A further case of chondrodysplasia with growth failure occurring after hematopoietic stem cell transplantation (HSCT).

There is an emerging body of evidence showing that young patients, post haematopoietic stem cell transplantation (HSCT), can develop skeletal changes that mimic an osteochondrodysplasia process. The key discriminator is that these children have had otherwise normal growth and skeletal development before the therapeutic intervention (HSCT), typically for a haematological malignancy. Herein we present that case of a boy who underwent HSCT for Haemophagocytic Lymphohistiocytosis (HLH) aged 2 years. Following Intervention with HSCT this boy's growth has severely decelerated (stature less than 1st centile matched for age) and he has developed a spondyloepiphyseal dysplasia.

A health survey of the reef forming scleractinian cold-water corals Lophelia pertusa and Madrepora oculata in a remote submarine canyon on the European continental margin, NE Atlantic.

Monitoring of cold-water corals (CWCs) for pathogens and diseases is limited due to the environment, protected nature of the corals and their habitat and as well as the challenging and sampling effort required. It is recognised that environmental factors such as temperature and pH can expedite the ability of pathogens to cause diseases in cold-water corals therefore the characterisation of pathogen diversity, prevalence and associated pathologies is essential. The present study combined histology and polymerase chain reaction (PCR) diagnostic techniques to screen for two significant pathogen groups (bacteria of the genus Vibrio and the protozoan Haplosporidia) in the dominant NE Atlantic deep-water framework corals Lophelia pertusa (13 colonies) and Madrepora oculata (2 colonies) at three sampling locations (canyon head, south branch and the flank) in the Porcupine Bank Canyon (PBC), NE Atlantic. One M. oculata colony and four L. pertusa colonies were collected from both the canyon flank and the south branch whilst five L. pertusa colonies were collected from the canyon head. No pathogens were detected in the M. oculata samples. Neither histology nor PCR detected Vibrio spp. in L. pertusa, although Illumina technology used in this study to profile the CWCs microbiome, detected V. shilonii (0.03%) in a single L. pertusa individual, from the canyon head, that had also been screened in this study. A macroborer was observed at a prevalence of 0.07% at the canyon head only. Rickettsiales-like organisms (RLOs) were visualised with an overall prevalence of 40% and with a low intensity of 1 to 4 (RLO) colonies per individual polyp by histology. L. pertusa from the PBC canyon head had an RLO prevalence of 13.3% with the highest detection of 26.7% recorded in the south branch corals. Similarly, unidentified cells observed in L. pertusa from the south branch (20%) were more common than those observed in L. pertusa from the canyon head (6.7%). No RLOs or unidentified cells were observed in corals from the flank. Mean particulate organic matter concentration is highest in the south branch (2,612 µg l-1) followed by the canyon head (1,065 µg l-1) and lowest at the canyon flank (494 µg l-1). Although the route of pathogen entry and the impact of RLO infection on L. pertusa is unclear, particulate availability and the feeding strategies employed by the scleractinian corals may be influencing their exposure to pathogens. The absence of a pathogen in M. oculata may be attributed to the smaller number of colonies screened or the narrower diet in M. oculata compared to the unrestricted diet exhibited in L. pertusa, if ingestion is a route of entry for pathogen groups. The findings of this study also shed some light on how environmental conditions experienced by deep sea organisms and their life strategies may be limiting pathogen diversity and prevalence.

Development, behaviour and sensory processing in Marshall-Smith syndrome and Malan syndrome: phenotype comparison in two related syndromes.

BACKGROUND: Ultrarare Marshall-Smith and Malan syndromes, caused by changes of the gene nuclear factor I X (NFIX), are characterised by intellectual disability (ID) and behavioural problems, although questions remain. Here, development and behaviour are studied and compared in a cross-sectional study, and results are presented with genetic findings. METHODS: Behavioural phenotypes are compared of eight individuals with Marshall-Smith syndrome (three male individuals) and seven with Malan syndrome (four male individuals). Long-term follow-up assessment of cognition and adaptive behaviour was possible in three individuals with Marshall-Smith syndrome. RESULTS: Marshall-Smith syndrome individuals have more severe ID, less adaptive behaviour, more impaired speech and less reciprocal interaction compared with individuals with Malan syndrome. Sensory processing difficulties occur in both syndromes. Follow-up measurement of cognition and adaptive behaviour in Marshall-Smith syndrome shows different individual learning curves over time. CONCLUSIONS: Results show significant between and within syndrome variability. Different NFIX variants underlie distinct clinical phenotypes leading to separate entities. Cognitive, adaptive and sensory impairments are common in both syndromes and increase the risk of challenging behaviour. This study highlights the value of considering behaviour within developmental and environmental context. To improve quality of life, adaptations to environment and treatment are suggested to create a better person-environment fit.

