X linked hydrocephalus: a survey of a 20 year period in Victoria, Australia.

This study ascertained 164 males with non-communicating hydrocephalus in live or stillborn patients in Victoria. Australia in 1962 to 1982, after excluding those cases secondary to brain malformations other than aqueduct stenosis. Ascertainment was considered near complete, especially for the period since 1974, but details of the aqueduct pathology were inadequate in half the cases. A total of 91 families was seen to record detailed family information. The overall incidence of primary non-communicating hydrocephalus was estimated to be 0.6 +/- 0.2 per 1000 live and stillbirths, with three-fifths of the cases male. Twelve patients were classified as having definite X linked hydrocephalus and 13 others as probable cases of this condition. Deformities of the thumbs (generally adduction deformity) were present in nearly half of these cases. The pyramids were absent from sections of the medulla whenever these were available. Four of five survivors had signs suggesting pyramidal tract lesions, compared to four of 25 surviving non-X linked cases. The intellectual outcome was notably poorer in the X linked cases. Poor school performance was also described in five of 19 mothers of X linked cases but in only one of 64 mothers of the remaining cases. Familial recurrence in the whole group of patients was almost confined to the X linked families. The exceptions were two families in whom autosomal recessive inheritance is possible. It is important to remember X linked hydrocephalus in genetic counselling. Examination of the thumbs, search for clinical signs of pyramidal tract lesions, and anatomical examination of the pyramids in medullary sections are all important, along with careful questioning for a history of affected maternal relatives. The presence of any of these features is grounds for counseling on the basis of X linked inheritance. An empirical figure was derived to use when counseling about a male with non-communicating hydrocephalus in whom there is no adequate information about the thumbs or the pyramids: a 4% recurrence risk in male sibs and 2% in females.     

Autosomal dominant inheritance of adducted thumbs and other digital anomalies

Isolated adducted thumbs is an uncommon malformation that occurs sporadically in the majority of cases although some affected families have been reported. Previously, autosomal dominant inheritance was suggested in two familial cases, but this mode of inheritance has not been confirmed. Here we describe a family with adducted thumbs and other digital anomalies in which seven members (six females and one male) are affected in three consecutive generations. Additionally, the patients showed mild abnormalities of fingers 2nd–4th bilaterally and hypoplasia of the middle phalanx of the 5th fingers. This family represents an autosomal dominant condition that apparently has not been previously reported.     

Report of a further family with dominant deafness-onychodystrophy (DDOD) syndrome

Deafness and onychodystrophy is a presumed autosomal dominant condition previously reported in five families. We report on a three-generation family with three affected members with absent finger and toenails, finger-like thumbs, and severe sensorineural deafness. In the hands, the first and fifth digits had absent nails and bulbous swelling of the distal phalanx. The second, third, and fourth digits were relatively spared. In the feet,there were hypoplastic great toenails and absent nails on second to fifth toes. Intelligence was normal. In addition to deafness and onychodystrophy, other features in this family included subtle facial dysmorphism in two individuals, cutis aplasia in one individual, epilepsy in one individual, and sudden infant death in two family members, one of whom had deafness and onychodystrophy and one who did not. A full autopsy of both infants did not reveal a cause. SNP microarray analysis of one family member showed no evidence of copy number change. This family's condition fits within the spectrum of dominant deafness-onychodystrophy syndrome (DDOD) and further characterises this rare condition.     

X-linked aqueductal stenosis.

A family is reported in which eight members of one generation were affected by the syndrome hydrocephalus with aqueductal stenosis. With the exception of one child who lived for several weeks, they all died at or within 10 days of birth. Autopsy of a pair of affected twins showed marked stenosis of the aqueduct of Sylvius with fusion of the lamina quadrigemina. There were no signs of previous or present inflammatory changes or neoplasia. All the affected individuals were males, and the familial and pathological data presented support the concept that aqueductal stenosis in this family was due to an X-linked gene, and may have a developmental origin.     

