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We report on 3 girls and one boy from 2 sibships with Fraser syndrome and renal agenesis. They were born to consanguineous parents, which supports an autosomal recessive mode of inheritance.
We report on a term stillborn female infant with multiple congenital anomalies (MCA) which have not previously been reported as occurring together. The malformations include a first and second branchial arch sequence, ectopia cordis with congenital heart defect, caudal "regression" sequence with absent sacrum and hypoplastic right femur, ectrodactyly, left radial abnormality, islet cell hyperplasia, and skin lesions. The pregnancy was complicated by abdominal cramping with exercise, heavy vaginal bleeding, maternal obesity, and a normal screening glucose tolerance test at 6 months gestation. The infant was born to 20-year-old G3P1SAB2 Mexican-American parents who are first cousins. There was strong maternal family history of adult-onset diabetes. The malformations have some findings in common with those seen in infants of diabetic mothers. Structural defects similar to, but not inclusive of, those in our infant have been reported in 2 sibs born to a prediabetic mother with a first cousin marriage as well as in focal dermal hypoplasia. Parental consanguinity is suggestive of an autosomal recessive disorder. Alternatively, it may represent a combined multifactorial effect making the conceptus more sensitive to metabolic teratogens and thus placing it at increased risk for disruption of normal development.
We report on 2 sibs with manifestations of the Kenny-Caffey syndrome born to normal, consanguineous parents. Clinical manifestations included dwarfism, internal cortical thickening and medullary stenosis of tubular bones, poorly ossified skull bones, and hypocalcemia. The younger of the two died during a tonic convulsion. The older had neonatal hypoparathyroidism and is now a short intelligent, 1-year-old child. This family gives new support to the existence of an autosomal recessive variant of the syndrome.
We report on an infant (born to consanguineous parents) with an unusual face, microphthalmia, cleft palate, dextrocardia, choreoathetosis, and mental retardation. This child has many traits in common with an infant recently described by Aughton [1990] as a probable new syndrome.
We report on a Brazilian girl, born to consanguineous parents and presenting a multiple congenital anomaly (MCA) syndrome, mainly characterized by blepharophimosis, cleft palate, and arachnodactyly. The clinical aspects involving this patient suggest an apparently undescribed "new" autosomal recessive syndrome.
We report on a Brazilian boy (F = 1/16) born to consanguineous parents and presenting with typical Aarskog syndrome. Genetic aspects and phenotypic manifestations of this patient are compared with those of the (X-linked) Aarskog syndrome and with the autosomal recessive faciodigitogenital syndrome.
We report on a sibship from a consanguineous couple consisting of one boy with anophthalmia, one boy with buphthalmos and multiple congenital skeletal, muscle, and cardiac abnormalities, and a stillborn girl with anophthalmia and cardiac and skeletal abnormalities. A possible new syndrome of autosomal recessive inheritance and variable expressivity is discussed, comparing this report with others.
Two cases of Hirschsprung disease associated with infantile osteopetrosis are reported in 2 consanguineous families living in the same area. Both died early.
We describe two mentally retarded brothers with craniofacial anomalies, polydactyly, and other clinical manifestations compatible with the acrocallosal syndrome (ACS). These are the first black patients from Africa with this diagnosis. They are also the fourth set of sibs described with ACS, and together with the parental consanguinity documented in this family, confirm autosomal recessive inheritance of this syndrome. The clinical manifestations in our patients confirm the intrafamilial variability of the syndrome. Postnatal onset of growth retardation is proposed as an additional manifestation of ACS.
Knobloch syndrome is a rare genetic disorder characterized by high myopia, vitreoretinal degeneration with retinal detachment and occipital cephalocele. The inheritance has been described as autosomal recessive (AR) but in addition to the original report with 5 affected patients [Knobloch and Layer, 1971] only one other family with 2 affected sibs has been described [Czeizel et al., 1992]. We have studied a large consanguineous kindred in which there are 12 patients with severe ocular alterations associated with a congenital occipital encephalocele, compatible with the diagnosis of Knobloch syndrome. CT scan and MRI performed in one of the patients, allowed a better understanding of the cranial and ocular alterations in this syndrome. The pattern of occurrence in this highly inbred family clearly confirms autosomal recessive inheritance of Knobloch syndrome.