Novel COL4A2 variant in a large pedigree: Consequences and dilemmas.

Pathogenic COL4A2 variants cause abnormalities in collagen production and can have serious implications for a range of organ systems, most notably the brain. Herein, we describe a large family of first-degree relatives affected by a novel heterozygous variant in COL4A2 (c.3490G.A). A wide disease spectrum is described, from asymptomatic to symptomatic, including 2 children with porencephaly and co-existing juvenile idiopathic polyarthritis. During a subsequent pregnancy, antenatal testing identified a positive fetus. In view of the literature, we review management and genetic counselling dilemmas.

Craniofacial bony defect with developmental abnormality of facial bones, dental malalignment and ectopic neural tissue in the internal auditory meati--a new syndrome?

We present a previously undescribed skeletal dysplasia with dental anomalies and ectopic neural tissue in the internal auditory meati.

Duplication of 17q11.2 and Features of Albright Hereditary Osteodystrophy Secondary to Methylation Defects within the GNAS Cluster: Coincidence or Causal?

We report a case of Albright hereditary osteodystrophy (AHO) in a three-year-old girl with a microduplication at 17q11.2. The child developed obesity within the first 6 months of life. A diagnosis of Albright was made at age 2 years when biochemical evidence of parathyroid resistance was found. No mutations were identified in guanine nucleotide-binding protein G (s) subunit alpha (GNAS1). Subsequent investigations revealed methylation disturbance at GNAS1A, neuroendocrine secretory protein antisense (NESPAS) and neuroendocrine secretory protein 55 (NESP55) confirming a diagnosis of pseudohypothyroidism type 1B. A deletion of NESP55 and uniparental disomy chromosome 20 were excluded which suggested that the features of AHO arose through a purely epigenetic mechanism. Further investigation revealed a de novo microduplication at 17q11.2 encompassing the neurofibromatosis type 1 (NF1) gene. The combination of two rare de novo events in the same child raises the possibility that duplication of a gene within the 17q11.2 region may have triggered abnormal methylation in the GNAS cluster region on chromosome 20.

Case report: unusual dental morphology in a child with ankyloblepharon-ectodermal defects-cleft lip/palate (AEC) syndrome.

BACKGROUND: Anomalies of dental anatomy are common in the ectodermal dysplasia syndromes. These anomalies, when found in combination with dental caries, can pose a restorative challenge for the paediatric dentist. Modification of traditional techniques and approaches may help the practitioner provide a successful treatment outcome. CASE REPORT: A 3 years and 11 months old girl with a diagnosis of ankyloblepharon-ectodermal dysplasiacleft lip/palate (AEC) syndrome was referred for treatment to a specialist paediatric dental service. Her abnormal dental anatomy, hypodontia and dental caries formed a triad of challenges for the team. Under general anaesthesia, her dentition was restored using a combination of restorative approaches and techniques, including the placement of both composite resin and preformed metal crown restorations. FOLLOW-UP: At 18-month followup, the family had successfully implemented good home care and dietary practices, and the local dental service had instituted a preventive programme consisting of regular examination, advice and fluoride varnish placement. The restorations remained intact and no further caries was detected. At 24-month follow-up, the first permanent molars were partially erupted, and displayed unusually deep fissures. There was also a degree of ectopic eruption of the first permanent molars, and possibly of one of the maxillary permanent incisors. CONCLUSION: Dental care for children with AEC syndrome is optimised by early intervention, good home care and regular professional review. Dental care providers should be aware of the possibility of complex dental anatomy, and bear this in mind should it become necessary to formulate a restorative treatment plan.

Bannayan-Riley-Ruvalcaba syndrome: a cause of extreme macrocephaly and neurodevelopmental delay.

