Blaschkolinear malformation syndrome in complex trisomy-7 mosaicism

Results of repeated peripheral blood chromosome studies were normal in a boy with intrauterine growth retardation, short stature, moderate mental retardation, and multiple minor anomalies. At age 9 years it was recognized that the swirls of pigmentation/depigmentation on his trunk, linear streaks on his limbs, and body asymmetry were suggestive of chromosomal mosaicism. Four skin biopsies were obtained under anesthesia during a dental procedure. All showed mosaicism for a normal cell line, a line with an extra chromosome 7, and a cell line with an extra small ring. In one biopsy, there was a fourth cell line with an extra chromosome 7 and the ring. Fluorescence in situ hybridization (FISH) with a chromosome 7 paint confirmed trisomy 7 and the chromosome 7 derivation of the ring. This young man's intra-uterine and postnatal growth retardation is an aneuploidy effect, whereas his asymmetry reflects a mosaicism effect that should have aroused suspicion of tissue-limited mosaicism before the development of obvious Blaschkolinear skin pigmentary dysplasia.     

45,X/46,X,+r(X) can have a distinct phenotype different from Ullrich-Turner syndrome.

We present a patient with 45,X/46,X,+r(X) mosaicism and lack of inactivation of either the normal or the ring X in the 46,X,+r(X) cells. The patient has mental retardation, syndactyly, minor facial anomalies, and a congenital heart defect. Although most patients with 45,X/46,X,+r(X) have the Ullrich-Turner syndrome, 2 previously described patients with this karyotype also had a distinct phenotype consisting of severe mental retardation, syndactyly, and abnormal face. The unusually severe phenotype in these patients was thought to be due to lack of X-inactivation of the ring X chromosome. The findings in our patient support this hypothesis.     

45,X/46,X, + r(X) can have a distinct phenotype different from Ullrich-Turner syndrome

We present a patient with 45,X/46,X, + r(X) mosaicism and lack of inactivation of either the normal or the ring X in the 46,X, + r(X) cells. The patient has mental retardation, syndactyly, minor facial anomalies, and a congenital heart defect. Although most patients with 45,X/46,X, + r(X) have the Ullrich-Turner syndrome, 2 previously described patients with this karyotype also had a distinct phenotype consisting of severe mental retardation, syndactyly, and abnormal face. The unusually severe phenotype in these patients was thought to be due to lack of X-inactivation of the ring X chromosome. The findings in our patient support this hypothesis.     

"Essentially pure" partial trisomy (6)(p23-->pter) in two brothers due to maternal t(6;17)(p23;p13.3).

We report on two brothers with low birth weight, growth retardation, microcephaly, minor facial anomalies, mental retardation, and trisomy (6)(p23-->pter) due to a maternal t(6;17)(p23;p13.3). As demonstrated by fluorescent in situ hybridisation (FISH) with the Miller-Dieker cosmid probe (D17S379) and with a subtelomeric probe (D17S34) the additional deletion on 17p13 is very small, and therefore, the phenotype of these two boys is most likely the result of essentially pure partial trisomy 6p. Comparison of the clinical findings with those of ten cases from the literature of dup(6p) with a breakpoint in or more distal to 6p23 allows delineation of a specific phenotype of dup(6)(p23-->pter) characterized by low birth weight, growth retardation, microcephaly, and blepharophimosis, blepharoptosis, microstomia, and abnormal ears.     

Preferential involvement of the short arm in chromosome 8-derived supernumerary markers and ring as identified by chromosome arm painting

We report on the use of fluorescence in situ hybridization (FISH) with specific chromosome 8 arm painting to characterize further small supernumerary chromosome 8-derived markers/rings (SMC/SRC) identified in three patients. Two patients (patients 1 and 2) who carried the marker (SMC) were evaluated because of mental retardation and minor facial anomalies. The patient (patient 3) who carried the ring (SRC) had ventriculomegaly. Parental blood chromosomes of patients 2 and 3 were normal and unavailable on patient 1. The identification of the SMC/SRC was first characterized by FISH specific alpha-repeat centromeric probes, second by FISH whole chromosome painting (WCP), and finally by FISH chromosome arm painting (CAP). The latter showed involvement of only the short arm of chromosome 8 in all three SMC/SRC cases, suggesting a U-type exchange mechanism.     

