Rendu-Osler-Weber disease: update of medical and dental considerations.

Rendu-Osler-Weber disease, also known as hereditary hemorrhagic telangiectasia (HHT), is an autosomal dominant inherited disorder characterized by an aberrant vascular development. The reported prevalence is approximately 1 per 5,000-10,000. The clinical manifestations consist of recurrent spontaneous nosebleeds, telangiectasias characteristically at the lips, oral cavity, fingers, and nose, and visceral arteriovenous malformations. Timely recognition of this syndrome makes screening for complications, preventive measurements, and genetic counselling possible. The important role of the dental profession in the recognition of this genetic disease is emphasized. In addition, a brief overview of the current literature is presented.

First case of ataxia with isolated vitamin E deficiency in the Netherlands.

We present a 36-year-old Dutch woman who suffered from a progressive form of cerebellar ataxia since school age. In her childhood she was diagnosed with Friedreich's ataxia. Genetic analysis of the frataxin gene at 34 years of age, however, had revealed no abnormal GAA triplet expansion. We identified two point mutations in the alpha-tocopherol transport protein (alpha-TTP) gene on chromosome 8q13, and the diagnosis ataxia with isolated vitamin E deficiency (AVED) was made. This report illustrates the diagnosis AVED and its relation to vitamin E metabolism. It is important to evaluate previously made diagnoses when newly developed tests can be performed for confirmation.

[A Dutch family with the hereditary periodic fever or tumour necrosis factor receptor-associated periodic syndrome (TRAPS)]. / Een nederlandse familie met het erfelijke periodieke koortssyndroom 'tumornecrosisfactor receptor-associated periodic syndrome' (TRAPS).

A 9-month-old girl was referred to the paediatrician because of fever of unknown origin. Since the age of 4 years she had recurrent attacks of muscle, joint and abdominal pain, in addition to periodic fever. Her sister and her mother had similar symptoms. The tumour necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS) was suspected and confirmed by DNA analysis. Several members of the extended family were carriers of the same mutation. In patients with recurrent unexplained periods offever in combination with myalgia, arthralgia and abdominal pain, and in whom these symptoms also occur in members of the family, TRAPS should be considered as the cause. Glucocorticosteroids and etanercept, a TNF-receptor antagonist, may be effective in the treatment of attacks. Early recognition of this syndrome is important because of the risk of developing amyloidosis.

Camurati-Engelmann disease (progressive diaphyseal dysplasia) in a Moroccan family.

We report on a 46-year-old mother of Moroccan origin, suffering mainly from painful, swollen legs, and her 26-year-old son who had experienced intense pain in his legs, without fever, for approximately 3 years. They did not have dysmorphic features or abnormal gaits. Radiographic studies of the mother revealed diaphyseal sclerosis of the tibia and spondylosis of the thoracal and lumbar vertebrae. The son had sclerosis of the diaphyses of the metacarpalia of the left hand, the femur and the fibula. The other parts of the skeleton were normal. Several osteosclerotic/hyperostotic disorders, such as melorheostosis (present mostly in sporadic cases and affecting lower extremities) and van Buchem's disease (autosomal recessive and commonly affecting the mandible) were considered as a diagnosis in the proposita. However, similar symptoms in the son of the proposita suggested an autosomal dominant inheritance pattern. This brought us to the diagnosis of progressive diaphyseal dysplasia (PDD) or Camurati-Engelmann disease (CED), an autosomal dominant disorder characterized by limb pain, reduced muscle mass, weakness, a waddling gait, progressive periosteal and endosteal sclerosis of the diaphyses of the long bones and sclerosis of the skull base. Mutations in the transforming growth factor (TGF)-beta1 gene on chromosome 19q13.1 have been reported to cause this disorder. The diagnosis of PDD/CED in this family was confirmed at the molecular level by detection of a C-to-T transition at position 466, leading to an arginine-to-cysteine amino acid change (position 156) in exon 2 of the transforming growth factor-beta1 (TGFB1) gene.

Mesomelic dysplasia, Kantaputra type: clinical report, prenatal diagnosis, no evidence for SHOX deletion/mutation.

A grandmother, her three children, and three grandchildren had skeletal abnormalities consisting of a short stature, bilateral symmetrical very short, broad and bowed radii, very short and broad ulna, mildly short lower legs, short proximal end of fibula, abnormal ankles, abnormal calcaneus and talus and pes equinus. They had normal craniofacial features, normal intelligence and normal chromosomes. We concluded that this skeletal dysplasia resembles the autosomal dominant mesomelic dysplasia, Kantaputra type. Prenatal diagnosis by ultrasound examination early in the pregnancy was possible. We found no evidence for a SHOX gene deletion or point mutation. As far as we know this is the third reported family with this skeletal dysplasia.

Association of complementation group and mutation type with clinical outcome in fanconi anemia. European Fanconi Anemia Research Group.

