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Robertsonian (15q;15q) translocation in a child with Angelman syndrome: evidence of uniparental disomy.

A balanced Robertsonian translocation 45,XY,t(15q15q) was detected in a patient with mental retardation, microcephaly, and hypertonia. Deletion of the 15q11q13 region was unlikely based on fluorescence in situ hybridization studies that revealed hybridization of appropriate DNA probes to both arms of the Robertsonian chromosome. Inheritance of alleles from 13 highly polymorphic DNA markers on chromosome 15 showed paternal uniparental isodisomy. The clinical, cytogenetic, and molecular results are consistent with a diagnosis of Angelman syndrome.

Angelman Syndrome↗

Craniofacial anomalies and malformations in respiratory chain deficiency.

We report on facial anomalies including round face, high forehead, flat philtrum, apparently low-set ears, and short neck in 4 unrelated patients with mitochondrial respiratory enzyme deficiency. Pre- and postnatal growth retardation with microcephaly, brachydactyly, and hypoplasia of distal and middle phalanges was present in all 4 cases. The diagnosis of respiratory chain deficiency was confirmed by enzymatic and molecular studies. The combination of facial anomalies, prenatal growth failure, and malformations is suggestive of antenatal expression of the disease, and raises the question of the part that respiratory chain deficiencies play in human malformations.

Abnormalities, Multiple↗

Chromosome instability with bleomycin and X-ray hypersensitivity in a boy with Nijmegen breakage syndrome.

We report on a Mexican boy with microcephaly, short stature, and a high frequency of chromosome aberrations with rearrangements involving chromosomes 7 and 14, typical of ataxia telangiectasia (AT) patients. He had neither ataxia nor telangiectasia, and his immunological status and serum alpha feto protein (AFP) level were normal. Bleomycin hypersensitivity, which has been demon-strated in AT patients, was tested in the patient using AT and normal subjects for comparison. The frequency of spontaneously occurring chromosome aberrations in lymphocyte cultures was significantly higher in the patient and the AT patient than in the normal subject. Four cells from the patient showed structural rearrangements involving chromosomes 7 or 14, with breakpoints typical for AT. When exposed to 5.0 micrograms bleomycin, the lymphocytes from the AT patient showed the highest sensitivity to this agent; our patient had an intermediate sensitivity. In both patients several rearrangements involving chromosomes 7 and 14 were scored, while none were observed in the normal subject. A colony survival assay (CSA) [Huo et al., 1994: Cancer Res 54:2544-2547], using a lymphoblastoid cell line (LCL) derived from our patient, showed a survival fraction (SF) of 7%, which is in the same range as in AT patients. The clinical picture, together with the cytogenetic and radiosensitivity results, suggests that our patient fits the variable spectrum of Nijmegen breakage syndrome.

Abnormalities, Multiple↗

Manifestations in institutionalised adults with Angelman syndrome due to deletion.

Undiagnosed institutionalised patients were reviewed in an attempt to identify those with Angelman syndrome (AS). The aim was to test these patients for deletion of chromosome 15(q11-13) and to describe the adult phenotype. The selection criteria included severe intellectual disability, ataxic or hypermotoric limb movements, lack of speech, a "happy" demeanour, epilepsy, and facial appearance consistent with the diagnosis. Patients were examined, medical records perused, and patients' doctors contacted as required. Genetic tests performed included routine cytogenetics, DNA methylation analysis (with probe PW71B), and fluorescence in situ hybridisation (with probes D15S10, GABRbeta3, or SNRPN). A deletion in the AS region was detected in 11 patients (9 males and 2 females) of 22 tested. The mean age at last review (March 1996) was 31.5 years (range 24 to 36 years). Clinical assessment documented findings of large mouth and jaw with deep set eyes, and microcephaly in nine patients (two having a large head size for height). No patient was hypopigmented; 1/11 patients was fair. Outbursts of laughter occurred in all patients but infrequently in 7/11 (64%) and a constant happy demeanour was present in 5/11 (46%). All had epilepsy, with improvement in 5/11 (46%), no change in 4 (36%), and deterioration in 2 (18%). The EEG was abnormal in 10/10 patients. Ocular abnormalities were reported in 3/8 patients (37.5%) and 4/11 (36%) had developed kyphosis. Two had never walked. All nine who walked were ataxic with an awkward, clumsy, heavy, and/or lilting gait. No patient had a single word of speech but one patient could use sign language for two needs (food and drink). Our data support the concept that AS resulting from deletion is a severe neurological syndrome in adulthood. The diagnosis in adults may not be straightforward as some manifestations change with age. Kyphosis and keratoconus are two problems of older patients.

