Familial cancer on a Scottish island.

When the causes of death were determined in 18 relations of a child with Fanconi''s anaemia 10 deaths were found to be due to carcinoma of various organs. Cases of osteogenic sarcoma, leukaemia, and Marfan''s syndrome were also discovered among relatives. The family was from a remote community in the hebrides and there was considerable intermarriage. Suggestive evidence of heterozygosity was found by chromosome analysis.     

Ocular Findings in Several Metabolic Diseases

Changes in ocular findings have been noted in association with several metabolic diseases.In homocystinuria the crystalline lens in the majority of cases is subluxated inferiorly, while in Marfan''s syndrome the dislocation was upward.In cystinosis, slit-lamp examination reveals numerous gold crystal-like cystine deposits in both the cornea and bulbar conjunctiva.Patients with galactosemia have cataracts of the “oil drop” type, which usually can be seen with an ophthalmoscope even though the opacity is not dense.Eight patients with Lowe''s syndrome who were observed had cataracts, and four of them had severe glaucoma.Three of five patients with glycogen storage disease Type I had yellowish deposits in the macular and paramacular areas, thought to be due to hypercholesterolemia.     

A 27-bp deletion from one allele of the type III collagen gene (COL3A1) in a large family with Ehlers-Danlos syndrome type IV

Summary A large family with Ehlers-Danlos syndrome type IV (EDS IV) has previously been described. Unlike most cases of EDS IV, fibroblasts from affected members secreted near normal amounts of type III collagen. We have localised the mutation in this family to the CB5 peptide of type III collagen, by using both protein and cDNA mapping techniques. Sequence analysis of cDNA revealed a 27-bp deletion within exon 37, a deletion that removed nine amino acids and maintained the Gly-X-Y repeat of the collagen helix. Further sequencing of genomic DNA confirmed its location, and amplification of DNA from family members showed that it was absent in unaffected individuals but present in all the affected individuals tested. This deletion is flanked by two short direct repeats of CTCC; it may have arisen by slipped mispairing, and has subsequently been transmitted to all affected family members.     

Cosegregation of elastin-associated microfibrillar abnormalities with the Marfan phenotype in families.

The Marfan syndrome is a serious heritable connective-tissue disorder characterized primarily by ocular, cardiovascular, and musculoskeletal abnormalities but also involving multiple other tissues and organs of the body. Inherited as an autosomal dominant disorder, the etiology and pathogenesis of the Marfan syndrome are presently unknown. We have documented consistent apparent deficient content of elastin-associated microfibrillar fibers by indirect immunofluorescent (IF) studies of Marfan skin, as well as deficient accumulation of related fibrous materials in cultures of Marfan fibroblasts as compared with normal controls and patients with other heritable disorders of connective tissue. These data have suggested that abnormalities in the microfibrillar component of elastic-fiber systems may have a role in the etiology and pathogenesis of the Marfan syndrome. In the present study, we have analyzed the IF staining patterns of skin and fibroblast cultures from Marfan syndrome patients and normal first-degree relatives in nine Marfan kindreds. Three of these families had at least one affected individual in each of 2 generations, permitting intergenerational comparison of IF patterns. Six kindreds had one or more affected individuals in a single generation, making comparisons between siblings and/or parent-child possible. In all cases, IF abnormalities cosegregated with the Marfan phenotype and all nonaffected family members were normal. Within family groups containing more than one affected individual, the IF staining patterns were similar between affected patients. These data provide further confirmation of consistent and relatively specific deficiency of microfibrillar fibers in Marfan syndrome.     

A progeroid syndrome with neonatal presentation and long survival maps to 19p13.3p13.2

We report on a Palestinian family with three affected individuals exhibiting progeroid syndrome characterized by intrauterine growth retardation, a progeroid appearance, failure to thrive, short stature, and hypotonia. The progeroid features were evident at birth. All the affected members of this family have survived beyond the neonatal period and one of them is currently a 27‐year‐old adult. As parental consanguinity suggested an autosomal recessive mode of inheritance, we employed homozygosity mapping using single nucleotide polymorphism arrays followed by next generation whole exome sequencing to identify the disease‐causing gene. We were able to identify a single block of homozygosity shared between all the affected members of the studied family spanning 2.3 Mb on chromosome 19p13.3p13.2. However, Sanger sequencing of known genes and whole exome sequencing of the three affected sibs did not reveal a convincing causal mutation. These findings are anticipated to open the way for the identification of the molecular causes underlying this syndrome. Birth Defects Research (Part A) 97:456–462, 2013. © 2013 Wiley Periodicals, Inc.     

