients. ECM1 (extracellular matrix protein 1). Working on was one paediatric clinic a month for the severest “Until 2007, we used to get the children, babies this protein, he then found a link to a much more cases run by a consultant from Great Ormond Street with eczema and all the rest and put them in with common inflammatory skin condition, lichen Hospital for Sick Children. the adults. Now that seems extraordinary,” she said. 22 Paediatrics and Genetics CHAPTER 2 PAEDIATRICS AND GENETICS History John McGrath Geoffrey Dowling Bob Meara George Wells Robin Eady at work in the 1960s The origins of St John’s expertise in genetics can be Geoffrey Dowling , consultant and director of EB and ichthyosis. He was also an inspirational traced back to the 1950s when dermatologists from St Johns from 1951-56, described with registrar Bob teacher, raised money to upgrade the dermatology around London used to meet at the hospital, then in Meara a form of the blistering skin disease section of Guy’s medical museum to become a Lisle Street, to discuss unusual cases. “It was the Epidermolysis Bullosa (EB, see below) since called “teaching laboratory” and by the early 1980s St collection of these cases and their careful Dowling-Meara EB simplex . John’s was producing one quarter of all the description that laid the groundwork for future R S Wells – known as Charlie – developed dermatologists in the country. advance,” said Professor McGrath. prototype classifications for the different types of By then Robin Eady , another pioneer, was using Healthy Skin EB Hemidesmosome plaque EB Simplex a6ß4 integrin Epidermis Collagen Anchoring Laminin 5 Lamina lucida XVII Filaments Dermis Lamina densa Junctional Subcutaneous EB tissue Muscles Type VII collagen Anchoring Fibrils Sublima densa Dystrophic EB The development of the blistering skin disease Epidermolysis Bullosa Paediatrics and Genetics 23 electron microscopy to see inside cells and inspect whether to seek a termination. It would have been Signal their structure. It was a long laborious process, but far better to make the diagnosis before the mother Fluorescent Tag it led ultimately to quicker diagnosis through the became pregnant. introduction of immunohistochemistry (staining With the development of single cell polymerase Labeled Secondary techniques), reducing the wait for results from three chain reaction (PCR) technology , which could Antibody weeks to three days. amplify a single piece of DNA by several orders of Primary Antibody Eady, working with obstetricians, also pioneered magnitude, pre-natal diagnosis became possible in Proteins the development of foetal skin biopsy – taking tiny the late 1990s. Parents could opt for in-vitro skin samples from babies in the womb to examine fertilisation (IVF) with pre-implantation diagnosis to for EB. The test was offered to parents who already select unaffected embryos for replacement in the had an affected child to give them the option of a womb. It was the natural extension of Eady’s work Cell/ Tissue termination. But the biopsy could not be done until Eady, who was awarded an MBE in the New Year 16 weeks, very late in the pregnancy. Foetal skin Honours 2014, was also a pioneer in a different way. Signal biopsy has now largely been superseded by He is the world’s longest surviving kidney failure Fluorescent Tag chorionic villus sampling , taking a tiny sample from patient, at the time of writing, who as a medical the placenta, which is carried out at 10-11 weeks student in 1963 flew to North America for Labeled Primary and has already been applied to over 400 couples treatment. He was so weak he had to be carried off Light Antibody Proteins at St John’s. the Boeing 707. He spent 24 years on dialysis and Nevertheless, this still left parents carrying an the last 26 with a kidney transplant. affected baby facing the heartrending decision of Cell/ Tissue Indirect immunohistochemistry and immunofluorescence methods Pre-natal diagnosis of certain skin diseases became possible with the development of polymerase chain reaction (PCR) technology Polymerase chain reaction - PCR original DNA to be replied 5´ 3´ 5´ 3´ 5´ 3´ 3´ 5´ 5´ 3´ 1 1 1 2 3 2 2 3 3 3´ 5´ 5´ 3´ 3´ 5´ DNA primer 3´ 5´ 3´ 5´ nucleotide 24 Paediatrics and Genetics CHAPTER 2 PAEDIATRICS AND GENETICS Genetic breakthrough Plakophilin 1 Protein “It was going through the analyser and I could see there was an exciting mutation. It was a Eureka moment. We had discovered a new disease” – Professor John McGrath Intercellular space Desmosome In 1995, McGrath, who returned to St John’s from a in 1997 the condition subsequently became Plaque sojourn in the US, began his gene hunting in earnest. recognised as a form of EB . He established a molecular diagnostics laboratory Over the next 15 years, McGrath examined the and raised money for an automated gene sequencer, structure, function and protein composition of then regarded as a “new-fangled” piece of kit. As it was being installed, McGrath pulled a tissue sample from his “special bottom draw” of mystery patients, to use as a test. Intermediate filament Special Characteristics of Epithelia-Cell Junction Linker glycoproteins “It was going through the analyser and I could (keratin) see the company technician frowning. He thought Microvilli Desmosomes: there was a malfunction. But I could see something Narrow Apical region of an Anchoring exciting was unfolding - there was an exciting Cillia extracellular junctions bind space epithelian cell frame-shift mutation. It was a Eureka moment – we adjacent cells together and help had found a new disease.” Cell junctions form an internal The sample in the sequencer was from a patient Tight junction tension-reducing Adhesive belt network of fibers. with ectodermal dysplasia -skin fragility syndrome Desmosome and it had revealed the cause to be a demosomal Gap junction gene disorder resulting from a mutation in Basal region Basement plakophilin 1 . It was the world’s first genetic Basal lamina Nerve ending Reticular fibers membrane disorder of cell attachment complexes called desmosomes . After McGrath published his findings Capillary Paediatrics and Genetics 25 1 2 tissue samples from a range of patients to gain some idea of what was going wrong in order to target the search for the genetic culprit with what is known as the “candidate gene” approach.