Abnormalities, Multiple↗

Maternal balanced translocation leading to partial duplication of 4q and partial deletion of 1p in a son: cytogenetic and FISH studies using band-specific painting probes generated by chromosome microdissection.

A 9-month-old boy with pre- and post-natal growth retardation, microcephaly, plagiocephaly, and several minor anomalies had the initial karyotype: 46,XY,der(1)t(1;?) (p36.1;?). Further analysis showed that the der(1) was derived from an unfavorable segregation of a maternal complex chromosome rearrangement, i.e., 46,XX,der(1)t(1;?) (p36.1;?), der(4)t(4;?)(q?;?). Whole chromosome fluorescence in situ hybridization (FISH) and chromosome microdissection were used to clarify the maternal karyotype as: 46,XX,der(1)t(1;4)(4qter-->4q33::1p36.13-->1qter),der( 4)t(1;4)inv(4)(4pter-->4q31.3::1p36.33-->1p36.13::4q33 -->4q31.3::1p36.33-->1pter). Therefore, the karyotype of the boy actually was 46,XY,der(1)t(1;4) (p36.13;q33). Clinical comparison of the patient's clinical findings showed similarities to individuals with partial del(1p) and dup(4q). To our knowledge the above cytogenetic abnormalities have not been described previously. This case further demonstrates the advantages of chromosome microdissection and FISH in the identification of anomalous chromosome regions and breakpoints.

Abnormalities, Multiple↗

Rubinstein-Taybi syndrome: objective evaluation of craniofacial structure.

Rubinstein-Taybi syndrome (RTS) is a rare multiple congenital anomaly syndrome comprising mental and growth retardation, broad thumbs and great toes, and an unusual face. The classical facial appearance is well-established, striking and easy to recognize. It includes downslant of the palpebral fissures, epicanthic folds, ptosis, strabismus, highly arched palate, simple ears and a small mouth. The nose is distinctive with a beaked appearance, broad fleshy bridge, deviated septum and short low columella. Previous studies have documented considerable change in this facial phenotype with time. In this study, we evaluated 31 individuals with RTS from Great Britain and The Netherlands. They range in age from 1 to 39 years. Detailed craniofacial measurements were obtained on each subject and composite pattern profiles were compiled. There was remarkable concordance of patterns at all ages from infancy to adulthood. Microcephaly was present consistently. The head was relatively round with head width equal to head length. There was narrowness at the skull base with relative broadening of the minimal frontal diameter and lower facial width. The mouth was small and ears were broad and short. Eyes were wide-spaced in comparison to upper facial width and head circumference. The child under 4 years demonstrated some differences. Width and depth of the upper face exceeded that of the lower face, whereas with increasing age, mandibular dimensions were closer to normal than their maxillary counterparts. Despite these differences, the similarity of the profiles of all age groups seems to belie the phenotypic changes that can be appreciated subjectively. This suggests that major components of the change in appearance are those which have not been assessed in this study, such as palpebral fissure slant, deviation of the nasal bridge, presence of epicanthal folds or ptosis; or for which norms are not available, for example, beaking of the nose, and low nasal septum.

Adolescent↗

Microphthalmia, marked short stature, hearing loss, and developmental delay: extension of the phenotype of GOMBO syndrome?

An adult male with microphthalmia, severe developmental delay, conductive hearing loss, marked short stature of prenatal onset, and radiographic skeletal changes is described. A review of the literature, focusing on his major findings, suggests that his manifestations might be an extension of the phenotype of GOMBO (growth retardation, ocular abnormalities, microcephaly, brachydactyly, oligophrenia) syndrome.

Abnormalities, Multiple↗

Evaluation of mental retardation: recommendations of a Consensus Conference: American College of Medical Genetics.