A novel locus for split-hand/foot malformation associated with tibial hemimelia (SHFLD syndrome) maps to chromosome region 17p13.1-17p13.3

Split-hand/foot malformation (SHFM) associated with aplasia of long bones, SHFLD syndrome or Tibial hemimelia-ectrodactyly syndrome is a rare condition with autosomal dominant inheritance, reduced penetrance and an incidence estimated to be about 1 in 1,000,000 liveborns. To date, three chromosomal regions have been reported as strong candidates for harboring SHFLD syndrome genes: 1q42.2–q43, 6q14.1 and 2q14.2. We characterized the phenotype of nine affected individuals from a large family with the aim of mapping the causative gene. Among the nine affected patients, four had only SHFM of the hands and no tibial defects, three had both defects and two had only unilateral tibial hemimelia. In keeping with previous publications of this and other families, there was clear evidence of both variable expression and incomplete penetrance, the latter bearing hallmarks of anticipation. Segregation analysis and multipoint Lod scores calculations (maximum Lod score of 5.03 using the LINKMAP software) using all potentially informative family members, both affected and unaffected, identified the chromosomal region 17p13.1–17p13.3 as the best and only candidate for harboring a novel mutated gene responsible for the syndrome in this family. The candidate gene CRK located within this region was sequenced but no pathogenic mutation was detected.     

Mutation in type II procollagen (COL2A1) that substitutes aspartate for glycine alpha 1-67 and that causes cataracts and retinal detachment: evidence for molecular heterogeneity in the Wagner syndrome and the Stickler syndrome (arthro-ophthalmopathy)

A search for mutations in the gene for type II procollagen (COL2A1) was carried out in affected members of a family with early-onset cataracts, lattice degeneration of the retina, and retinal detachment. They had no symptoms suggestive of involvement of nonocular tissues, as is typically found in the Stickler syndrome. The COL2A1 gene was amplified with PCR, and the products were analyzed by denaturing gradient gel electrophoresis. The results suggested a mutation in one allele for exon 10. Sequencing of the fragment demonstrated a single-base mutation that converted the codon for glycine at position alpha 1-67 to aspartate. The mutation was found in three affected members of the family available for study but not in unaffected members or 100 unrelated individuals. Comparison with previously reported mutations suggested that mutations introducing premature termination codons in the COL2A1 gene are a frequent cause of the Stickler syndrome, but mutations in the COL2A1 gene that replace glycine codons with codons for bulkier amino acid can produce a broad spectrum of disorders that range from lethal chondrodysplasias to a syndrome involving only ocular tissues, similar to the syndrome in the family originally described by Wagner in 1938.     

Waardenburg's Syndrome and Heterochromia Iridum in a Deaf School Population

Waardenburg''s syndrome consists of lateral displacement of the inner canthi of the eyes (dystopia canthorum), a broad nasal root and confluent eyebrows, heterochromia iridum, a white forelock and congenital deafness. The syndrome is inherited as a dominant, but affected individuals do not necessarily have all of the characteristics cited.Five hundred and fourteen pupils at a school for the deaf were screened for features of this syndrome. Three cases were discovered. Eleven other deaf children were found to have heterochromia iridum and two more had white forelocks. The interocular dimensions of the remaining children were recorded as standards by which to judge the presence of dystopia canthorum. The results of chromosomal analysis in two cases with Waardenburg''s syndrome were normal.The findings provide further evidence that Waardenburg''s syndrome is a distinct entity and call in question Mackenzie''s concept of a comprehensive “first arch syndrome”.     

Stickler's syndrome (hereditary progressive arthro-ophthalmopathy)

The clinical features of Stickler''s syndrome are described in two families with a total of 22 affected members and compared with those of the three previously reported families. Progressive joint degeneration (85%), myopia (83%) and retinal detachment (61%) are the most frequent manifestations. Cleft palate (28%), micrognathia (17%) and sensorineural hearing loss (9%) are also liable to occur in affected individuals. Inheritance is autosomal dominant with virtually complete penetrance. Genetic counselling is extremely important and relatively straightforward since most of the findings are manifest in the first two decades of life and represent severe incapacities to the affected families. All six of the affected individuals tested had increased urinary hydroxyproline excretion, a feature that may lead to earlier postnatal and possibly prenatal diagnosis.     