Ring 2 chromosome: ten-year follow-up report.

C?té et al. [1981: Ann Genet 24:231-235] suggested that ring chromosomes without a preceding deletion share a common pattern of phenotypic anomalies, independent of what chromosome is involved. The phenotype of such a "general ring syndrome" consists of growth failure without malformations, few or no minor anomalies, and mild-to-moderate mental retardation. We report on a patient with a ring 2 chromosome with features suggestive of Silver-Russell syndrome at birth and striking postnatal growth retardation with minor intellectual involvement supporting C?té's suggestion. This would be the ninth case of ring 2 chromosome published; the patient is the longest reported survivor, with a 10-year follow-up.     

“Essentially pure” partial trisomy (6)(p23→pter) in two brothers due to maternal t(6;17)(p23;p13.3)

We report on two brothers with low birth weight, growth retardation, microcephaly, minor facial anomalies, mental retardation, and trisomy (6)(p23→pter) due to a maternal t(6;17)(p23;p13.3). As demonstrated by fluorescent in situ hybridisation (FISH) with the Miller-Dieker cosmid probe (D17S379) and with a subtelomeric probe (D17S34) the additional deletion on 17p13 is very small, and therefore, the phenotype of these two boys is most likely the result of essentially pure partial trisomy 6p. Comparison of the clinical findings with those of ten cases from the literature of dup(6p) with a breakpoint in or more distal to 6p23 allows delineation of a specific phenotype of dup(6)(p23→pter) characterized by low birth weight, growth retardation, microcephaly, and blepharophimosis, blepharoptosis, microstomia, and abnormal ears. Am. J. Med. Genet. 85:389–394, 1999. © 1999 Wiley-Liss, Inc.     

Identification of supernumerary ring chromosome 1 mosaicism using fluorescence in situ hybridization

We report on a 15-year-old black boy with severe mental retardation, multiple congenital anomalies, and a supernumerary ring chromosome mosaicism. Fluorescence in situ hybridization with a chromosome 1 painting probe (pBS1) identified the ring as derived from chromosome 1. The karyotype was 46,XY/47,XY,+r(1)(p13q23). A review showed 8 reports of ring chromosome 1. In 5 cases, the patients had a non-supernumerary ring chromosome 1 resulting in partial monosomies of the short and/or long arm of chromosome 1. In 3 cases, the presence of a supernumerary ring resulted in partial trisomy of different segments of chromosome 1. In one of these cases the supernumerary ring was composed primarily of the centromere and the heterochromatic region of chromosome 1, resulting in normal phenotype. Our patient represents the third report of a supernumerary ring chromosome 1 resulting in abnormal phenotype. © 1995 Wiley-Liss, Inc.     