A Consensus Conference utilizing available literature and expert opinion sponsored by the American College of Medical Genetics in October 1995 evaluated the rational approach to the individual with mental retardation. Although no uniform protocol replaces individual clinician judgement, the consensus recommendations were as follows: 1. The individual with mental retardation, the family, and medical care providers benefit from a focused clinical and laboratory evaluation aimed at establishing causation and in providing counseling, prognosis, recurrence risks, and guidelines for management. 2. Essential elements of the evaluation include a three-generation pedigree: pre-, peri-, and post-natal history, complete physical examination focused on the presence of minor anomalies, neurologic examination, and assessment of the behavioral phenotype. 3. Selective laboratory testing should, in most patients, include a banded karyotype. Fragile X testing should be strongly considered in both males and females with unexplained mental retardation, especially in the presence of a positive family history, a consistent physical and behavioral phenotype and absence of major structural abnormalities. Metabolic testing should be initialed in the presence of suggestive clinical and physical findings. Neuroimaging should be considered in patients without a known diagnosis especially in the presence of neurologic symptoms, cranial contour abnormalities, microcephaly, or macrocephaly. In most situations MRI is the testing modality of choice. 4. Sequential evaluation of the patient, occasionally over several years, is often necessary for diagnosis, allowing for delineation of the physical and behavioral phenotype, a logical approach to ancillary testing and appropriate prognostic and reproductive counseling.

Diagnosis, Differential↗

Private multiple congenital anomaly syndromes may result from unbalanced subtle translocations: t(2q;4p) explains the Lambotte syndrome.

In 1990, Lambotte syndrome was reported as an apparently autosomal recessive multiple congenital anomaly/mental retardation (MCA/MR) syndrome observed in 4 of 12 sibs from a probably consanguineous mating [Verloes et al., Am J Med Genet 1990; 37:119-123]. Major manifestations included intrauterine growth retardation (IUGR), microcephaly, large soft pinnae, hypertelorism, beaked nose, and extremely severe neurologic impairment, with holoprosencephaly in one instance. After the observation of a further affected child born of one unaffected sister, in situ hybridization analysis and chromosome painting techniques demonstrated a subtle t(2;4)(q37.1; p16.2) translocation in the mother, suggesting a combination of 2q/4p trisomy/monosomy in all of the affected children of the family. Many private sporadic or recurrent MCA/MR syndromes maybe due to similar symmetric translocations, undetectable by conventional banding techniques.

Abnormalities, Multiple↗

Chromosome 18q paracentric inversion in a family with mental retardation and hearing loss.

We report on a mother and child with a paracentric inversion of the long arm of chromosome 18: 46,XX,inv(18)(q21.1q23). The child had findings in common with those seen in 18q- syndrome including: microcephaly, epicanthal folds, midface hypoplasia, and abnormally modeled ears, dermatoglyphic whorls on fingertips, clubfeet, hearing loss, and developmental delay. The mother and several maternal relatives had mild mental retardation and hearing loss. Magnetic resonance imaging of the child's brain showed abnormal myelination. Molecular studies including PCR-based markers for the MBP locus and fluorescent in situ hybridization with a P1 genomic clone on mother and child demonstrated only one copy of the MBP locus (18q23) with the deletion extending beyond the MBP locus. Therefore, the deletion in the MBP region may account for the abnormal myelination seen in the patient. The other clinical findings, including mental retardation and hearing loss in this family, may reflect disruption of distal or proximal genes within the deleted MBP region or at the more proximal breakpoint 18q21.1, and may represent a contiguous gene syndrome. Further study of this family may help define those genes functioning in the MBP region that contribute to the phenotype of 18q- syndrome.

Adult↗

Mosaic variegated aneuploidy with multiple congenital abnormalities: homozygosity for total premature chromatid separation trait.

Separation of chromatids of all mitotic chromosomes, here called total premature chromatid separation (total PCS), was observed in 67 to 87.5% of repeated cultures of peripheral blood lymphocytes from two unrelated infants. Also noted was a variety of mosaic aneuploidies, especially trisomies, double trisomies, and monosomies, to be called mosaic variegated aneuploidy. The infants both showed severe pre- and postnatal growth retardation, profound developmental retardation, uncontrollable seizures, severe microcephaly, hypoplasia of the brain, Dandy-Walker anomaly, abnormal facial appearance, and bilateral cataract. Patient 1, a girl, in addition had a cleft palate, multiple renal cysts, and Wilms tumor of the left kidney. Whereas patient 2, a boy, had ambiguous external genitalia. They both died within 2 years of age. In the two families of the infants, their parents and three other members showed 2.5 to 47% lymphocytes with total PCS but without mosaic variegated aneuploidy or phenotypic abnormalities. Another 10 relatives studied showed 0 to 1% cells with total PCS and so were judged negative for the total PCS trait. It was deduced that the total PCS trait in the two families was transmitted in an autosomal-dominant fashion, and the two affected infants were homozygous for the trait.