Human kin recognition is self- rather than family-referential

Inclusive fitness theory predicts that organisms will tend to help close kin more than less related individuals. In a variety of birds and mammals, relatives are recognized by comparing their phenotype to an internal representation or template, which might be learned through either repeated exposure to family members or self-inspection. Mirrors are ubiquitous now, but were absent during our evolutionary history; hence it is hard to predict, and empirically unknown, whether human kin recognition is family- or self-referential. Here we put this issue to the strongest possible test by comparing nepotistic behaviour towards self- versus co-twin-resemblant individuals. Seventy monozygotic and dizygotic twins were shown same-sex faces, covertly manipulated to resemble either themselves or their co-twin, and indicated which individual they would prefer in two prosocial contexts. Self-resemblant faces were significantly preferred to twin-resemblant faces, showing that visual information about the self supersedes that about close family members in the kin-recognition template. Because, under conditions of paternal uncertainty, a reliable family-referent template could be based only on one''s mother and maternal relatives, a unique advantage of self-referent phenotype matching is the possibility of (consciously or unconsciously) identifying one''s father and paternal relatives as kin.     

The heterogeneity of Streptococcus viridans: therapeutic considerations in infective endocarditis

A 24-year-old woman with Marfan''s syndrome and mitral regurgitation had clinical features suggestive of infective endocarditis. The causative organism was Streptococcus viridans. Initial therapy with penicillin G, in a dose that should have been bactericidal and hence curative according to the results of the initial quantitative antimicrobial studies, became inadequate. The strain of S. viridans displayed considerable variation in both growth properties and antimicrobial sensitivity during the course of therapy. In addition, a different strain of S. viridans was cultured 1 month after treatment had begun. It is therefore important to repeat cultures and antimicrobial sensitivity testing during treatment of infective endocarditis.     

Indirect effects of parasitism: costs of infection to other individuals can be greater than direct costs borne by the host

Parasitic infection has a direct physiological cost to hosts but may also alter how hosts interact with other individuals in their environment. Such indirect effects may alter both host fitness and the fitness of other individuals in the host''s social network, yet the relative impact of direct and indirect effects of infection are rarely quantified. During reproduction, a host''s social environment includes family members who may be in conflict over resource allocation. In such situations, infection may alter how resources are allocated, thereby redistributing the costs of parasitism between individuals. Here, we experimentally reduce parasite burdens of parent and/or nestling European shags (Phalacrocorax aristotelis) infected with Contracaecum nematodes in a factorial design, then simultaneously measure the impact of an individual''s infection on all family members. We found no direct effect of infection on parent or offspring traits but indirect effects were detected in all group members, with both immediate effects (mass change and survival) and longer-term effects (timing of parents’ subsequent breeding). Our results show that parasite infection can have a major impact on individuals other than the host, suggesting that the effect of parasites on population processes may be greater than previously thought.     

Identification of a novel EYA1 splice-site mutation in a Danish branchio-oto-renal syndrome family

Branchio-oto-renal (BOR) syndrome is an autosomal dominant disorder characterized by variable clinical manifestations including branchial fistulae, preauricular pits, ear malformations, hearing impairment, and renal anomalies. BOR is caused by mutations in the genes EYA1 and SIX1. A Danish BOR family with five affected individuals in three generations was analyzed for mutations in all 17 exons of EYA1 using direct sequencing of polymerase chain reaction (PCR) amplified genomic DNA. A novel splice-site mutation (IVS9+1 G>C) was detected in all affected family members but not in unaffected family members or in 96 controls. We conclude that this mutation is causing BOR in the family, most likely as a result of haploinsufficiency or an abnormal protein product caused by aberrant splicing of EYA1 mRNA.     

Hereditary site-specific colon cancer in a Canadian kindred.

