Frontal sinus anatomy of the noble Swéerts-Sporck family and verification of their biological relationships using similarity analysis

The evaluation of frontal sinus similarity is one way to detect biological relationships, especially in small groups, including families of historically known personalities. However, possibilities for studying this issue are currently limited. This contribution deals with the frontal sinuses of a rare osteological sample with known genealogical data, members of the noble Swéerts-Sporck family from the 17th to 20th centuries. The aim is to verify whether the frontal sinuses reflect documented family relationships. Basic dimensions of the frontal sinus such as total surface area and volume, and maximum height and width, and also morphology and anatomical features were evaluated using computed tomography scans. The portions of the frontal sinus above the “external supraorbital line” were analyzed. The degree of similarity between biologically related individuals was determined for each variable and compared with their known biological distance. The degree of similarity based on dimensions was evaluated using both the unadjusted measured data and standardized data adjusted to size. For the unadjusted dimensions, a positive correlation between morphological similarity and biological relatedness was apparent. On the other hand, no positive correlation was apparent for most of the standardized data. Only total volume showed a very weak indication of a positive trend in the standardized data, but this was weaker than in the original values. A positive quantifiable relationship between morphological patterns and biological distance is not clearly indicated. However, nonmetric features do support the documented relationships of the individuals.     

Biological relationships and frontal sinus similarity in skeletal remains with known genealogical data

Frontal sinus analysis has potential utility for detecting biologically related individuals. However, the methodological approach to its evaluation, as well as its informative value, have been questioned. The aim of this work is to introduce a new approach to evaluating the frontal sinus using the ‘external supraorbital line’ (ESOL) and to determine whether there are sex differences within families in frontal sinus measurements and whether frontal sinus similarity reflects known genetic relationships in both measurements and morphology. We examined the skeletal remains of 41 adult individuals (25 males, 16 females), all members of one family over four generations (19th to 20th centuries), including individuals with very close consanguinity. CT images of skulls were acquired, and both the dimensions and morphology of the frontal sinuses were analyzed using their portions above the ESOL. No significant sex differences were found within families based on frontal sinus dimensions. Significant relationships were found between biological distance and the maximum height and morphology of the frontal sinuses. The greatest degree of similarity was found among closely related individuals. Additionally, in several cases, there was a greater degree of similarity between first cousins or grandparents and their grandchildren than among siblings or parents and their children. Total surface, volume and width are not significant indicators of relatedness. Known genetic relationships are also supported by individual morphological features. Variability within families with very close consanguineous relationships was lower than within families with common degrees of consanguinity, although differences are significant only for some variables.     

Scimitar vein anomaly with multiple cardiac malformations,craniofacial, and central nervous system abnormalities in a brother and sister: familial scimitar anomaly or new syndrome?

The scimitar vein "syndrome" is an anomaly of lobar aplasia or hypoplasia and total or partial anomalous venous drainage of one lung. We report a brother and sister born to nonconsanguineous Italian parents with a fatal infantile form of scimitar vein anomaly associated to multiple cardiac anomalies. The infants had major craniofacial anomalies. In addition, the boy had iris coloboma and enlarged cisterna magna; both sibs showed poor brain myelination at neuroimaging confirmed by histopathology in the girl. The cardiovascular system in the family members was fully investigated and all results were completely normal. The association of the above craniofacial anomalies has been occasionally mentioned in syndromes with anomalous venous return. The familial occurrence of isolated total anomalous pulmonary venous return has been documented in sibs, first cousins, and through consecutive generations. Familial pulmonary hypoplasia, as an isolated finding, has been observed in siblings and twins. To the best of our knowledge, even though five familial cases of scimitar "syndrome" have been described thus far, the constellation of anomalies shown by these two sibs has not been reported previously. It appears that scimitar vein "syndrome" is not a "syndrome" per se: it is most likely an anomaly of heterogeneous etiology. This family may represent its own novel syndrome of multiple congenital anomalies of which scimitar vein is a component.     