Fanconi anemia (FA) is a clinically and genetically heterogeneous disorder. Clinical care is complicated by variable age at onset and severity of hematologic symptoms. Recent advances in the molecular biology of FA have allowed us to investigate the relationship between FA genotype and the nature and severity of the clinical phenotype. Two hundred forty-five patients from all 7 known complementation groups (FA-A to FA-G) were studied. Mutations were detected in one of the cloned FANC genes in 169 patients; in the remainder the complementation group was assigned by cell fusion or Western blotting. A range of qualitative and quantitative clinical parameters was compared for each complementation group and for different classes of mutation. Significant phenotypic differences were found. FA-G patients had more severe cytopenia and a higher incidence of leukemia. Somatic abnormalities were less prevalent in FA-C, but more common in the rare groups FA-D, FA-E, and FA-F. In FA-A, patients homozygous for null mutations had an earlier onset of anemia and a higher incidence of leukemia than those with mutations producing an altered protein. In FA-C, there was a later age of onset of aplastic anemia and fewer somatic abnormalities in patients with the 322delG mutation, but there were more somatic abnormalities in patients with IVS4 + 4A --> T. This study indicates that FA patients with mutations in the FANCG gene and patients homozygous for null mutations in FANCA are high-risk groups with a poor hematologic outcome and should be considered as candidates both for frequent monitoring and early therapeutic intervention. (Blood. 2000;96:4064-4070)

Kabuki syndrome - report of six cases and review of the literature with emphasis on ocular features.

Six cases of Kabuki syndrome (KS) with ocular anomalies are reported and the variety of ocular features reported in the literature for this syndrome is described. Routine ocular examinations are recommended for every patient with KS because of the high proportion of ocular anomalies found in these patients, the presence of which can hamper development if not adequately addressed.

Heterogeneous spectrum of mutations in the Fanconi anaemia group A gene.

Fanconi anaemia (FA) is a genetically heterogeneous autosomal recessive disorder associated with chromosomal fragility, bone-marrow failure, congenital abnormalities and cancer. The gene for complementation group A (FAA), which accounts for 60-65% of all cases, has been cloned, and is composed of an open reading frame of 4.3 kb, which is distributed among 43 exons. We have investigated the molecular pathology of FA by screening the FAA gene for mutations in a panel of 90 patients identified by the European FA research group, EUFAR. A highly heterogeneous spectrum of mutations was identified, with 31 different mutations being detected in 34 patients. The mutations were scattered throughout the gene, and most are likely to result in the absence of the FAA protein. A surprisingly high frequency of intragenic deletions was detected, which removed between 1 and 30 exons from the gene. Most microdeletions and insertions occurred at homopolymeric tracts or direct repeats within the coding sequence. These features have not been observed in the other FA gene which has been cloned to date (FAC) and may be indicative of a higher mutation rate in FAA. This would explain why FA group A is much more common than the other complementation groups. The heterogeneity of the mutation spectrum and the frequency of intragenic deletions present a considerable challenge for the molecular diagnosis of FA. A scan of the entire coding sequence of the FAA gene may be required to detect the causative mutations, and scanning protocols will have to include methods which will detect the deletions in compound heterozygotes.

Somatic mosaicism in Fanconi anemia: molecular basis and clinical significance.

Approximately 25% of patients with Fanconi anemia (FA) have evidence of spontaneously occurring mosaicism as manifest by the presence of two subpopulations of lymphocytes, one of which is hypersensitive to cross-linking agents (e.g. mitomycin C) while the other behaves normally in response to these agents. The molecular basis of this phenotypic reversion has not yet been determined. We have investigated 8 FA patients with evidence of mosaicism. Epstein-Barr virus-immortalized lymphoblastoid cell lines established from these patients exhibited an IC50 for mitomycin C of 25 to > 100 nM compared to a mean of 2 +/- 2 nM for 20 nonmosaic FA patients and 49 +/- 11 nM for 8 healthy controls. In 3 patients who were compound heterozygotes for pathogenic FAC gene mutations the molecular mechanism of the mosaicism was investigated by haplotype analysis. The results indicated that an intragenic mitotic recombination must have occurred leading to a segregation of a wild-type allele in the reverted cells and suggested two patterns of recombination. In 1 patient a single intragenic crossover between the maternally and paternally inherited mutations occurred associated with markers located distally to the FAC gene; in the other 2 patients (sibs) the mechanism appears to have been gene conversion resulting in segregants which have lost one pathogenic mutation. In 6 of the 8 patients the hematological symptoms were relatively mild despite an age range of 9-30 years.

An atypical case of Fanconi anemia in elderly sibs.

We describe a 56-year-old woman suspected of Fanconi anemia on the basis of the following clinical findings: microcephaly, short stature, congenital deafness, and the clinical findings in her deceased brother. Hematologic or other signs of malignancy were absent. The diagnosis was confirmed by demonstrating hypersensitivity of her lymphocytes to mitomycin C (MMC). Cell fusion experiments indicated that the patient belongs to complementation group A. The patient's brother died at the age of 50 of heart and renal failure, and anemia. He had clinical findings similar to those of his sister, and a horseshoe kidney. From 31 years on he had thrombocytopenia and leucopenia. Both patients had insulin-dependent diabetes mellitus. A chromosomal breakage test carried out elsewhere before his death failed to demonstrate MMC hypersensitivity of his lymphocytes, which led to the investigation of his sister. To our knowledge these two cases are the oldest Fanconi anemia patients reported thus far.