X-linked aqueductal stenosis

A family is reported in which eight members of one generation were affected by the syndrome hydrocephalus with aqueductal stenosis. With the exception of one child who lived for several weeks, they all died at or within 10 days of birth. Autopsy of a pair of affected twins showed marked stenosis of the aqueduct of Sylvius with fusion of the lamina quadrigemina. There were no signs of previous or present inflammatory changes or neo-plasia. All the affected individuals were males, and the familial and pathological data presented support the concept that aqueductal stenosis in this family was due to an X-linked gene, and may have a developmental origin.     

Inhaled zanamivir for the prevention of influenza in families. Zanamivir Family Study Group

BACKGROUND: As prophylaxis against influenza in families, amantadine and rimantadine have had inconsistent effectiveness, partly because of the transmission of drug-resistant variants from treated index patients. We performed a double-blind, placebo-controlled study of inhaled zanamivir for the treatment and prevention of influenza in families. METHODS: We enrolled families (with two to five members and at least one child who was five years of age or older) before the 1998-1999 influenza season. If an influenza-like illness developed in one member, the family was randomly assigned to receive either inhaled zanamivir or placebo. The family member with the index illness was treated with either 10 mg of inhaled zanamivir (163 subjects) or placebo (158) twice a day for 5 days, and the other family members received either 10 mg of zanamivir (414 subjects) or placebo (423) once a day as prophylaxis for 10 days. The primary end point was the proportion of families in which at least one household contact had symptomatic, laboratory-confirmed influenza. RESULTS: The proportion of families with at least one initially healthy household contact in whom influenza developed was smaller in the zanamivir group than in the placebo group (4 percent vs. 19 percent, P<0.001); the difference represented a 79 percent reduction in the proportion of families with at least one affected contact. Zanamivir provided protection against both influenza A and influenza B. A neuraminidase-inhibition assay and sequencing of the neuraminidase and hemagglutinin genes revealed no zanamivir-resistant variants. Among the subjects with index cases of laboratory-confirmed influenza, the median duration of symptoms was 2.5 days shorter in the zanamivir group than in the placebo group (5.0 vs. 7.5 days, P=0.01). Zanamivir was well tolerated. CONCLUSIONS: When combined with the treatment of index cases, prophylactic treatment of family members with once-daily inhaled zanamivir is well tolerated and prevents the development of influenza. In this study there was no evidence of the emergence of resistant influenza variants.     

Polydactyly: a study of a five generation Indian family.

Preaxial polydactyly was observed in up to five generations of an Indian family living in a village in the Rajkot district (Gujarat). Among the 71 affected members, 45 were males and 26 were females. All these affected members showed preaxial polydactyly manifesting as a well formed, articulated extra digit of the hand or foot. Twenty other cases were also identified with polydactyly involving triphalangeal digits replacing the thumbs or duplication of the big toe(s). To the best of our knowledge, the present family is the largest in which several members have preaxial polydactyly of different types. No other abnormalities were apparent. The present study strongly suggests that preaxial polydactyly with a well formed extra digit, triphalangeal thumbs, and duplication of the big toe can be manifestations of the same autosomal dominant gene. It is likely that other factors are modifying the expression of this gene.     

Radial ray defect and Duane anomaly: report of a family with autosomal dominant transmission

We report on a family in which a mother and her 2 offspring presented with bilateral radial defects and absent thumbs. In addition, Duane anomaly was present in both offspring, one of whom also had anal stenosis. Clinical investigation showed no skeletal, cardiac, or urogenital abnormalities. Autosomal dominant transmission of radial defects is suggested, with Duane anomaly and anal stenosis representing manifestations of the same gene.     

An autosomal dominant syndrome of radial hypoplasia,triphalangeal thumbs,hypospadias, and maxillary diastema

We describe a family in which eight persons (three males, five females) in three generations had a syndrome of bilateral and strikingly symmetrical triphalangeal thumbs and radial hypoplasia. The affected males also had a first-degree hypospadias and all affected family members had an anterior maxillary diastema. The syndrome was inherited in an autosomal dominant fashion.     

