van der Woude syndrome in two families in China.

We report on two unrelated families from the Beijing area in which the autosomal dominant gene for van der Woude syndrome (VWS) is segregating. The clinical features include paramedian lower lip pits (fistula labii inferioris congenita), cleft palate, and cleft lip with or without cleft palate. All three of the clinical features may occur together in an affected individual, or any two together, or any one as a single feature of an individual who carries the gene. The probands in each of our families also have ankyloglossia. This is the first report of VWS from China.

Genetic epidemiology and control of genetic expression in van der Woude syndrome.

By three pedigree and statistical criteria van der Woude syndrome (VWS) appears to have been underreported and frequently not diagnosed. Eight percent of gene carriers are not diagnosed because they are nonpenetrant. But among penetrant gene carriers as many as 80% may not have been recognized in the past. A direct estimate of incidence of VWS is 3.6/100,000 births; indirect estimates are more than double that. The relative risk of inheriting a cleft from an affected parent is 22.43%; the risk of inheriting lip pits only, or being nonpenetrant is 27.57%. (This corrects a similar statement in the abstract of Burdick et al [J Craniofacial Genet Dev Biol 5:181-208, 1985], which was incorrectly calculated). The idea of unitary control of the action of the VWS gene in the three target tissues appears not to be supported. Rather, we tend to support the idea that the gene is controlled independently in the three tissues. Indications of a family at risk are listed and discussed.

Genetic analysis in families with van der Woude syndrome.

We have brought together information on 864 affected individuals in 164 families (including three new pedigrees) reported in the 137 year period since 1845 when Demarquay first described a family with what was later called van der Woude syndrome (VWS). Both types of oral cleft, cleft palate (CP) and cleft lip with or without CP (CLP), segregate in these families together with lower lip pits or fistulae in an autosomal dominant mode with high penetrance estimated to be K = .89 and .99 by different methods. Cleft types (CLP and CP) occur in VWS in the same proportions as in the general non-VWS population, ie, about twice as many cleft-bearing individuals have CLP as have CP. On the other hand, we do not find the usually observed excess of females with CP and excess of males with CLP; in VWS the sex ratios are more nearly equal. Lip pits also are equally distributed between the sexes. Affected males and females are equally likely to transmit VWS. However, there is an excess of less severely affected individuals among transmitters and a deficiency of more severely affected, brought about by a proband bias and differential fecundity. The expression of VWS is significantly modified by the genetic background: More extreme phenotypes in parents tend to produce more extreme expression in their children. For a VWS gene carrier the relative risk of transmitting a cleft is 26.45%; that of transmitting lower lip pits is 23.55%. Three pedigrees of lip pits in the literature show no clefts among a significant number of affected individuals. Control of gene expression in VWS in the three target tissues appears to be independent and separately designated. Mutation rate of the VWS gene is calculated to be 1.8 X 10(-5).

Familial spastic paraplegia: a clinical and electrodiagnostic evaluation.

Twenty members of a family with an autosomal dominant variety of a familial spastic paraplegia (FSP) underwent neurologic and electrodiagnostic examination. The degree of clinical involvement ranged from severe to none. This study investigated the presence of peroneal H reflex of Hoffmann along with other electrodiagnostic parameters in each family member and compared this with the presence of other neurologic findings. An H reflex in the peroneal nerve was found in all subjects with a definite diagnosis of FSP and in 4 of the 6 subjects with a diagnosis of probable FSP. It was not elicited in any subject with fewer than 3 neurologic signs or below the age of 25. The H reflex was found to have value as an indicator of upper motor neuron involvement when taken together with the neurologic findings, but its predictive value for individuals at risk to develop FSP has not been established.

Slowly progressive autosomal dominant spastic paraplegia with late onset, variable expression and reduced penetrance: a basis for diagnosis and counseling.

We have examined a pedigree in which familial spastic paraplegia (FSP) is segregating in four generations. The data show a high rate of transmission of the trait, late onset, reduced penetrance, variable age and symptom expressivity, and an autosomal dominant mode of transmission. A summary of our data together with the FSP data of other shows a 1:1 transmission from males and from females, and an overall 1:1 transmission ratio. The risks for the children of symptomatic and non-symptomatic parents are illustrated.

Ultrastructural changes induced by steroids and gonadotropins in cultured rat Sertoli cells.

Testicular cells readily grew in cultures of seminiferous tubule fragments derived from adult rat testes. They formed confluent monolayers and continued to grow through four passages. The majority of cells had ultrastructural features characteristic of Sertoli cells. They exhibited large nuclei lacking heterochromatin, having nuclear membrane clefts, prominent nucleoli, significant amounts of agranular endoplasmic reticulum, large and numerous mitochondria, and lipid droplets. Cultured Sertoli cells responded to follicle-stimulating hormone (FSH), androgens, and dbcAMP by undergoing distinct morphological and ultrastructural changes. FSH induced parallel arrays of granular endoplasmic reticulum. Testosterone and dbcAMP resulted in the swelling of mitochondria, the formation of parallel cristae that stretched across the lumen, and the appearance of lipid droplets. Sertoli cells, cultured in a medium containing testosterone and FSH since their initiation, developed extensive agranular endoplasmic reticulum, strikingly large lipid droplets, and mitochondria that were characterized by either a dark matrix and vesicular cristae, or a light matrix and parallel cristae. These results indicate that Sertoli cells respond in vitro to hormones that are active in vivo, and support the suggestion that the Sertoli cell is a site of steroid synthesis in the mammalian testis.

Frequency of the gene for cystic fibrosis with a view of replacement and recognition effects and reproduction by homozygotes.

The apparent frequency of the recessive autosomal allele for cystic fibrosis (cf) is too high to be satisfactorily explained by mutation equilibrium. However, higher reproductive fitness by heterozygotes (expressed by t greater than 0) or higher gametic viability of the cf allele (expressed by a greater than 0.5) can provide reasonable explanations of the present frequency. Furthermore, birth replacement in families with CF children (RPE) can account for the estimated historical values of t. Today, however, t is probably at or approaching zero as a result of discontinuation of RPE. In the future we can look for an imperceptibly slow decrease in the incidence of CF. Reproduction by CF females will not cause an increase in incidence; it will only slightly slow the rate of decrease.