Early prenatal diagnosis of Fanconi anaemia in a twin pregnancy, using DNA analysis.

We present a case of prenatal diagnosis of Fanconi anaemia (FA) in a pair of twins at 14 weeks of gestation. The parents had previously had two children: a healthy boy and a boy with FA belonging to complementation group C (FAC). The FA patient is a compound heterozygote, carrying a 322delG and a IVS4+4A-->T mutation in the FAC gene. Prenatal DNA analysis showed that both fetuses were heterozygous for different mutations in the FAC gene. Both fetuses had normal male karyotypes. At 36 weeks the twins were born. They did not show congenital anomalies.

Kabuki syndrome in son and low grade mosaic 45,X/46,XX in mother.

We report on a two-year-old boy with Kabuk syndrome and a normal male karyotype whose mother is a low grade mosaic 45,X/46,XX. We hypothesized that the son's Kabuki syndrome might have been caused by gonosomal uniparental (paternal) disomy DNA analysis proved this hypothesis to be incorrect. A review of twelve patients with Kabuki syndrome or Kabuki-syndrome-like features and chromosome abnormalities is presented.

Acardius acephalus after induced ovulation: a case report.

An excess of structural defects occurs in monozygotic twins compared to dizygotic twins or singletons. Among these defects the acardius acephalus or chorangiopagus parasiticus is one of the most rare and severe and a possible cause of pathology to the other twin. Ovulation induction by clomiphene causes an increased frequency of multiple gestation and possibly of monozygotic multiple pregnancy. In the present report, we describe a prenatally diagnosed and autopsied case of acardius acephalus from a pregnancy established after ovulation induction by clomiphene. Approximately 1.4% of pregnancies are accomplished after use of ovulation inducing medication in the Netherlands. A possible etiological role of clomiphene justifies close monitoring of future cases.

Clinical features of an affected father and daughter with Ehlers-Danlos syndrome type VIIB.

The clinical features of a father and daughter with Ehlers-Danlos syndrome type VIIB are described. They included severe cutaneous fragility, generalized joint laxity, kyphoscoliosis and a slightly dysmorphic face in the adult, with generalized joint laxity and congenital hip dislocation, hyperextensible skin and easy bruising in the child. The dermis contained slightly distorted collagen fibrils when examined by electron microscopy. The disorder is caused by G to A point mutation in the first base of intervening sequence 6 with resultant mis-splicing.

Joubert syndrome: a clinical and pathological description of an affected male and a female fetus from the same sibship.

A severely retarded male child with Joubert syndrome is described. He had severe neurological anomalies including Dandy-Walker malformation, hypoplasia of the corpus callosum, occipital meningo-encephalocele, and bilateral coloboma of the optic nerve with retrobulbar cystic mass. This is the first male described so far with both coloboma and other midline defects. A detailed autopsy on an affected female fetus from the mother's second pregnancy is presented.

Tuberous sclerosis. Diagnostic problems in a family.

This paper describes a family in which the first child, a girl born in 1988, has tuberous sclerosis (TS). The 28-year-old mother had no symptoms of TS but at ocular examination she presented with progressively increasing prominence of the optic nerve heads with a few glistening spots due to deep and superficial drusen, and tilted disks. Visual fields showed enlarged blind spots. Fluorescein angiography showed lobular drusen of the optic nerve heads. The ERG showed an absent B-wave. The family history was negative for TS. The question arises whether these ocular findings have to be interpreted as part of the syndrome of TS. In that case the recurrence risk for the disease is 50% for each next child. Assuming a spontaneous mutation in the first child, however, the risk can be nearly neglected. Until the genetic defect in TS is found, these problems in genetic counselling of parents with a child with TS will remain unsolved. Prenatal diagnosis by DNA-analysis is not yet possible; however a few cases of TS have been diagnosed prenatally by fetal ultrasonography of the heart, as was the case in the affected child.

Van der Woude syndrome--recognition of lesser expressions: case report.

A family with Van der Woude syndrome is described. The proband, whose mother and brother had facial clefting, showed inconspicuous abnormalities of the lower lip and a bifid uvula. Lesser expressions of Van der Woude syndrome are common and should be actively looked for in counseling families about cleft lip or cleft lip and palate.

Prenatal ultrasound diagnosis of the Holt-Oram syndrome.

The Holt-Oram syndrome is an autosomal dominant disorder consisting of a congenital heart defect in combination with characteristic upper limb abnormalities. This report presents the ultrasonographic follow-up of two fetuses at risk for the Holt-Oram syndrome. In the first fetus, the existence of Holt-Oram syndrome was suspected at 22 weeks of gestation; a ventricular septal defect, an atrial septal defect, and a minor skeletal defect were found. In the second fetus, no structural abnormalities were discovered until the 30th week, when a small atrial septal defect was detected. In both pregnancies, it was possible to exclude early in gestation the more severe forms of the Holt-Oram syndrome.