Ophthalmic manifestations of Czech dysplasia.

Czech dysplasia is an autosomal dominant type 2 collagenopathy that is caused by heterozygosity for the recurrent p.(Arg275Cys) COL2A1 variant. Affected individuals usually present with skeletal abnormalities such as metatarsal hypoplasia of the third and fourth toes and early-onset arthropathy, as well as hearing loss. To date, no ophthalmic findings have been reported in patients with Czech dysplasia even though COL2A1 has been implicated in other ocular conditions such as type 1 Stickler syndrome. For the first time, we report the ocular findings in four families with Czech dysplasia, including type 1 vitreous anomaly, hypoplastic vitreous, retinal tears, and significant refractive error. These novel ocular findings expand the phenotype associated with Czech dysplasia and may aid clinicians as an additional diagnostic feature. Patients with congenital abnormalities of vitreous gel architecture have an increased risk of retinal detachment, and as such, patients may benefit from prophylaxis. Considering that many of the patients did not report any ocular symptoms, vitreous phenotyping is of key importance in identifying the need for counseling with regard to prophylaxis.

Legg-Calve-Perthes' disease: an opportunity to prevent blindness?

Legg-Calve-Perthes' disease (LCP) is defined as avascular necrosis of the femoral head in a child and may present to a variety of disciplines from general practice to orthopaedics, paediatrics, rheumatology and more. The Stickler syndromes are a group of disorders of type II, IX and XI collagen associated with hip dysplasia, retinal detachment, deafness and cleft palate. The pathogenesis of LCP disease remains an enigma but there have been a small number of cases reporting variants in the gene encoding the α1 chain of type II collagen (COL2A1). Variants in COL2A1 are known to cause type 1 Stickler syndrome (MIM 108300, 609508), which is a connective tissue disorder with a very high risk of childhood blindness, and it is also associated with dysplastic development of the femoral head. It is unclear whether COL2A1 variants make a definitive contribution to both disorders, or whether the two are indistinguishable using current clinical diagnostic techniques. In this paper, we compare the two conditions and present a case series of 19 patients with genetically confirmed type 1 Stickler syndrome presenting with a historic diagnosis of LCP. In contrast to isolated LCP, children with type 1 Stickler syndrome have a very high risk of blindness from giant retinal tear detachment, but this is now largely preventable if a timely diagnosis is made. This paper highlights the potential for avoidable blindness in children presenting to clinicians with features suggestive of LCP disease but with underlying Stickler syndrome and proposes a simple scoring system to assist clinicians.

Autosomal Recessive Stickler Syndrome.

Stickler syndrome (SS) is a genetic disorder with manifestations in the eye, ear, joints, face and palate. Usually inherited in a dominant fashion due to heterozygous pathogenic variants in the collagen genes COL2A1 and COL11A1, it can rarely be inherited in a recessive fashion from variants in COL9A1, COL9A2, and COL9A3, COL11A1, as well as the non-collagen genes LRP2, LOXL3 and GZF1. We review the published cases of recessive SS, which comprise 40 patients from 23 families. Both homozygous and compound heterozygous pathogenic variants are found. High myopia is near-universal, and sensorineural hearing loss is very common in patients with variants in genes for type IX or XI collagen, although hearing appears spared in the LRP2 and LOXL3 patients and is variable in GZF1. Cleft palate is associated with type XI collagen variants, as well as the non-collagen genes, but is so far unreported with type IX collagen variants. Retinal detachment has occurred in 18% of all cases, and joint pain in 15%. However, the mean age of this cohort is 11 years old, so the lifetime incidence of both problems may be underestimated. This paper reinforces the importance of screening for SS in congenital sensorineural hearing loss, particularly when associated with myopia, and the need to warn patients and parents of the warning signs of retinal detachment, with regular ophthalmic review.

Dominant Stickler Syndrome.

The Stickler syndromes are a group of genetic connective tissue disorders associated with an increased risk of rhegmatogenous retinal detachment, deafness, cleft palate, and premature arthritis. This review article focuses on the molecular genetics of the autosomal dominant forms of the disease. Pathogenic variants in COL2A1 causing Stickler syndrome usually result in haploinsufficiency of the protein, whereas pathogenic variants of type XI collagen more usually exert dominant negative effects. The severity of the disease phenotype is thus dependent on the location and nature of the mutation, as well as the normal developmental role of the respective protein.

Therapeutic and diagnostic advances in Stickler syndrome.