BACKGROUND: Bannayan-Riley-Ruvalcaba syndrome (BRRS) is an autosomal dominant condition characterised by macrocephaly, developmental delay and subtle cutaneous features. BRRS results from mutations in the PTEN gene. In adults, PTEN mutations cause Cowden syndrome where, in addition to the macrocephaly, there is a higher risk of tumour development. Diagnosis of BRRS is often delayed as presentation can be variable, even within families. AIMS: To identify characteristics of this condition which might facilitate early diagnosis. Prompt diagnosis not only avoids unnecessary investigations in the child but potentially identifies heterozygote parents who are at risk of tumour development. METHODS AND RESULTS: Six children with a PTEN mutation were identified. All had extreme macrocephaly. Four parents and a male sibling were found to have a PTEN mutation on subsequent testing. Affected parents had extreme macrocephaly and a history of thyroid adenoma, or breast or skin lesions. All six children had presented to medical attention before the age of 2.5 years (3/6 were investigated as neonates), but the median age at diagnosis was 5 years. Four of the children had multiple investigations prior to identification of a PTEN mutation. CONCLUSION: BRRS should be considered in children with extreme macrocephaly as it is the most consistent clinical feature seen, particularly where there is a family history of macrocephaly.

Incidence and prevalence of mucopolysaccharidosis type 1 in the Irish republic.

Mucopolysaccharidosis type 1 (MPS1) is an autosomal recessive disorder with severe, moderate and mild phenotypes: Hurler, Hurler-Scheie and Scheie syndromes. We estimated incidence (2001-2006) and prevalence (2002 census) of MPS1 in the Irish Republic (ROI) using population data, database and chart review of all live MPS1 patients attending two specialised centres. Patient genotypes, ethnicity, province of origin, age at diagnosis and presenting features were recorded. Thirty-one patients (14 females, 17 males) were alive, 27 of whom were <15 years. Twenty-six patients had Hurler syndrome, four had Hurler-Scheie and one had Scheie syndrome. The birth incidence was 1 in 26 206 births with a carrier frequency of 1 in 81. Of note, 19/26 (73%) Hurler patients were Irish Travellers. Amongst Irish Travellers the incidence was 1 in 371 with a carrier frequency of 1 in 10. This is the highest recorded incidence worldwide. Given the morbidity and mortality associated with delayed treatment we recommend targeted newborn screening for this population.

Cascade screening in BRCA1/2 mutation carriers.

Genetic counselling for families with BRCA1 & 2 has been available in Ireland since 1998. We describe the follow-on cascade from the initial 29 index cases that tested positive for either gene. 28 of the index cases were female and 1 was male. Their combined sibship and offspring totalled 125 and 129 respectively. Of the 125 siblings, 21/72 (29%) females and 10/53 (19%) males came forward for counselling and all were tested. Of the 129 at risk offspring, 56 (43%) [25 females and 31 males] were over 18 years and therefore were eligible for testing. 20/25 (80%) females and 6/31 (19%) males came for counselling and all bar one female was tested. In summary, 31/125 (25%) at risk siblings were tested and 25/56 (45%) offspring were tested. Only one person, a daughter of an affected individual who attended clinic, declined testing. The remaining 197 (77%) individuals have not come forward for counselling. Our results suggest that a) there is a low-moderate testing rate in Ireland when compared to other European centres; and that b) daughters of BRCA1/2 carriers are more likely to come forward for testing than female siblings. Specific factors which appeared to influence attendance included poor dissemination of information among families about the test; and lower levels of communication among siblings than within the nuclear family.

Recurrence risk for psoriasis and psoriatic arthritis within sibships.

OBJECTIVE: To quantify the frequency of siblings of patients with psoriatic arthritis (PsA) having psoriasis and/or inflammatory arthritis. To describe the similarity or otherwise of patterns of arthritis in siblings. METHODS: Available and consenting index cases with PsA and one or more siblings living locally were assessed. Mean sibling concordance rates and Weinberg's segregation analysis were calculated. Heritability was also estimated. To assess whether the same type of arthritis occurred within the same sibship, the dually affected sibships were then classified for type of arthritis according to methods suggested by Moll, Helliwell, Veale and McGonagle. RESULTS: Eighty index cases and 112 siblings were assessed. The median age of index cases was 49 yr (range 24-80 yr) and for siblings 46 yr (range 18-79 yr). The concordance rate for all types of PsA was 14% (9% if enthesitis is excluded) and for psoriasis 21%. There was no difference in the two methods used to calculate concordance rates. Sixteen dually affected sib pairs were found. Four of the 16 sibships (25%) had the same pattern of joint involvement (Moll and Wright classification). The most frequent pattern seen was joint involvement identical to rheumatoid arthritis (3/5). The most common symptom in affected siblings was enthesitis (approximately 5%). When the dually affected sibships were analysed using the other classifications, the simpler the classification the greater the concordance for joint pattern. CONCLUSION: The concordance for psoriasis is greater than for PsA, but the concordance rate for PsA was similar to that in HLA identical siblings with rheumatoid arthritis. There was discordance in pattern of arthritis for most sib pairs. There is no support for the use of more complex classifications of PsA.