Impact of a common mutation of the LDL receptor gene, in French-Canadian patients with familial hypercholesterolemia, on means, variances and correlations among traits of lipid metabolism

Structural and functional studies of the gene coding for the low density lipoprotein receptor in patients with familial hypercholesterolemia have uncovered over 180 mutant alleles of the gene. Although the classical familial hypercholesterolemia phenotype is well known, the range of phenotypic variability in lipid traits associated with particular mutations in familial hypercholesterolemia has not been extensively documented. We investigated the phenotypic distributions of plasma markers of lipid metabolism from a large sample of unrelated individuals who are heterozygous for a single mutation, a > 10 kb deletion in the low density lipoprotein receptor gene, and compared these distributions with those from a sample of healthy controls. Patients were pair-matched for sex and age with healthy individuals selected from a previously studied French-Canadian population from the same region. We examined the level and variation of seven lipid traits, the correlations between the traits, and the amount of overlap of the sample distributions for each trait. The low density lipoprotein receptor defect was found to affect the levels and variability of traits, and correlations between traits. There was some overlap of the distributions of lipid traits including that for low density lipoprotein cholesterol, which is a cardinal feature of familial hypercholesterolemia. The low density lipoprotein receptor gene has a sex-specific pleiotropic effect and should be considered as a variability gene as well as a level gene. The extensive dynamic changes observed in the relationships between lipid traits testify to the biological complexity of genome type-environment interactions.     

Otodental dysplasia: a "new" ectodermal dysplasia

Otodental dysplasia is an ectodermal dysplasia characterized by abnormal crown morphology of the teeth and sensorineural hearing loss. It was documented in six generations of a kindred of Italian extraction. Thirty-three of the 119 examined family members were affected. Twenty-six persons had characteristic dental anomalies combined with a hearing loss. Two had the dental anomalies alone, four had a hearing loss only and one of those with dental anomalies could not be tested for hearing. The teeth of the 29 with dental anomalies had large, bulbous crowns. The normal relationship between cusps and grooves was obliterated. Molars, both deciduous and permanent, were involved. Deciduous canines were large and bulbous. Absence of premolars was documented in 14 of the 29 individuals with abnormal teeth. Those premolars which were present were frequently small. Radiographs of the teeth showed denticles and taurodontia. Twenty-six of the 30 individuals with a hearing loss had concomitant dental anomalies. Of the four with isolated hearing loss, one was proven to have the syndrome. The remaining three were conjectured to be affected. The age of onset of the hearing deficit ranged from early childhood to middle age. The results of a chi-square test supported autosomal dominant inheritance. The pleiotropy in this syndrome is postualed to be due to a genetic defect in the neuroectoderm.     

Familial MCA/MR syndrome due to inherited submicroscopic translocation t(18;21)(q22.1q21.3) with breakpoint at the Down syndrome critical region

We report three generation family that includes two patients with severe mental retardation and additional anomalies who have been studied, clinically, cytogenetically, and molecular cytogenetically. A clinical diagnosis could not be made in the propositus, but facial anomalies of Down syndrome (DS) were recognized in the maternal uncle of the propositus. In view of a strong family history of recurrent miscarriage, a familial translocation was highly suggestive. Standard cytogenetic analysis did not reveal any abnormalities. Fluorescence in situ hybridization (FISH) using subtelomeric DNA probes identified a familial cryptic translocation of chromosomes 18 and 21, resulting in partial trisomy 21 and partial monosomy 18q in both patients. FISH analysis of obligate carriers demonstrated a balanced translocation between the terminal parts of 18q and 21q. Including this family, a total of six different familial cases with cryptic or subtle subtelomeric translocations of chromosome 21q has been reported, of which three involved terminal parts of chromosome 18q. The remarkable similarity of the chromosomal breakpoints of our patients and the described families prompted us to refine the breakpoints and to discuss phenotypic differences between these patients. Our results reinforce the role of cryptic subtelomeric rearrangements in patients with mental retardation associated with physical anomalies and stress the importance of FISH technology to supplement routine cytogenetics.     