X-linked recessive aqueductal stenosis without macrocephaly

A normocephalic, severely retarded boy with a family history suggesting aqueductal stenosis was found by computerized tomography to have aqueductal stenosis. His parents' concurrent pregnancy was monitored by ultrasonography and amniocentesis; these disclosed a male fetus which developed marked hydrocephalus after the 20th week. The pregnancy was terminated and an autopsy of the fetus demonstrated several major CNS malformations in addition to a very narrowed aqueduct. This case illustrates the diffuse CNS disease present in at least some cases of X-linked aqueductal stenosis (XLAS) and the importance of considering this variable syndrome in normocephalic, non-dysmorphic mentally retarded males. Important aspects of the prenatal diagnosis of XLAS are also illustrated.     

Probable autosomal dominant infantile pyloric stenosis in a large kindred

The proposita was operated on in this hospital in 1980 for pyloric stenosis, at the age of 13 days, after vomiting had started 5 days previously, and the diagnosis had been confirmed on radiological investigation. Her older sister and two male cousins of the father had the same operation in Israel in infancy. The other nine affected individuals in the family were known to have had projectile vomiting for several months in infancy, and two of them died in infancy. They were all born in the Jewish community in Georgia, U.S.S.R. The male:female sex ratio was 2:2 for the operated cases, and 4:5 for those with projectile vomiting history. There was no skipping of a generation. This family indicates that pyloric stenosis can exceptionally be inherited as a simple autosomal dominant trait.     

Variability of the Holt-Oram syndrome in Saudi individuals

We studied three families in which patients with the Holt-Oram syndrome (HOS) had various skeletal abnormalities and congenital heart defects. Two patients had absent thumbs and first metacarpals, hypoplastic radii, and atrial and ventricular septal defects. Patient 2 had pulmonary stenosis, an atrial septal defect, and triphalangeal thumbs. A sister had atrial septal defect and abnormalities of the thumbs; two brothers had abnormalities of the thumbs. The mother had unilateral defect of the thumb with a normal heart. The third patient had tetralogy of Fallot and hypoplastic pulmonary artery. In two families the HOS appeared to be the result of new mutations; in one it was transmitted as an autosomal dominant trait.     

A family study of craniosynostosis, with probable recognition of a distinct syndrome.

A family study was based on 184 consecutive patients who had undergone surgery for craniosynostosis at The Hospital for Sick Children, London, between 1953 and 1976. Of these, 127 were traced and visited and are the probands for this study. Crouzon syndrome was recognised in 16, Apert in 11, Saethre-Chotzen in nine, and Pfeiffer in two. In addition, two probands had Saethre-Chotzen-like facies and bilaterally broad big toes owing to partial or complete duplication of the distal phalanx. This syndrome is distinct from Pfeiffer syndrome, in which the facies more closely resembles that in Crouzon syndrome and in which it is the proximal phalanx of the big toe (and often of the thumb) which is abnormal. It is suggested that this newly recognised syndrome be called after Robinow and Sorauf, who appear to be the first to have described a family with the condition. One proband with coronal stenosis had a mother and brother affected, but no syndrome was recognised in them. Excluding this last case, no non-syndromic proband had an affected parent. The 58 probands with predominantly sagittal synostosis had 106 sibs, none of whom was affected. The 21 probands with predominantly coronal synostosis included one sib pair both affected; the remaining 17 sibs were unaffected. The four probands with predominantly metopic stenosis had 13 unaffected sibs and the four with multiple sutures involved had eight unaffected sibs. One sagittal proband had an unaffected monozygotic twin and another an unaffected dizygotic twin.     