The Stickler syndromes are the leading cause of inherited retinal detachment and the most common cause of rhegmatogenous retinal detachment in childhood. The clinical and molecular genetic spectrum of this connective tissue disorder is discussed in this article, emphasising the key role the ophthalmologist has to play in the identification, diagnosis and prevention of blindness in the increasingly widely recognised sub-groups with ocular-only (or minimal systemic) involvement. Without diagnosis and prophylaxis in such high-risk subgroups, these patients are at high risk of Giant Retinal Tear detachment and blindness, especially in the paediatric population, where late or second eye involvement is common. Initially considered a monogenic disorder, there are now known to be at least 11 distinct phenotypic subgroups in addition to allied connective tissue disorders that can present to the clinician as part of the differential diagnosis. Plain language summary: Treatment and diagnostic advances in Stickler syndrome The Stickler syndromes are a group of related connective tissue disorders that are associated with short-sight and a very high risk of blindness from detachment of the retina - the light sensitive film at the back of the eye. Other features include cleft palate, deafness and premature arthritis. It is the most common cause of retinal detachment in children and the most common cause of familial or inherited retinal detachment. In contrast to most other forms of blinding genetic eye disease, blindness from retinal detachment in Stickler syndrome is largely avoidable with accurate diagnosis and prophylactic (preventive) surgery. Recent advances in the understanding of the genetic causes of Stickler syndrome mean that the diagnosis can now be confirmed in over 95% of cases and, most importantly, the patient's individual risk of retinal detachment can be graded. Preventative surgery is hugely effective in reducing the incidence of retinal detachment in those patients shown to be at high risk. NHS England have led the way in the multidisciplinary care for patients with Stickler syndrome by launching a highly specialist service that has been free at point of care to all NHS patients in England since 2011 (https://www.england.nhs.uk/commissioning/spec-services/highly-spec-services, www.vitreoretinalservice.org).

Molecularly proven mosaicism in phenotypically normal parent of a girl with Freeman-Sheldon Syndrome caused by a pathogenic MYH3 mutation.

We report a case of a female child who has classical Freeman-Sheldon syndrome (FSS) associated with a previously reported recurrent pathogenic heterozygous missense mutation, c.2015G > A, p. (Arg672His), in MYH3 where the phenotypically normal mother is a molecularly confirmed mosaic. To the best of our knowledge, this is the first report in the medical literature of molecularly confirmed parental mosaicism for a MYH3 mutation causing FSS. Since proven somatic mosaicism after having an affected child is consistent with gonadal mosaicism, a significantly increased recurrence risk is advised. Parental testing is thus essential for accurate risk assessment for future pregnancies and the use of new technologies with next generation sequencing (NGS) may improve the detection rate of mosaicism. © 2016 Wiley Periodicals, Inc.

Somatic Mutation Screening Using Archival Formalin-Fixed, Paraffin-Embedded Tissues by Fluidigm Multiplex PCR and Illumina Sequencing.

High-throughput somatic mutation screening using FFPE tissues is a major challenge because of a lack of established methods and validated variant calling algorithms. We aimed to develop a targeted sequencing protocol by Fluidigm multiplex PCR and Illumina sequencing and to establish a companion variant calling algorithm. The experimental protocol and variant calling algorithm were first developed and optimized against a series of somatic mutations (147 substitutions, 12 indels ranging from 1 to 33 bp) in seven genes, previously detected by Sanger sequencing of DNA from 163 FFPE lymphoma biopsy specimens. The optimized experimental protocol and variant calling algorithm were further ascertained in two separate experiments by including the seven genes as a part of larger gene panels (22 or 13 genes) using FFPE and high-molecular-weight lymphoma DNAs, respectively. We found that most false-positive variants were due to DNA degradation, deamination, and Taq polymerase errors, but they were nonreproducible and could be efficiently eliminated by duplicate experiments. A small fraction of false-positive variants appeared in duplicate, but they were at low alternative allele frequencies and could be separated from mutations when appropriate threshold value was used. In conclusion, we established a robust practical approach for high-throughput mutation screening using archival FFPE tissues.

Profiling of somatic mutations in phaeochromocytoma and paraganglioma by targeted next generation sequencing analysis.

At least 12 genes (FH, HIF2A, MAX, NF1, RET, SDHA, SDHB, SDHC, SDHD, SDHAF2, TMEM127, and VHL) have been implicated in inherited predisposition to phaeochromocytoma (PCC), paraganglioma (PGL), or head and neck paraganglioma (HNPGL) and a germline mutation may be detected in more than 30% of cases. Knowledge of somatic mutations contributing to PCC/PGL/HNPGL pathogenesis has received less attention though mutations in HRAS, HIF2A, NF1, RET, and VHL have been reported. To further elucidate the role of somatic mutation in PCC/PGL/HNPGL tumourigenesis, we employed a next generation sequencing strategy to analyse "mutation hotspots" in 50 human cancer genes. Mutations were identified for HRAS (c.37G>C; p.G13R and c.182A>G; p.Q61R) in 7.1% (6/85); for BRAF (c.1799T>A; p.V600E) in 1.2% (1/85) of tumours; and for TP53 (c.1010G>A; p.R337H) in 2.35% (2/85) of cases. Twenty-one tumours harboured mutations in inherited PCC/PGL/HNPGL genes and no HRAS, BRAF, or TP53 mutations occurred in this group. Combining our data with previous reports of HRAS mutations in PCC/PGL we find that the mean frequency of HRAS/BRAF mutations in sporadic PCC/PGL is 8.9% (24/269) and in PCC/PGL with an inherited gene mutation 0% (0/148) suggesting that HRAS/BRAF mutations and inherited PCC/PGL genes mutations might be mutually exclusive. We report the first evidence for BRAF mutations in the pathogenesis of PCC/PGL/HNPGL.