We report on a Brazilian girl born to consanguineous parents and presenting with craniosynostosis, telecanthus, blepharophimosis, blepharoptosis, epicanthus inversus, cleft lip and palate, skeletal defects, and hearing loss. This combination of anomalies appears to constitute the Michels syndrome.
We report a patient with a syndrome of MR/MCA who was the product of a highly consanguineous family. The patient was the result of a union between a man and his daughter. The daughter was in turn the product of a mating between this same man and his mother. Major findings include: severe psychomotor and mental retardation, microcephaly with cerebral dysgenesis and cerebellar hypoplasia, early hypotonia and late hypertonia, short stature, early swallowing incoordination with aspiration pneumonias, distinctive face with striking hypertelorism, hypospadias, cryptorchidism, overlapping fingers, and rocker-bottom feet. Chromosome and metabolic studies were normal. The severity and uniqueness of his phenotype suggests a new, probably private, autosomal recessive disorder due to homozygosity for one or more loci.
Cleft lip with or without cleft palate (CL/P) is a common congenital anomaly, with birth prevalence ranging from 1/500 to 1/1,000. A number of genetic loci have shown positive linkage or association results in European Caucasian populations. The purpose of the current study was to assess whether any of those loci have positive results in Turkish Caucasian CL/P families, and to perform a 10 cM genome scan to identify other regions potentially containing cleft susceptibility loci. Eighteen affected individuals with consanguineous parents were identified as part of our on-going studies of orofacial clefts in Ankara, Turkey. Genotyped were 383 genome-scan markers, and 70 additional markers, including markers in six candidate loci or regions on chromosomes 2, 4, 6, 14, 17, and 19 (TGFA, D4S175, F13A1, TGFB3, D17S250, and APOC2) that have been implicated in other studies of families with orofacial clefting. LOD scores (two point and multiple point) and family-based association statistics (TDT) were calculated between each of the markers and CL/P. For the LOD score calculations, an autosomal recessive model was assumed for the inheritance of CL/P. Of the six candidate markers, significant TDT results were obtained with TGFA (P = 0.05). The most statistically significant multipoint results from the linkage genome scan were between putative genes controlling risk of CL/P and regions on chromosomes 4, 10, 12, and 15 (maximum multipoint HLOD's of 1.25, 1.30, 2.73, and 1.28 respectively). These results demonstrate the power of small numbers of families with inbred probands to detect linkage and association.
Keutel syndrome (KS) [OMIM 245150] is a rare autosomal recessive condition, characterized by abnormal cartilage calcification. Mutations in the matrix Gla protein gene (MGP) have been previously reported in three unrelated KS families. MGP is an extracellular matrix protein that acts as a calcification inhibitor by repressing bone morphogenetic protein 2 (BMP2). Loss-of-function mutations of MGP result in abnormal calcification of the soft tissues, a cardinal feature of KS. We report the fourth MGP mutation (IVS2 + 1G > A) in a consanguineous Arab family, which results in the loss of the consensus donor splice site at the exon 2-intron 2 junction. In addition to the typical manifestations, we observed abnormalities in the white matter of the brain, optic nerve atrophy, and mid-dermal elastolysis in the affected individuals of this family. This report broadens the clinical phenotype observed in patients with KS. The effect of the IVS2 + 1G > A mutation is consistent with the previously reported loss-of-function mutations of MGP.
We report on a 24-week fetus with multiple organ anomalies secondary to biparental inheritance of an apparently balanced t(17;20) reciprocal translocation. The pregnancy was terminated following the discovery by ultrasound of an abnormal heart and micrognathia. At autopsy, the following anomalies were found: Pierre-Robin sequence, hypoplasia of the right ventricle with muscular hypertrophy, and endocardial fibroelastosis, hypoplastic lungs, dysplastic left kidney, bilateral pelvicalyceal dilatation, central nervous system periventricular heterotopias and right sided club foot. Given the endocardial fibroelastosis and cleft palate, Eastman-Bixler syndrome (Facio-cardio-renal) is a possible diagnosis. The parents were first cousins and each had an identical t(17;20)(q21.1;p11.21) translocation. The fetal karyotype was 46,XX,t(17;20)(q21.1;p11.21)mat,t(17;20)(q21.1;p11.21)pat. While there are a few reports of consanguineous families where both the mother and father had the same reciprocal translocation and offspring with unbalanced karyotypes, we were unable to find any reports of a fetus/child with double identical reciprocal translocations. We propose that although the fetus had an apparently balanced karyotype, inheriting only the translocated chromosomes led to the unmasking of a recessive syndrome. It seems most likely that a gene (or genes) was disrupted by the breaks but the parents might also be heterozygous carriers of a recessive gene mutation since the fetus must be homozygous by descent for many loci on both chromosomes 17 and 20 (as well as on other chromosomal segments). It was not possible to totally exclude segmental uniparental disomy as a cause of the anomalies as no recombinations were detected for chromosome 17. However, there is no evidence to suggest that chromosome 17 is imprinted and UPD 20 was excluded thus making an imprinting error unlikely.
