Nevoid basal-cell carcinoma syndrome.

Background A major source of new mutations in humans is the male germ line, with mutation rates monotonically increasing as father's age at conception advances, possibly because of accumulating replication errors in spermatogonial cell lines. Method We investigated whether the risk of schizophrenia was associated with advancing paternal age in a population-based birth cohort of 87 907 individuals born in Jerusalem from 1964 to 1976 by linking their records to the Israel Psychiatric Registry. Results Of 1337 offspring admitted to psychiatric units before 1998, 658 were diagnosed as having schizophrenia and related nonaffective psychoses. After controlling for maternal age and other confounding factors (sex, ethnicity, education [to reflect socioeconomic status], and duration of marriage) in proportional hazards regression, we found that paternal age was a strong and significant predictor of the schizophrenia diagnoses, but not of other psychiatric disorders. Compared with offspring of fathers younger than 25 years, the relative risk of schizophrenia increased monotonically in each 5-year age group, reaching 2.02 (95% confidence interval, 1.17-3.51) and 2.96 (95% confidence interval, 1.60-5.47) in offspring of men aged 45 to 49 and 50 years or more, respectively. Categories of mother's age showed no significant effects, after adjusting for paternal age. Conclusions These findings support the hypothesis that schizophrenia may be associated, in part, with de novo mutations arising in paternal germ cells. If confirmed, they would entail a need for novel approaches to the identification of genes involved in schizophrenia.

https://jamanetwork.com/journals/jamapsychiatry/articlepdf/481752/yoa20250.pdf

Advancing Paternal Age and the Risk of Schizophrenia

Hutchinson-Gilford progeria syndrome (HGPS) is a rare but well known entity characterized by extreme short stature, low body weight, early loss of hair, lipodystrophy, scleroderma, decreased joint mobility, osteolysis, and facial features that resemble aged persons. Cardiovascular compromise leads to early demise. Cognitive development is normal. Data on 10 of our own cases and 132 cases from literature are presented. The incidence in the last century in the Netherlands was 1:4,000,000. Sex ratio was 1.2:1. Main first symptoms were failure to thrive (55%), hair loss (40%), skin problems (28%), and lipodystrophy (20%). Mean age at diagnosis was 2.9 years. Growth in weight was more disturbed than growth in height, and growth delay started already prenatally. Mean height > 13 years was 109.0 cm, mean weight was 14.5 kg. Osteolysis was wide-spread but not expressed, except in the viscerocranium, and remained limited to membranous formed bone. Lipodystrophy is generalized, only intra-abdominal fat depositions remain present. Cardiovascular problems are extremely variable, both in age of onset and nature. Stroke and coronary dysfunctioning are most frequent. Pathologic findings in coronaries and aorta resemble sometimes the findings in elderly persons, but can also be much more limited. Loss of smooth muscle cells seems the most important finding. Mean age of demise was 12.6 years. Patients can be subdivided in patients with classical HGPS, which follows an autosomal dominant pattern of inheritance, (almost) all cases representing spontaneous mutations, and in non-classical progeria, in whom growth can be less retarded, scalp hair remains present for a longer time, lipodystrophy is more slowly progressive, osteolysis is more expressed except in the face, and survival well into adulthood is not uncommon. Pattern of inheritance of non-classical progeria is most probably autosomal recessive. The cause of HGPS is an abnormally formed Lamin A, either directly by a mutated LMNA gene, or through abnormal posttranslational processing (ZMPSTE24 gene mutations). Of 34 LMNA mutations found in progeria patients, there were 26 classical p.G608G mutations (76%). Pathogenesis is most likely to follow several different pathways. Potential therapeutic strategies are developed along these lines and include RNA interference techniques and inhibition of the dominant-negative influence of abnormally formed Lamin A on polymerization with normally formed Lamin A.

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Hutchinson-Gilford progeria syndrome: review of the phenotype.

The first well-documented observation of retinoblastoma (Rb) in several members of one family was published by Lerche (1821). Four of seven siblings, children of healthy parents, were affected. At that time, the tumor almost invariably led to death during infancy or early childhood. The first pedigrees with transmission through two or more generations were observed only after enucleation of the affected eye had been introduced by von Graefe. More recently, the mode of inheritance has been identified as autosomal dominant with incomplete penetrance; Fig. 13.1 shows a typical pedigree. Unilateral as well as bilateral cases may occur in the same family, and the tumor may even skip one generation. Statistical analysis of many families (see Vogel 1979) led to the conclusion that the penetrance of the dominant gene causing Rb is about 90%; i.e., 90% of heterozygotes will be affected.