Neumonía necrotizante asociada a infección por influenza A H1N1 en un niño con mucopolisacaridosis tipo II: Caso clínico / Necrotizing pneumonia associated with influenza A H1N1 infection in a child with mucopolysaccharidosis type II: Case report

La mucopolisacaridosis tipo II (MPS II) es un desorden recesivo ligado al cromosoma X, caracterizado por una deficiencia de la enzima iduronato-2-sulfatasa, que lleva a una afectación multisistémica por acumulación tisular de los glicosaminoglicanos heparan y dermatan sulfato. Reportamos el caso de un niño de 9 años diagnosticado con MPS II a los 4 años de edad, catalogado como portador de una variante grave. Presentó neumonía necrotizante asociada a infección A H1N1, que requirió ventilación mecánica por 1 mes y 10 días. Este caso enfatiza la importancia de que los trabajadores de la salud estén alerta a las potenciales complicaciones en pacientes con MPS II, tales como la infección por influenza A H1N1, la que, a su vez, puede estar asociada con neumonía necrotizante.

Mucopolysaccharidosis type II (MPS II) is an X-linked recessive disorder characterized by a deficiency of the enzyme iduronate-2-sulfatase leading to a multisystem involvement by tissue accumulation of glycosaminoglycans heparan and dermatan sulfate. We report a case of a 9-year-old boy diagnosed with mucopolysaccharidosis type II at 4 years of age, classified as severe variant. He presented necrotizing pneumonia associated with influenza A H1N1 infection, requiring mechanical ventilation for 1 month and 10 days. This case emphasizes the importance of healthcare workers to be aware of potentially lethal complications in patients with MPS II, such as influenza A H1N1 infection, which in turn may be associated with necrotizing pneumonia.

Primary liver cancer incidence among American Indians and Alaska Natives, US, 1999-2004.

BACKGROUND: American Indians and Alaska Natives (AI/AN) experience higher morbidity and mortality from primary liver cancer than other United States (US) populations, but racial misclassification in medical records results in underestimates of disease burden. METHODS: To reduce misclassification, National Program of Cancer Registries and Surveillance, Epidemiology, and End Results data were linked with Indian Health Service (IHS) enrollment records to compare primary liver cancer incidence and stage at diagnosis between AI/AN and non-Hispanic whites (NHW) living within the regionalized IHS Contract Health Service Delivery Area counties. Incidence rates are expressed per 100,000 persons and age-adjusted by 19 age groups to the 2000 US standard population. RESULTS: Overall, AI/AN have a higher proportion of hepatocellular carcinoma compared with NHW, 77.8% versus 66.7%. Liver cancer incidence rates among AI/AN males and females were higher than those among NHW males and females for all regions except for the East. Among males, rates ranged from 7.3 (95% confidence interval [CI], 3.8-12.6) in the East to 17.2 (95% CI, 10.4-26.3) in Alaska. Among females, rates ranged from 3.8 (95% CI, 1.4-8.2) in the East to 6.9 (95% CI, 3.6-11.6) in Alaska. The AI/AN rates for all regions were consistently higher than the NHW rates at every age. An increasing trend among AI/AN was suggested but did not achieve statistical significance. CONCLUSIONS: Reducing racial misclassification revealed higher disparities in primary liver cancer incidence between NHW and AI/AN populations than previously reported. Further description of the reasons for regional differences in this disparity is needed, as are programs to reduce risk factors and to diagnose primary liver cancer at earlier, more treatable stages.

Cancer in Appalachia, 2001-2003.

