Homozygous variegate porphyria presenting with developmental and language delay in childhood.

Variegate porphyria is an autosomal dominant disorder that usually presents with photosensitivity and acute neurological crises in adulthood. It is caused by heterozygous mutations in the protoporphyrinogen oxidase gene (PPOX). A rarer variant, homozygous variegate porphyria (HVP), presents in childhood with recurrent skin blisters and scarring. More variable features of HVP are short stature, brachydactyly, nystagmus, epilepsy, developmental delay and mental retardation. We describe a child who presented with nystagmus, developmental delay and ataxia, combined with a photosensitive eruption. Analysis of porphyrins in plasma, urine and stool supported a clinical diagnosis of HVP. DNA from the patient showed that he is compound heterozygous for two novel missense mutations in the PPOX coding region: c.169G>C (p.Gly57Arg) and c.1259C>G (Pro420Arg). Interestingly, cranial magnetic resonance imaging showed an absence of myelin, a feature not previously reported in HVP, which expands the differential diagnosis of childhood hypomyelinating leucoencephalopathies.

Rapp-Hodgkin and Hay-Wells ectodermal dysplasia syndromes represent a variable spectrum of the same genetic disorder.

BACKGROUND: Rapp-Hodgkin syndrome (RHS) and Hay-Wells [also known as ankyloblepharon-ectodermal defects-cleft lip/palate (AEC)] syndrome have been designated as distinct ectodermal dysplasia syndromes despite both disorders having overlapping clinical features and the same mutated gene, TP63. OBJECTIVES: To search for TP63 mutations in two unrelated cases of RHS and two of AEC syndrome and to review the TP63 mutation database and clinical descriptions of affected individuals, the goal being to refine genotype-phenotype correlation and to determine the clinical/molecular justification for RHS and AEC continuing to exist as separate entities. METHODS: Clinical examination of four affected cases and sequencing of genomic DNA using TP63-specific primers. Literature review of published clinical descriptions of RHS and AEC syndrome cases containing TP63 mutation data. RESULTS: Cases of RHS and AEC show considerable clinical overlap, particularly with regard to hypotrichosis and mid-face hypoplasia, and the clinical feature of ankyloblepharon in AEC is often subtle, transient and a poor distinguishing clinical sign. We identified two new and two recurrent heterozygous mutations in TP63: c.1456insA (p.Leu486fsX52), RHS; c.1537T>G (p.Phe513Val), RHS; c.1787delG (p.Gly596fsX68), AEC; and c.1682G>A (p.Gly561Asp), AEC. Including this study, 42 different mutations in TP63 in RHS and AEC have now been reported, three of which are exactly the same in both syndromes. CONCLUSIONS: Our clinicopathological and molecular findings indicate that there is no justification for the continued use of eponyms in referring to these particular ectodermal dysplasia syndromes. We support the view that the terms 'Hay-Wells' and 'Rapp-Hodgkin' should be abandoned in favour of the all-inclusive diagnosis 'AEC syndrome', notwithstanding the inconsistency or often transient nature of the ankyloblepharon.

PORCN gene mutations and the protean nature of focal dermal hypoplasia.

Focal dermal hypoplasia (FDH) is an X-linked dominant disorder featuring developmental abnormalities of ectodermal and mesodermal tissues. Pathogenic mutations in the PORCN gene (locus Xp11.23) were identified in 2007 and thus far 27 different mutations have been reported. PORCN encodes a putative O-acyltransferase which facilitates secretion of Wnt proteins required for ectomesodermal tissue development. We investigated PORCN gene pathology and pattern of X-chromosome inactivation analysis in two unrelated Caucasian female patients who presented with multiple developmental abnormalities consistent with FDH. We also reviewed the clinical and molecular data for all reported PORCN mutations and assessed genotype-phenotype correlation for sporadic and familial cases of FDH. DNA sequencing revealed two new PORCN gene mutations: p.W282X and c.74delG (p.G25fsX51). X-chromosome inactivation analysis revealed a random pattern in one case but was uninformative in the other. Collectively, point/small mutations account for 24 out of the 29 PORCN mutations and are typically seen in sporadic cases; larger deletions are more common in familial cases. Identification of two new PORCN gene mutations confirms the importance of PORCN-associated Wnt signalling in embryogenesis. Both new cases showed Blaschko-linear dermal hypoplasia and extensive ectomesodermal abnormalities, including severe limb developmental anomalies and a giant cell tumour of bone in one patient. Clinical variability can be attributed to the degree of lyonization and postzygotic genomic mosaicism, which are important mechanisms in determining the clinical presentation.

Fanconi anaemia complementation group B presenting as X linked VACTERL with hydrocephalus syndrome.