Genetics of retinoblastoma

VACTERL/VATER association is typically defined by the presence of at least three of the following congenital malformations: vertebral defects, anal atresia, cardiac defects, tracheo-esophageal fistula, renal anomalies, and limb abnormalities. In addition to these core component features, patients may also have other congenital anomalies. Although diagnostic criteria vary, the incidence is estimated at approximately 1 in 10,000 to 1 in 40,000 live-born infants. The condition is ascertained clinically by the presence of the above-mentioned malformations; importantly, there should be no clinical or laboratory-based evidence for the presence of one of the many similar conditions, as the differential diagnosis is relatively large. This differential diagnosis includes (but is not limited to) Baller-Gerold syndrome, CHARGE syndrome, Currarino syndrome, deletion 22q11.2 syndrome, Fanconi anemia, Feingold syndrome, Fryns syndrome, MURCS association, oculo-auriculo-vertebral syndrome, Opitz G/BBB syndrome, Pallister-Hall syndrome, Townes-Brocks syndrome, and VACTERL with hydrocephalus. Though there are hints regarding causation, the aetiology has been identified only in a small fraction of patients to date, likely due to factors such as a high degree of clinical and causal heterogeneity, the largely sporadic nature of the disorder, and the presence of many similar conditions. New genetic research methods offer promise that the causes of VACTERL association will be better defined in the relatively near future. Antenatal diagnosis can be challenging, as certain component features can be difficult to ascertain prior to birth. The management of patients with VACTERL/VATER association typically centers around surgical correction of the specific congenital anomalies (typically anal atresia, certain types of cardiac malformations, and/or tracheo-esophageal fistula) in the immediate postnatal period, followed by long-term medical management of sequelae of the congenital malformations. If optimal surgical correction is achievable, the prognosis can be relatively positive, though some patients will continue to be affected by their congenital malformations throughout life. Importantly, patients with VACTERL association do not tend to have neurocognitive impairment.

/pdf/vacterl-vater-association-1df3fzx19q.pdf

VACTERL/VATER Association

The VATER association. Vertebral defects, Anal atresia, T-E fistula with esophageal atresia, Radial and Renal dysplasia: a spectrum of associated defects.

Older paternal age and fresh gene mutation: data on additional disorders.

Older paternal age has previously been documented as a factor in sporadic fresh mutational cases of several autosomal dominant disorders. In this collaborative study, an older mean paternal age has been documented in sporadic cases of at least five additional dominantly inheritable disorders: the basal cell nevus syndrome, the Waardenburg syndrome, the Crouzon syndrome, the oculo-dental-digital syndrome, and the Treacher-Collins syndrome. It was also found to be a factor in acrodysostosis and progeria, suggesting a fresh mutant gene etiology for these two conditions in which virtually all cases have been sporadic and the mode of genetic etiology has been unknown.

Older paternal age and fresh gene mutation: data on additional disorders

Older paternal age has been recognized as a factor in fresh gene mutations and has been documented in sporadic cases of 5 autosomal dominant conditions. In this collective study an older paternal age factor was additionally documented in sporadic cases of the Basal Cell Nevus syndrome the Crouzon syndrome and the Waardenburg syndrome 3 conditions in which autosomal dominant inheritance has been implied; and in sporadic cases of Acrodysostosis and Progeria suggesting a fresh mutant gene itology for these 2 conditions in which the mode of inheritance has been unknown. Paternal age data from a number of other disorders showed inconclusive or no older paternal age factor. Recognition that older paternal age is a major factor leading to fresh gene mutation in man should be incorporated into general recommendations relative to family planning. (FULL TEXT)

Linda Quan

Papers

The VATER association. Vertebral defects, Anal atresia, T-E fistula with esophageal atresia, Radial and Renal dysplasia: a spectrum of associated defects.

Older paternal age and fresh gene mutation: data on additional disorders.

Older paternal age and fresh gene mutation: data on additional disorders

Additional data relative to paternal age and fresh gene mutation. (Abstract only)

Dominant polysyndactyly: A report of two families