BACKGROUND: Researchers have not been able to examine cancer incidence rates in Appalachia because high-quality data have not been uniformly available across the region. This study is the first to report cancer incidence rates for a large proportion of the Appalachian population and describe the differences in incidence rates between Northern, Central, and Southern Appalachia. METHODS: Forty-four states and the District of Columbia provided information for the diagnosis years 2001 through 2003 from cancer registries that met high-quality data criteria. Eleven of 13 states with counties in Appalachia, covering 88% of the Appalachian population, met these criteria; Virginia and Mississippi were included for 2003 only. SEER(*)Stat was used to calculate age-adjusted rates per 100,000 population and 95% gamma confidence limits. RESULTS: Overall, cancer incidence rates were higher in Appalachia than in the rest of the US; the rates for lung, colon/rectum, and other tobacco-related cancers were particularly high. Central Appalachia had the highest rates of lung (men: 143.8; women: 75.2) and cervical cancer (11.2)-higher than the other 2 regions and the rest of the US. Northern Appalachia had the highest rates for prostate, female breast, and selected other sites, and Southern Appalachia had the lowest overall cancer incidence rates. CONCLUSIONS: Cancer incidence rates in Appalachia are higher than in the rest of the US, and they vary substantially between regions. Additional studies are needed to understand how these variations within Appalachia are associated with lifestyle, socioeconomic factors, urban/rural residence, and access to care.

Geographic patterns of prostate cancer mortality and variations in access to medical care in the United States.

BACKGROUND: Striking geographic variation in prostate cancer death rates have been observed in the United States since at least the 1950s; reasons for these variations are unknown. Here we examine the association between geographic variations in prostate cancer mortality and regional variations in access to medical care, as reflected by the incidence of late-stage disease, prostate-specific antigen (PSA) utilization, and residence in rural counties. METHODS: We analyzed mortality data from the National Center for Health Statistics, 1996 to 2000, and incidence data from 30 population-based central cancer registries from the North American Association of Central Cancer Registries, 1995 to 2000. Ecological data on the rate of PSA screening by registry area were obtained from the 2001 Behavioral Risk Factor Surveillance System. Counties were grouped into metro and nonmetro areas according to Beale codes from the Department of Agriculture. Pearson correlation analyses were used to examine associations. RESULTS: Significant correlations were observed between the incidence of late-stage prostate cancer and death rates for Whites (r = 0.38, P = 0.04) and Blacks (r = 0.53, P = 0.03). The variation in late-stage disease corresponded to about 14% of the variation in prostate cancer death rates in White men and 28% in Black men. PSA screening rate was positively associated with total prostate cancer incidence (r = 0.42, P = 0.02) but inversely associated with the incidence of late-stage disease (r = -0.58, P = 0.009) among White men. Nonmetro counties generally had higher death rates and incidence of late-stage disease and lower prevalence of PSA screening (53%) than metro areas (58%), despite lower overall incidence rates. CONCLUSION: These ecological data suggest that 10% to 30% of the geographic variation in mortality rates may relate to variations in access to medical care.

Incidence of noncutaneous melanomas in the U.S.

BACKGROUND: Description of the epidemiology of noncutaneous melanoma has been hampered by its rarity. The current report was the largest in-depth descriptive analysis of incidence of noncutaneous melanoma in the United States, using data from the North American Association of Central Cancer Registries. METHODS: Pooled data from 27 states and one metropolitan area were used to examine the incidence of noncutaneous melanoma by anatomic subsite, gender, age, race, and geography (northern/southern and coastal/noncoastal) for cases diagnosed between 1996 and 2000. Percent distribution by stage of disease at diagnosis and histology were also examined. RESULTS: Between 1996 and 2000, 6691 cases of noncutaneous melanoma (4885 ocular and 1806 mucosal) were diagnosed among 851 million person-years at risk. Ocular melanoma was more common among men compared with women (6.8 cases per million men compared with 5.3 cases per million women, age-adjusted to the 2000 U.S. population standard), whereas mucosal melanoma was more common among women (2.8 cases per million women compared with 1.5 cases per million men). Rates of ocular melanoma among whites were greater than eight times higher than among blacks. Rates of mucosal melanoma were approximately two times higher among whites compared with blacks. CONCLUSIONS: In contrast to cutaneous melanoma, there was no apparent pattern of increased noncutaneous melanoma among residents of southern or coastal states, with the exception of melanoma of the ciliary body and iris. Despite their shared cellular origins, both ocular and mucosal melanomas differ from cutaneous melanoma in terms of incidence by gender, race, and geographic area.

Secondary parathyroid hyperplasia in tuberous sclerosis: report of a case with large eosinophilic ganglion-like cells similar to those of subependymal giant cell astrocytoma, tubers, and atypical angiomyolipoma.

We report a case of secondary parathyroid hyperplasia in a 49-year-old man with tuberous sclerosis. Two parathyroid glands had collections of large, eosinophilic ganglion-like endocrine cells that to our knowledge have not been previously described at this site. These cells are morphologically similar to those of subependymal giant cell astrocytoma, tubers, and atypical angiomyolipoma, all of which may arise in the setting of tuberous sclerosis. These large, eosinophilic ganglion-like cells found in different affected organs appear to be distinctive of tuberous sclerosis. We suggest these large eosinophilic cells arise from a common stem cell precursor that acquires variable phenotypes according to alterations in the cellular microenvironment.