Familial patent ductus arteriosus and bicuspid aortic valve with hand anomalies: a novel heart-hand syndrome.

The association between cardiac and limb defects, particularly those affecting the hand, has been well documented by the delineation of several heart-hand syndromes. Based on observations with a three-generation family with seven affected individuals, we describe a novel heart-hand syndrome comprising patent ductus arteriosus, bicuspid aortic valve, 5th metacarpal hypoplasia, and brachydactyly. The inheritance pattern was consistent with autosomal dominance, although X-linked dominance could not be excluded. Penetrance appeared to be complete, but there was variability of the cardiac and hand phenotypes. Because this new syndrome closely resembled Char syndrome (patent ductus arteriosus, 5th finger middle phalangeal hypoplasia, and minor facial anomalies), multipoint linkage analysis was performed using polymorphic DNA markers spanning the recently identified Char syndrome critical region at chromosomal bands 6p12-p21.1. This analysis formally excluded this 3-cM region, documenting that the two traits are not allelic. In sum, a novel heart-hand syndrome involving left ventricular outflow and aortic arch as well as an ulnar ray derivative has been identified. Because the hand anomalies can be subtle, thorough evaluation is suggested for families inheriting these cardiac defects as a mendelian trait.     

Unusual autosomal recessive lymphatic anomalies in two unrelated Amish families

We report on two unrelated Amish families with familial occurrence of unusual lymphatic anomalies. The first family had two children, a boy and a girl, with congenital chylothorax both of whom died as a consequence of this condition (one prenatally and one neonatally). The second family has two brothers with isolated cystic hygroma. Neither family has any other individuals affected with any type of lymphatic anomaly. Differential diagnosis and presumed autosomal recessive inheritance pattern will be discussed. Familial cystic hygroma not associated with hydrops fetalis and neonatal death has not been reported previously. Am. J. Med. Genet. 73:286–289, 1997. © 1997 Wiley-Liss, Inc.     

HARD (± E) syndrome: Report of a sixth family with support for autosomal-recessive inheritance

We report on two sibs with hydrocephalus, encephalocele, agyria and ocular anomalies, an association known as the HARD ± E syndrome. This is thought to be the sixth reported family and third instance of familial occurrence of this autosomal-recessive syndrome which deserves consideration in the nosology of every case of neural tube defect (hydrocephalus).     

Brief clinical report: HARD (+/- E) syndrome: report of a sixth family with support for autosomal-recessive inheritance

We report on two sibs with hydrocephalus, encephalocele, agyria and ocular anomalies, an association known as the HARD +/- E syndrome. This is thought to be the sixth reported family and third instance of familial occurrence of this autosomal-recessive syndrome which deserves consideration in the nosology of every case of neural tube defect (hydrocephalus).     

Pericentric inversions of chromosome 4: report of a new family and review of the literature

A family was cytogenetically studied because of the birth of a male child with a multiple congenital anomaly pattern, in whom a dup (4q) recombinant was found. His phenotypically normal mother's karyotype showed an apparently balanced pericentric inversion in a chromosome 4. So as to analyze the occurrence of recombinants, the cytogenetic data from this family are compared with those of the 18 previously reported familial cases of pericentric inversions (PIs) of chromosome 4. The congenital anomalies observed in the child strongly suggest Wolf-Hirschhorn syndrome but some of his clinical features seem to be pathogenetically related to the presence of lymphedema during the intrauterine period. In the multiple congenital anomaly pattern observed in this patient, the lymphedema could be the consequence of the large 4q duplication. The review of chromosome 4 PIs with 4q duplication suggests that the q3 region should be examined when edema is detected prenatally.     

Say syndrome: report of a familial case.

We describe a new case of Say syndrome. This syndrome is an autosomal dominant condition characterized by cleft palate, short stature of prenatal onset, large protruding ears and microcephaly, delayed bone age, and renal anomalies. The first report was in 1975 by Say et al. in three generations of a family. Three additional reports of isolated cases were published. Our propositus is a 12-month-old boy with the cardinal signs of the syndrome whose mother has only microcephaly. To our knowledge this is the second familial report with evidence of highly variable expressivity. The occurrence of renal anomalies in a son of a normal sister of his mother suggests incomplete penetrance.     