NBCCS secondary to an interstitial chromosome 9q deletion.

Naevoid basal cell carcinoma syndrome (NBCCS) or Gorlin syndrome is a rare autosomal dominant cancer disorder. The Gorlin's gene, Patched 1 (PTCH1), maps to Chromosome 9q. Germline mutations of PTCH1 occur in patients with NBCCS. The subsequent loss of the remaining allele results in cancer formation. We present a patient with NBCCS and additional phenotypic features including severe developmental delay, short stature and hypotelorism who was found to have an interstitial chromosome 9q deletion. The NBCCS phenotype in our patient occurred as a result of PTCH1 deletion in contrast with an inherited mutation of this gene.

Gene-gene interaction in folate-related genes and risk of neural tube defects in a UK population.

OBJECTIVE: To investigate the contribution of polymorphic variation in genes involved in the folate-dependent homocysteine pathway in the aetiology of neural tube defects (NTD). DESIGN: Case-control association study. SUBJECTS: A total of 530 individuals from families affected by NTD, 645 maternal controls, and 602 healthy newborn controls from the northern UK. MAIN OUTCOME MEASURES: Seven polymorphisms in six genes coding for proteins in the folate-dependent homocysteine pathway (MTHFR 677C-->T, MTHFR 1298A-->C, MTRR 66A-->G, SHMT 1420C-->T, CbetaS 844ins68, GCPII 1561C-->T, RFC-1 80G-->A). The impact of each polymorphism and the effect of gene-gene interactions (epistasis) upon risk of NTD were assessed using logistic regression analysis. RESULTS: The MTHFR 677C-->T polymorphism was shown to represent a risk factor in NTD cases (CC v CT+TT odds ratio (OR) 2.03 [95% confidence interval (CI) 1.09, 3.79] p = 0.025) and the MTRR 66A-->G polymorphism was shown to exert a protective effect in NTD cases (AA v AG+GG OR 0.31 [95% CI 0.10, 0.94] p = 0.04). When statistical tests for interaction were conducted, three genotype combinations in cases (MTRR/GCPII; MTHFR 677/CbetaS; MTHFR 677/MTRR) and one combination in case mothers (CbetaS/RFC-1) were shown to elevate NTD risk. Maternal-fetal interaction was also detected when offspring carried the MTHFR 677C-->T variant and mothers carried the MTRR 66A-->G variant, resulting in a significantly elevated risk of NTD. CONCLUSION: Both independent genetic effects and gene-gene interaction were observed in relation to NTD risk. Multi-locus rather than single locus analysis might be preferable to gain an accurate assessment of genetic susceptibility to NTD.

Genetic susceptibility to neural tube defect pregnancy varies with offspring phenotype.

Neural tube defects (NTDs) have a well-established genetic basis, although no single genetic factor has been identified as a major risk factor in NTD susceptibility. A large number of association studies have been conducted to investigate the possibility that NTD susceptibility is linked to polymorphic variation in genes involved in early embryonic development or in the absorption or metabolism of folate, a nutrient that has been clearly associated with a reduction in the risk of NTD pregnancy. A study of three candidate gene polymorphisms at loci implicated in folate absorption and metabolism has been conducted on a population of 211 mothers of a heterogeneous mix of NTD phenotypes: 59% spina bifida aperta (SBA), 20.3% spina bifida occulta (SBO), 17% anencephaly, and 3.7% other NTD. Allele and genotype frequencies were stratified according to offspring NTD phenotype, and variation in the level of NTD risk was associated with different phenotypes. All the three variants (MTHFR 677C > T, GCPII 1561C > T, and RFC-1 80G > A) were shown to significantly influence the risk of anencephalic pregnancy. In addition, the MTHFR 677C > T variant conferred a modest protective effect in SBO mothers and the total NTD mother group, but not in SBA mothers. The RFC-1 80G > A variant elevated the risk of SBO and anencephalic pregnancy. The findings of this study suggest that NTD phenotypic heterogeneity may help explain the mixed findings of previous association studies and that different polymorphisms may hold differing degrees of significance for the various NTD phenotypes.