Abnormalities, Multiple↗

Variant RSH/Smith-Lemli-Opitz syndrome with atypical sterol metabolism.

The RSH/Smith-Lemli-Opitz syndrome (RSH/SLOS) is an autosomal recessive malformation syndrome comprising microcephaly, developmental and growth retardation, characteristic facial anomalies, midline cleft palate, and genital and limb anomalies. Recently, biochemical evidence of an inborn error of cholesterol biosynthesis at the level of 7-dehydrocholesterol (7DHC) reductase was reported in children and adults with RSH/SLOS. We report on two sibs with a variant form of RSH/SLOS whose sterol metabolism in cultured lymphoblasts is abnormal but differs from that of patients with classical RSH/SLOS. The children have relatively mild physical and developmental abnormalities, but a phenotype still consistent with the diagnosis of RSH/SLOS. Their plasma cholesterol levels are only mildly depressed, and they have less markedly increased plasma levels of 7DHC than most patients with classical RSH/SLOS. Cultured lymphoblasts from our patients accumulated 7DHC to the same degree as classical RSH/SLOS lymphoblast when grown with cholesterol-depleted fetal calf serum. However, unlike other RSH/SLOS cells, the increase in cellular 7DHC levels was not suppressed when the cells were grown in the presence of cholesterol from untreated fetal calf serum. The parents' sterol metabolism was also strikingly abnormal in that the levels of 7DHC in their lymphoblasts were markedly elevated compared with those of lymphoblasts from other RSH/SLOS parents. Our findings suggest that these mildly affected RSH/SLOS sibs may have a genetic disorder of sterol metabolism that is related to but biochemically different from classical RSH/SLOS, possibly one affecting intracellular transport of sterols.

Cholesterol↗

Child with mosaic variegated aneuploidy and embryonal rhabdomyosarcoma.

We report on a 7-year-old boy with mosaic variegated aneuploidy (MVA) who developed embryonal rhabdomyosarcoma of the soft palate. This patient is the 11th case report of MVA and represents further documentation of the true existence of this rare mitotic mutant. Clinical findings share similarities to those previously described patients including microcephaly and growth retardation as the two most common abnormalities. Notably, mental retardation is not universally present. Results of serial cytogenetic analyses performed on somatic and neoplastic tissues are reviewed and compared with those of other previously reported patients. We postulate that mosaic variegated aneuploidy is causally related to the development of rhabdomyosarcoma in our patient. This is the first report of a patient with MVA who developed cancer and suggests that these patients may be at risk for malignancy and require long-term follow-up and cancer surveillance.

Adolescent↗

Miller-Dieker syndrome and trisomy 5p in a child carrying a derivative chromosome with a microdeletion in 17p13.3 telomeric to the LIS1 and the D17S379 loci.

Trisomy 5p and Miller-Dieker syndromes frequently are the result of unbalanced segregations of reciprocal translocations of chromosomes 5 and 17 with other autosomes. The critical regions for the expression of the mentioned syndromes have been mapped to 5p13-->pter, and 17p13.3-->pter. In this report, we describe an 8-year-old girl with mental retardation, postnatal growth deficiency, generalized muscular hypotonia, seizures, microcephaly, cortical atrophy, partial agenesis of corpus callosum, cerebral ventriculomegaly, facial anomalies, patent ductus arteriosus, pectus excavatum, long fingers, and bilateral talipes equinovarus caused by the presence of a 46,XX,der(17)t(5;17)(p13.1;p13.3)mat chromosome complement. Cytogenetic studies of the family confirmed a balanced reciprocal translocation (5;17)(p13.1;p13.3) in her mother, maternal grandfather, maternal aunt, and a female first cousin. Fluorescence in situ hybridization studies on the mother and the proposita using three probes, which map to distal 17p, confirmed the reciprocal translocation in the mother and a terminal deletion in the patient, which resulted in the retention of LIS1 and D17S379 loci and deletion of the 17p telomere. These findings and the phenotype of the proposita, strongly suggest that genes telomeric to LIS1 and locus D17S379 are involved in many clinical findings, including the minor facial anomalies of the Miller-Dieker syndrome.