An Inherited Restriction in the Idiotypic Variability as a Possible Explanation of a Genetic Predisposition for a Monoclonal Component

Genetic factors have been proposed to play a role in the aetiology of a monoclonal proliferation of B lymphocytes. As an additional genetic factor we postulate that a restriction in the idiotypic variability of an individual contributes to a genetic predisposition to monoclonal gammopathy. To support our hypothesis, we have examined three families with multiple occurrence of M-components for sharing of idiotypic antigenicity between the related M-components and between the M-components and the sera of unaffected relatives. Idiotypic antisera against five isolated M-components were raised in guinea-pigs and used in a radiobinding inhibition assay. In none of the three families was idiotypic cross-reactivity observed between the familial M-components. However, in a family with three members with an M-component, sera of first-degree relatives showed a higher inhibitory capacity than sera of non-related individuals when an idiotypic antiserum, raised against the M-component of proposita, was employed. Within this particular family the observed restriction in the idiotypic variability could have contributed to the multiple occurrence of M-components.     

The impact of familial environment on depression scores after genetic testing for cancer susceptibility

The associations between characteristics of family relationships and family trends in cancer worry and the psychological adjustment of recipients of genetic testing for cancer susceptibility were investigated. Data provided by 178 individuals from 24 families with Lynch syndrome who participated in a cohort study investigating psychological and behavioral outcomes of genetic testing were used. Responses from multiple family members were aggregated to construct family trends representing norms and departure from norms in cancer worry. Lower perceived family cohesion at baseline and decrease in this variable at 6 months after receipt of test results were associated with higher depression scores at 12 months. More variability in cancer worry among family members at baseline was also associated with higher depression scores at 12 months. Increase in family conflict was associated with decrease in depression scores among individuals from families with higher levels of cancer worry on average and less variability among the members. Family relationships and family trends in levels of cancer worry may play important roles in the psychological adjustment of genetic test recipients. The findings highlight the complexity of familial environment surrounding individuals that undergo genetic testing and suggest the benefits of considering these factors when providing genetic services.     

Hemifacial microsomia and variants: pedigree data

Ear malformations occur per se or together with other congenital anomalies. Many syndromes with ear malformations have been described. We have studied propositi with hemifacial microsomia (HFM) or Goldenhar syndrome (GS), also called oculoauriculovertebral "dysplasia" (OAV). In addition to ear malformations some individuals may have a small and/or malformed mandible, epibulbar, or conjunctival lipodermoids and anomalies of the cervical spine. Other malformations may also be seen. At present, the cause of these disorders is unclear. Here we present pedigree data on 97 propositi, 44 of whom had a family history of the same or similar anomaly. First-degree relatives were most often affected (35/433, 8%). Of 176 sibs tabulated, 11 (6%) were considered affected. The pattern of occurrence in many families suggested multifactorial determination, although other interpretations are possible. The occurrence of differing anomalies within a family suggests that the disorders constitute a single entity. The most frequent anomaly was a mild ear malformation (preauricular node or tag). This suggests a broad phenotypic spectrum. These data are useful for purposes of genetic counseling.     

Sacrococcygeal dysgenesis association.

In the malformation analysis of 445 patients ascertained only for a sacrococcygeal malformation, a new phenotype, the sacrococcygeal dysgenesis association (SDA), was delineated in 34%. In addition, sirenomelia patients were found in 12%, the VATER association in 27%, and 27% could not be classified. Heterogeneity in the patients with sacrococcygeal malformations was identified by the differences found in their associated malformations. SDA patients have a relatively small average number (3.3) of anomalies per patient as compared with 9.3 in sirenomelia and 6.2 in VATER patients. SDA abnormalities occurred to a significant degree only in 6 of 20 designated malformation categories (vertebral, rib, pelvic, lower limb, central nervous system [CNS], renal) in contrast to 17 in VATER and 18 in sirenomelia patients. The SDA vertebral malformation pattern also differed from that of VATER/sirenomelia patients as did the high sacrococcygeal agenesis:dysgenesis ratio and low thoracolumbar vertebrae and/or rib hypersegmentations. Most significantly, SDA patients had a large number of CNS anomalies and CNS-related dysfunctions of the urinary and distal intestinal tracts but no anatomic urinary or intestinal tract malformations. This contrasted sharply with the markedly increased occurrences of anatomic abnormalities in these body regions of the sirenomelia and VATER patients. Demographic data such as patient survival, twinning and, particularly, the high (28%) incidence of maternal diabetes in the SDA further support its differentiation from VATER/sirenomelia patients.     