X-linked dilated cardiomyopathy

To study the inheritance of idiopathic dilated cardiomyopathy, we investigated a large kindred in which 11 young male members had definite or possible evidence of the disorder. The five affected males for whom we had complete clinical data survived for 5 to 12 months after the onset of symptoms, which occurred early in life (ages 15 to 21 years). In six other males, clinical data were incomplete but suggested possible cardiomyopathy. Three mothers of affected males were given a diagnosis of definite, and two of possible, late-onset dilated cardiomyopathy. These women presented in their 40s with atypical chest pain, and progressive congestive heart failure developed gradually over a period of 10 or more years. X-linked inheritance of dilated cardiomyopathy is suggested in this family by the early onset in males, late onset in females, and no evidence of male-to-male transmission. The late onset of the disease in females, in contrast to the early onset in hemizygous males, is compatible with heterozygosity for the mutant allele. Since most cases of genetically lethal X-linked syndromes appear to be sporadic, for every case of "idiopathic" dilated cardiomyopathy in which X-linked inheritance can be confirmed from family information, it is possible that there are several nonfamilial cases due to a mutation at the same locus.     

A family with craniofrontonasal dysplasia, and fragile site 12q13 segregating independently

Coronal craniosynostosis, hypertelorism, telecanthus, broad grooved nasal tip, dental anomalies, mild syndactyly and broad thumbs, consistent with craniofrontonasal dysplasia are described in a family of four affected females over three generations. Documentation of the family is of interest because of variable clinical features and an excess of affected females. The excess of females observed in this condition is as yet unexplained, but cannot be referred simply to X-linked dominance with lethality in the male. Autosomal dominance with less frequent and less severe expression in the male is more tenable. Chromosome analysis on two affected family members revealed a fragile site at 12q13, which was also found in a phenotypically normal family member. A third affected individual did not exhibit this fragile site. Thus it appears that there is a heritable fragile 12q13 site segregating in this family separately from the gene for craniofrontonasal dysplasia.     

Clinical aspects of the MASA syndrome in a large family, including expressing females

We have evaluated, both clinically and by linkage analysis, a large family with 22 known affected males with the MASA syndrome (McKusick 303300). Clinical findings varied widely amongst the affected family members, with some appearing initially to have the MASA syndrome and others to have X-linked hydrocephalus (HSAS) (McKusick 307000). Important findings included the presence of adducted thumbs in two obligate carriers, learning problems or mild mental retardation in three females, two of whom were obligate carriers, and hydrocephalus with neonatal death in three females born to obligate carriers. X-inactivation analysis in lymphocytes from the two women with adducted thumbs revealed preferential inactivation of one X chromosome, suggesting that nonrandom X-inactivation may be responsible for clinical expression in females. The presence of HSAS in some individuals of this family and the MASA syndrome in others further supports the hypothesis that these two conditions are the result of a mutation in the same gene.     

Variable clinical presentation of cutis laxa

We present 2 families with 4 individuals suffering from congenital cutis laxa. Family A has a single affected male child with developmental delay and ligamentous laxity, making this only the second male of the total 15 patients so far reported with this particular syndrome. Family B has 3 affected males, 2 of whom have significant involvement of other systems. Only one of the 4 affected children had very obvious loose skin folds and dependency on this clinical feature alone could result in under-diagnosis of this disease. The clinical features and family pedigree information suggests recessive inheritance in Family B but the mode of inheritance in Family A is inconclusive.     

Hereditary myopathy with lactic acidosis, succinate dehydrogenase and aconitase deficiency in northern Sweden: a genealogical study.

A hereditary myopathy with lactic acidosis during physical exercise, low physical work capacity, and paroxysmal myoglobinuria (HML), called "Myopathy with deficiency of succinate dehydrogenase and aconitase" (McKusick 255125) has been described in 19 members of nine families who lived in two geographically separate areas in northern Sweden. By using the unique Swedish historical archives, including Catechetical Meeting Records from a number of northern Swedish parishes, it has been possible to trace ancestors of the nine families including all known 19 cases back in time to some key couples, who lived up to 300 years ago (that is seven to ten generations). No common single couple or common links between families in the past was found in these registers as a support for a single or several mutations that had developed far back in time. The mode of inheritance in this family is most likely autosomal recessive. This material will be used for the chromosomal localisation of the gene.