Familial neurofibromatosis microdeletion syndrome complicated by rhabdomyosarcoma.

Neurofibromatosis type 1 with dysmorphism and developmental delay is reported in a mother and two children. The son required treatment for a prostatic rhabdomyosarcoma. His sister has an optic pathway glioma. Fluorescence in situ hybridisation confirmed a submicroscopic deletion at 17q11.2. New evidence suggests an increased malignancy frequency in microdeletion cases.

ARC syndrome: an expanding range of phenotypes.

AIM: To describe the clinical phenotype in infants with ARC syndrome, the association of arthrogryposis, renal tubular acidosis, and cholestasis. METHODS: The medical records for six patients with ARC syndrome were reviewed, presenting over 10 years to three paediatric referral centres. RESULTS: All patients had the typical pattern of arthrogryposis. Renal Fanconi syndrome was present in all but one patient, who presented with nephrogenic diabetes insipidus. Although all patients had severe cholestasis, serum gamma glutamyltransferase values were normal. Many of our patients showed dysmorphic features or ichthyosis. All had recurrent febrile illnesses, diarrhoea, and failed to thrive. Blood films revealed abnormally large platelets. CONCLUSIONS: ARC syndrome exhibits notable clinical variability and may not be as rare as previously thought. The association of Fanconi syndrome, ichthyosis, dysmorphism, jaundice, and diarrhoea has previously been reported as a separate syndrome: our observations indicate that it is part of the ARC spectrum.

Groin injuries in sport: treatment strategies.

Groin pain in athletes is a common problem that can result in significant amounts of missed playing time. Many of the problems are related to the musculoskeletal system, but care must be taken not to overlook other more serious and potentially life threatening medical cases of pelvis and groin pain. Stress fractures of the bones of the pelvis occur, particularly after a sudden increase in the intensity of training. Most of these stress fractures will heal with rest, but femoral neck stress fractures can potentially lead to more serious problems, and require closer evaluation and sometimes surgical treatment. Avulsion fractures of the apophyses occur through the relatively weaker growth plate in adolescents. Most of these will heal with a graduated physical therapy programme and do not need surgery. Osteitis pubis is characterised by sclerosis and bony changes about the pubic symphysis. This is a self-limiting disease that can take several months to resolve. Corticosteroid injection can sometimes hasten the rehabilitation process. Sports hernias can cause prolonged groin pain, and provide a difficult diagnostic dilemma. In athletes with prolonged groin pain, with increased pain during valsalva manoeuvres and tenderness along the posterior inguinal wall and external canal, an insidious sports hernia should be considered. In cases of true sports hernia, treatment is by surgical reinforcement of the inguinal wall. Nerve compression can occur to the nerves supplying the groin. In cases that do not respond to desensitisation measures, neurolysis can relieve the pain. Adductor strains are common problems in kicking sports such as soccer. The majority of these are incomplete muscle tendon tears that occur just adjacent to, the musculotendinous junction. Most of these will respond to a graduated stretching and strengthening programme, but these can sometimes take a long time to completely heal. Patience is the key to obtain complete healing, because a return to sports too early can lead to chronic pain, which becomes increasingly difficult to treat. Management of groin injuries can be challenging, and diagnosis can be difficult because of the degree of overlap of symptoms between the different problems. By careful history and clinical examination, with judicious use of special tests and good team work, a correct diagnosis can be obtained.

The accuracy of diagnoses as reported in families with cancer: a retrospective study.

Assessment of risk of developing hereditary cancer and subsequent clinical surveillance is largely based on family history. It is considered standard practice to confirm as many diagnoses as possible in cancer families. Our aim was (1) to assess inaccuracies in reporting of cancers by families, (2) to assess the need for confirmation of diagnosis, and (3) to estimate how many families would have been entered unnecessarily or excluded from screening. A retrospective study of 595 case notes was performed in two centres. Methods of confirmation included information from the cancer registries, death certificates, hospital notes, and histopathological records. Accuracy varied by site of cancer and by the closeness of the relationship to the affected person. Reported abdominal malignancies were inaccurate in 20%, whereas 5% of reported breast cancers were inaccurate. In two families the family history of cancer proved fictitious. Management was altered in 231213 (11%) families following cancer confirmation. The results of the study favour verification of cancer diagnoses particularly if decisions regarding surveillance or prophylactic surgery are based on the family history.