1-Alkyl-2-acetylglycerophosphocholine Esterase↗

Neocentromere at 13q32 in one of two stable markers derived from a 13q21 break.

A 10-month-old girl with psychomotor retardation, microcephaly, bilateral microphthalmia, and postaxial polydactyly of the feet was karyotyped using banding techniques and (single or dual color) fluorescent in situ hybridization (FISH) with four probes: D13Z1/D21Z1, pancentromeric, pantelomeric, and a mix of 13q subtelomeric and 13/21 alphoid repeats. She was found to have a 47-chromosome karyotype in which a normal 13 was replaced by two stable markers derived from a breakpoint at 13q21.1, namely a del(13)(q21.1) and an isofragment(13) (qter-->q21.1::q21.1-->qter). The latter had a single C-negative but Cd-positive primary constriction at 13q32 which, however, was not obvious in about 12% of the cells. FISH studies showed that the small 13q- had the 13-centromere and a 13q telomere (as shown for a specific 13q subtelomeric signal) onto the broken end whereas the isofragment lacked alphoid signals but had 13q subtelomeric sequences on both ends. Parental karyotypes were normal. The patient's rearrangement represents the eighth chromosome-13-derived marker with a nonalphoid neocentromere located at 13q. All in all, such neocentromeres have been described in 29 markers derived from chromosomes 2, 3, 8-11, 13-15, 20, and Y, and plausibly result from the epigenetic activation of a latent centromere, which may even be a telomere with neocentric activity. The 13q telomere found in the del(13q) was probably captured from the homologous chromosome.

Abnormalities, Multiple↗

Albinism and agenesis of the corpus callosum with profound developmental delay: Vici syndrome, evidence for autosomal recessive inheritance.

We report on two sibs and two other unrelated patients with agenesis of corpus callosum, oculocutaneous albinism, repeated infections, and cardiomyopathy. All manifested postnatal growth retardation, microcephaly, and profound developmental delay. Additional central nervous system anomalies present in at least one patient included hypoplasia of the cerebellar vermis, white matter neuronal heterotopia, or bilateral schizencephaly. Repeated viral, bacterial, and fungal infections were consistent with a primary immunodeficiency. However, immunological studies showed variable, nonspecific findings. Cardiomyopathy with progressive heart failure or infection led to death before age 2 years in three of the patients. This syndrome was first described by Vici et al. [1988: Am. J. Med. Genet. 29:1-8]. The four patients reported herein confirm this unique disorder. Affected sibs of both sexes born to unaffected parents provide evidence for autosomal recessive inheritance.

Adult↗

Osteosclerosis, hypoplastic nose, and proptosis (Raine syndrome): further delineation.

We describe a newborn girl with a lethal sclerosing bone dysplasia leading to prenatal skeletal alterations and microcephaly, proptosis, hypoplastic nose and midface, small jaw, cleft palate, hypertrophied gums, intracranial calcifications, and generalized osteosclerosis. There is a remarkable similarity between our patient and six previously reported infants subsequently categorized as having a distinct entity: Raine syndrome. Autosomal recessive inheritance is postulated based on parental consanguinity in several of the previous cases and in our patient.

Brain Diseases↗

Detection of a cryptic translocation t(13;20)(q34;p13) in an unexplained case of MCA/MR: value of FISH over high resolution banding.

Cryptic unbalanced chromosome rearrangements in the telomeric bands of the chromosomes may constitute a significant cause of unexplained mental retardation with or without congenital anomalies. We report on a boy with a terminal deletion of the long arm of chromosome 13, combined with a partial duplication of the short arm of chromosome 20, owing to a cryptic balanced translocation in his father. The karyotype of the father was 46XY,t(13;20)(q34;p13). The propositus presented with severe mental and growth retardation, microcephaly, facial anomalies including ptosis of the right upper eyelid, a high nasal bridge, small palpebral fissures, and bilateral epicanthus, hypospadias, and scoliosis. A younger brother died at birth and had a low birth weight, hypospadias, and a horseshoe kidney. Repeated chromosome analyses with high resolution banding in the propositus and his parents were apparently normal. Chromosome painting eventually disclosed the cryptic translocation in the father with unbalanced karyotype in the propositus. The importance of additional FISH analysis in patients with unexplained mental retardation, physical anomalies, and apparently normal chromosomes is emphasized.

Abnormalities, Multiple↗