A large kindred with colorectal cancer unaccompanied by polyposis coli and characterized by autosomal dominant inheritance has been identified in eastern Canada. Ten family members from three successive generations have presented 17 documented colorectal cancers. The clinical features of the kindred are characteristic of hereditary site-specific colon cancer (HSSCC) (Lynch syndrome I): absence of multiple polyposis, autosomal dominant inheritance, onset of colorectal cancer at an early age and a high incidence of synchronous and metachronous colorectal cancers. A unique feature of this family is the high incidence of sporadic adenomatous polyps in affected members and their relatives. Patients with HSSCC have been managed by means of segmental colectomy followed by annual colonoscopic surveillance. All five patients with localized (Dukes'' stage A or B) cancer at initial diagnosis were alive and free of disease after 2 to 12 years of follow-up, although three had required further colonic resection for metachronous carcinomas. Five young family members without cancer have had sporadic adenomatous polyps removed and are being followed with annual colonoscopy. It is not known whether polypectomy will alter the subsequent incidence of colon cancer. Subtotal colectomy is recommended for patients with HSSCC because of the high incidence of multiple lesions. An aggressive screening protocol, including colonoscopy, is recommended for all adult first- and second-degree relatives of patients with HSSCC. Identification of a biomarker, which is currently being sought in this kindred, would help identify those at greatest risk of development of cancer and allow earlier intervention.     

Familial multiple-system tauopathy with presenile dementia is localized to chromosome 17.

An autosomal dominant presenile dementia affecting 39 individuals in a seven-generation, 383-member pedigree has been studied at Indiana University. In the affected members of this family, clinical symptoms occurred early in life, with an average age at onset of 48.8 years. The presenting clinical features include disequilibrium, neck stiffness, dysphagia, and memory loss. As the disease progresses, further cognitive decline, superior-gaze palsy, and dystaxia also are observed. The average duration from onset of symptoms to death is approximately 10 years. Neuropathologic studies of nine affected individuals showed neuronal loss in several areas of the CNS, as well as argentophilic tau-immunopositive inclusions in neurons and in oligodendroglia. A limited genomic screen by use of DNA samples from 28 family members localized the gene for this disorder to a 3-cM region on chromosome 17, between the markers THRA1 and D17S791. The gene for tau also was analyzed, through samples from the family.     

Screening for Down's syndrome using serum alpha fetoprotein: a retrospective study indicating caution.

A report was made on the outcome of a four year retrospective study in 27 064 pregnancies, of the clinical efficiency, sensitivity, and specificity of a screening programme for Down''s syndrome based on reported strategies related to the measurement of maternal serum alpha fetoprotein. This study identified 27 pregnancies affected by Down''s syndrome with a median multiple of the median maternal serum alpha fetoprotein concentration of 0.82. This figure is considerably higher than that obtained from previous reports on this subject. With an age related multiple of the median maternal serum alpha fetoprotein strategy, 30.8% of Down''s affected pregnancies were identified as well as 11.6% of unaffected pregnancies. Perhaps a United Kingdom collaborative study should begin to investigate the reasons for such wide population variance in the reports for the median multiple of the median for Down''s affected pregnancies. Until such studies are carried out, screening for Down''s syndrome based on low maternal serum alpha fetoprotein concentration is premature.     

A protein family immunorelated to a sperm-binding protein and its regulation in human semen

In human seminal plasma a family of proteins that is immunologically related to the RSV-IV protein secreted under androgen control from the epithelium of the rat seminal vesicles was detected by a radioimmunoassay. Evidence for the origin of these antigens from human seminal vesicle is presented. Quantitative measurements of this family of proteins were performed in men with low levels of serum testosterone (idiopathic hypogonadotropic hypogonadism) and in individuals having serum testosterone in the normal range of values but carrying sex chromosome aberrations (Klinefelter's syndrome). In the first case we have found a marked decrease in the total amount of the RSV-IV-related proteins. An increase of about 40% in the total amount of these antigens was obtained in these subjects by gonadotropin treatment. A decreased amount of these proteins was also detected in the subjects affected by Klinefelter's syndrome. The possibility that some factor(s) under genetic control is involved, in addition to testosterone, in the regulation of this family of proteins is discussed.     

Echocardiographic Findings in Marfan's Syndrome

Echocardiographic studies of 11 patients with Marfan''s syndrome showed that in all adult patients aortic root diameters were larger than 35 mm (normal range 24 to 35, mean 30±2 mm). Prolapse of the mitral valve was present in seven of 11 patients. There was no relationship between the degree of aortic root enlargement and the presence of prolapse. However, in five of seven patients with prolapse there were premature ventricular contractions recorded during the echocardiogram or on a separate electrocardiogram. In four patients without prolapse, no premature atrial or ventricular contractions were seen.