BACKGROUND: The VACTERL with hydrocephalus (VACTERL-H) phenotype is recognised to be a severe manifestation of autosomal recessive Fanconi anaemia. Several families have been described in which the VACTERL-H phenotype segregates as an X linked syndrome. The mutations which cause X linked VACTERL-H syndrome are not known. OBJECTIVE: To determine if mutations in FANCB, which are known to cause Fanconi anaemia complementation group B, are a cause of X linked VACTERL-H syndrome. METHODS: A three generation pedigree with X linked VACTERL-H syndrome was investigated. X inactivation was tested in carrier females, and fibroblasts from an affected male fetus were analysed for increased sensitivity to diepoxybutane. FANCB coding exons and flanking splice sites were screened for mutations by direct sequencing of polymerase chain reaction (PCR) fragments amplified from genomic DNA. cDNA from affected fetal fibroblasts was analysed by PCR and direct sequencing using specific exonic primers. RESULTS: A FANCB mutation which results in a premature stop codon by causing skipping of exon 7 was identified. Chromosomes from the affected fetus showed increased sensitivity to diepoxybutane, and carrier women were found to have 100% skewed X inactivation in blood. CONCLUSIONS: Mutations in FANCB are a cause of X linked VACTERL-H syndrome. The data presented are of relevance to the genetic counselling of families with isolated male cases of VACTERL-H and Fanconi anaemia.

Identification of a 650 kb duplication at the X chromosome breakpoint in a patient with 46,X,t(X;8)(q28;q12) and non-syndromic mental retardation.

A female patient with non-syndromic mental retardation was shown by high resolution GTL banding to have inherited an apparently balanced translocation, 46,X,t(X;8)(q28;q12)mat. Replication studies in the mother and daughter showed a skewed X inactivation pattern in lymphocytes, with the normal X chromosome preferentially inactivated. The mother also had significant intellectual disability. To investigate the possibility that a novel candidate gene for XLMR was disrupted at the X chromosome translocation breakpoint, we mapped the breakpoint using fluorescence in situ hybridisation (FISH). This showed that the four known genes involved in non-syndromic mental retardation in Xq28, FMR2, SLC6A8, MECP2, and GDI1, were not involved in the translocation. Intriguingly, we found that the X chromosome breakpoint in the daughter could not be defined by a single breakpoint spanning genomic clone and further analysis showed a 650 kb submicroscopic duplication between DXS7067 and DXS7060 on either side of the X chromosome translocation breakpoint. This duplicated region contains 11 characterised genes, of which nine are expressed in brain. Duplication of one or several of the genes within the 650 kb interval is likely to be responsible for the mental retardation phenotype seen in our patient. Xq28 appears to be an unstable region of the human genome and genomic rearrangements are recognised as major causes of two single gene defects, haemophilia A and incontinentia pigmenti, which map within Xq28. This patient therefore provides further evidence for the instability of this genomic region.

An investigation into the relationship between prostate size, peak urinary flow rate and male erectile dysfunction.

This study sought to identify whether a true relationship exists between benign prostatatic hyperplasia (BPH) and erectile dysfunction (ED). In a community-based study, 427 men underwent transrectal ultrasound (TRUS), uroflow studies and a questionnaire concerning erectile function. ED had a significant correlation to age (r = 0.19, P < 0.001). But comparisons of prostate volume and analysis of maximum flow rate showed no significant difference between three erectile functional groups; ranging from no ED to complete ED, (one way analysis of variance). However when these two parameters were correlated to age a significant association was found to exist (log prostate volume; r= 0.26, P < 0.001, log maximum flow rate; r= -0.13, P= 0.02). Prostate size and uroflow studies show no correlation with ED, but ED and BPH had a significant correlation with ageing. This makes a direct association between male ED and BPH unlikely but supports the theory that the association between the two pathologies could be due instead to the common link of ageing.

A significant proportion of patients with osteosarcoma may belong to Li-Fraumeni cancer families.

We studied the pedigrees of 17 index patients with osteosarcoma, recording malignant disease and cause of death for first- and second-degree relatives. There were seven cancers and five cancer deaths per 2151.5 person-years in first-degree relatives of osteosarcoma patients under the age of 50 years, a significantly greater incidence than in an age- and sex-matched population group (p < 0.001). This excess of malignancy was largely due to two families which fulfilled the criteria for the Li-Fraumeni cancer family syndrome. Both of these families were shown to have the genetic alterations in the p53 gene which have been implicated in this syndrome. Our study suggests that orthopaedic surgeons seeing new cases of osteosarcoma should arrange screening for familial malignancy.

An investigation of erectile dysfunction in Gwent, Wales.

OBJECTIVE: To quantify incidence of erectile dysfunction (ED) and the associated risk factors in men attending community clinics in a large population in Wales, UK. SUBJECTS AND METHODS: Of 4060 men who were invited to attend 11 community clinics, primarily to check for prostate disease, 2025 (aged 55-70 years) attended. Of these, 2002 men answered a questionnaire about personal details, medical, family and sexual history, and detailed alcohol and smoking habits. All had their serum prostate-specific antigen (PSA) analysed and those referred for investigation of prostatic disease underwent serum testosterone analysis. RESULTS: Complete ED was reported by 265 men (13.2%), and was closely related to age (r = 0.19, P < 0.001) and medication (r = 0.2, P < 0.001). ED occurred in 6.9% of men aged 55-60 years, 12.5% aged 61-65 and 22.2% of those aged 66-70. Patients taking diabetic medication had the highest relative risk for ED and 11.3% of men with ED were taking nitrates. The numbers of years of smoking had the third closest correlation with impotence (r = 0.16, P < 0.001). A low serum testosterone level was a poor predictor of ED and increasing serum PSA levels did not influence the distribution of ED. CONCLUSION: About 13% of these men aged 55-70 years had complete ED; if this value is extrapolated to the whole of the UK, this equates to almost half a million men being unable to achieve any erections. The estimate would be much greater if those with milder forms of ED are included.