A family study of congenital diaphragmatic defects

The occurrence of specific and nonspecific congenital anomalies was determined in first degree relatives of index patients with congenital diaphragmatic defects who were born in Hungary between 1970 and 1979 and were ascertained through a population-based registry. The cases were grouped into Bochdalek types (N = 156), other types (N = 26), unclassified types (N = 55), and multiple congenital anomalies (MCA) cases including those with congenital diaphragmatic defects (N = 96). The sib occurrence in the Bochdalek type was 0.9% (taking into consideration also the unclassified cases or the total material, it was 0.5% or 0.4%, respectively). Specific familial clusters were not found in other types. Neural tube defects were detected in 1.8% of sibs in the total material and 2.4% in MCA cases.     

Germline mosaicism resulting in the transmission of severe hemophilia B from a grandfather with a mild deficiency

We report a family in which the normal pattern of X-linked inheritance of hemophilia B (Factor IX deficiency) is complicated by mosaicism in the proband's maternal grandfather. The proband, an infant with severe Factor IX deficiency, was initially thought to be a sporadic case. Testing of other family members identified his mother as a carrier of the disorder, and his asymptomatic maternal grandfather as having very mild FIX deficiency. The causative familial mutation was identified as a two base pair deletion (AG within codons 134-135) in the Factor IX gene. The grandfather was shown to be "heterozygous" for the deletion. Karyotype analysis confirmed him to be 46XY thereby ruling out Klinefelter syndrome. The proband's aunt, who as the daughter of a man with hemophilia is theoretically an obligate carrier, was found not to carry this familial mutation, and thus not to be a carrier of hemophilia B. The grandfather must therefore be an X chromosome somatic and germline mosaic, with consequent segregation of the affected and non-affected Factor IX genes. This observation underlines the importance of confirming carrier status even in those individuals assumed to be obligate carriers, and has implications for genetic counseling.     

Sacrococcygeal dysgenesis association

In the malformation analysis of 445 patients ascertained only for a sacrococcygeal malformation, a new phenotype, the sacrococcygeal dysgenesis association (SDA), was delineated in 34%. In addition, sirenomelia patients were found in 12%, the VATER association in 27%, and 27% could not be classified. Heterogeneity in the patients with sacrococcygeal malformations was identified by the differences found in their associated malformations. SDA patients have a relatively small average number (3.3) of anomalies per patient as compared with 9.3 in sirenomelia and 6.2 in VATER patients. SDA abnormalities occurred to a significant degree only in 6 of 20 designated malformation categories (vertebral, rib, pelvic, lower limb, central nervous system [CNS], renal) in contrast to 17 in VATER and 18 in sirenomelia patients. The SDA vertebral malformation pattern also differed from that of VATER/sirenomelia patients as did the high sacrococcygeal agenesis: dysgenesis ratio and low thoracolumbar vertebrae and/or rib hypersegmentations. Most significantly, SDA patients had a large number of CNS anomalies and CNS-related dysfunctions of the urinary and distal intestinal tracts but no anatomic urinary or intestinal tract malformations. This contrasted sharply with the markedly increased occurrences of anatomic abnormalities in these body regions of the sirenomelia and VATER patients. Demographic data such as patient survival, twinning and, particularly, the high (28%) incidence of maternal diabetes in the SDA further support its differentiation from VATER/sirenomelia patients.