The present study examined the effect of consanguineous marriage in the Arab community on reading disabilities of offspring. It examined whether the rate of reading disabilities was higher among offspring of first-cousin parents than offspring of unrelated parents; and whether reading-disabled children of first-cousin parents were more disabled in phonological awareness and phonological decoding than reading-disabled children of unrelated parents and normally reading younger children. These questions were investigated among 814 pupils of the 4th, 5th, and 6th grades, using word recognition and reading comprehension tests. Two experimental groups were chosen from this population. These were a reading-disabled group of 22 pupils who were children of first-cousin marriages and 21 pupils who were children of unrelated parents. A control group was also selected, consisting of 21 younger normally reading pupils at the same reading level. All the groups were tested on non-words, real words, phonological, orthographic and working memory measures. The results indicated that the rate of reading disabilities among children of first-cousin parents was higher than that of with children of second-cousin parents, distantly related parents, or unrelated parents. Further, no differences were found in phonological awareness and decoding between the two reading-disabled groups. Moreover, the results indicate a significant advantage of the younger normal readers over the reading-disabled children in the measures of phonological awareness, decoding, and orthographical knowledge that requires spelling. However, in reading common words and choosing words in context, the performance of the reading-disabled groups and the normally reading group were similar. It has been suggested that further research is needed to evaluate the role of intelligence, nevertheless our results provide new evidence for a genetic basis to reading disabilities.
Recently the TMPRSS3 gene, which encodes a transmembrane serine protease, was found to be responsible for two non-syndromic recessive deafness loci located on human chromosome 21q22.3, DFNB8 and DFNB10. We found evidence for linkage to the DFNB8/10 locus in two unrelated consanguineous Tunisian families segregating congenital autosomal recessive sensorineural deafness. The audiometric tests showed a loss of hearing greater than 70 dB, in all affected individuals of both families. Mutation screening of TMPRSS3 revealed two novel missense mutations, W251C and P404L, altering highly conserved amino acids of the serine protease domain. Both mutations were not found in 200 control Tunisian chromosomes. The detection of naturally-occurring TMPRSS3 missense mutations in deafness families identifies functionally important amino acids. Comparative protein modeling of the TMPRSS3 protease domain predicted that W251C might lead to a structural rearrangement affecting the active site H257 and that P404L might alter the geometry of the active site loop and therefore affect the serine protease activity.
Selective intestinal malabsorption of vitamin B(12) causing juvenile megaloblastic anemia (MGA; MIM# 261100) is a recessively inherited disorder that is believed to be rare except for notable clusters of cases in Finland, Norway, and the Eastern Mediterranean region. The disease can be caused by mutations in either the cubilin (CUBN; MGA1; MIM# 602997) or the amnionless (AMN; MIM# 605799) gene. To explain the peculiar geographical distribution, we hypothesized that mutations in one of the genes would mainly be responsible for the disease in Scandinavia, and mutations in the other gene in the Mediterranean region. We studied 42 sibships and found all cases in Finland to be due to CUBN (three different mutations) and all cases in Norway to be due to AMN (two different mutations), while in Turkey, Israel, and Saudi Arabia, there were two different AMN mutations and three different CUBN mutations. Haplotype evidence excluded both CUBN and AMN conclusively in five families and tentatively in three families, suggesting the presence of at least one more gene locus that can cause MGA. We conclude that the Scandinavian cases are typical examples of enrichment by founder effects, while in the Mediterranean region high degrees of consanguinity expose rare mutations in both genes. We suggest that in both regions, physician awareness of this disease causes it to be more readily diagnosed than elsewhere; thus, it may well be more common worldwide than previously thought.