Familial complex 3q;10q rearrangement unraveled by subtelomeric FISH analysis

In recent years, subtelomeric rearrangements have been identified as a major cause of multiple congenital anomalies/mental retardation syndromes. Currently, more than 2,500 individuals with mental retardation have been tested and reported in whom subtelomeric rearrangements were detected ranging from 2% to 29%. Therefore, subtelomeric FISH analysis is indicated as a second tier test after high-resolution G-banding analysis in patients with otherwise unexplained developmental delay/mental retardation and/or multiple congenital anomalies. We describe a patient and her three maternal female cousins, all showing an undiagnosed MCA/MR syndrome, associated with the same complex subtelomeric rearrangement. Subtelomeric FISH testing performed between 3(1/2) and 18 years after the initial karyotype showed, in all four patients, distal trisomy 3q and distal monosomy 10q as follows: 46,XX,ish der(10)t(3;10)(q29;q26.3)mat(D10S2488+,D10S2490-, D3S1272+,D10Z1+). Parental subtelomeric FISH analysis showed that the proposita's mother and three of four brothers and one of two sisters had a cryptic balanced 3:10 telomere translocation. The three brothers with the balanced translocation were father to one each of the three proband's cousins. All four affected girls showed a similar phenotype with pre/postnatal growth retardation, microcephaly, severe developmental delay/mental retardation, poor/absent speech, and a distinct pattern of malformation. On examination there were coarsening of facial features with low fronto-temporal hairline; thick eyebrows; bilateral epicanthal folds; hypertelorism; prominent nose with squared nasal root and narrow alar base; low-set posteriorly rotated large ears with a prominent anthelix; high arched palate; prominent chin; hands/feet brachydactyly; bilateral squint; hypotonia; and muscle hypotrophy. A slow overall improvement was seen in all patients over time. To our knowledge, this complex subtelomeric rearrangement in our patients has never been reported so far. Monosomy 10q has recently been described either isolated or as part of a complex rearrangement involving telomeres other than the 3q. Trisomy 3q29 has not yet been reported, but our patients resembled cases with 3q26 trisomy suggesting that the critical region of duplication for this phenotype is in 3q29.     

Preferential involvement of the short arm in chromosome 8‐derived supernumerary markers and ring as identified by chromosome arm painting

We report on the use of fluorescence in situ hybridization (FISH) with specific chromosome 8 arm painting to characterize further small supernumerary chromosome 8‐derived markers/rings (SMC/SRC) identified in three patients. Two patients (patients 1 and 2) who carried the marker (SMC) were evaluated because of mental retardation and minor facial anomalies. The patient (patient 3) who carried the ring (SRC) had ventriculomegaly. Parental blood chromosomes of patients 2 and 3 were normal and unavailable on patient 1. The identification of the SMC/SRC was first characterized by FISH specific alpha‐repeat centromeric probes, second by FISH whole chromosome painting (WCP), and finally by FISH chromosome arm painting (CAP). The latter showed involvement of only the short arm of chromosome 8 in all three SMC/SRC cases, suggesting a U‐type exchange mechanism. Am. J. Med. Genet. 90:276–282, 2000. © 2000 Wiley‐Liss, Inc.     

Duplication 10p in a girl due to a maternal translocation t(10;14) (p11:p12)

We present a dup (10p) due to a t(10;14) (p11;p12)mat with a malformation syndrome in a girl. The analysis of 37 published cases shows that 31 patients (16 ♂; 15 ♀) had either a mother or a father carrying a balanced translocation; one case was due to a paternal and another due to a maternal pericentric inversion; two cases were due to de novo translocations; one case had a partial duplication of 10p; and one case had a supernumerary ring chromosome composed of 10p material. The phenotypic spectrum of the condition was analyzed. It is a specific multiple congenital anomalies/mental retardation (MCA/MR) syndrome which includes characteristic facial appearance (dolichocephaly, frontal bossing, short nose with a broad root, highly arched and upswept eyebrows, long philtrum, and thin lips), postnatal growth retardation, severe mental and psychomotor retardation, and several major and minor anomalies. Pseudohermaphroditism seems to be an important anomaly being present in 15 to 20% of affected males. A hypothenar crease together with a transverse crease forming a “crease triangle” seems a helpful sign in the clinical diagnosis of duplication 10p.     

Ring chromosome 17: phenotype variation by deletion size

Ring chromosome 17 is a rare cytogenetic abnormality, with 12 previous reports in the literature. Some have a relatively mild phenotype characterized by seizures, mental retardation, skin changes and short stature. Other patients have Miller-Dieker syndrome (MDS), which includes lissencephaly, multiple dysmorphic features, severe mental retardation and shortened life expectancy. We describe two new cases of ring chromosome 17 and review the literature. Our cases and the other reports of patients without a deletion encompassing the Miller-Dieker region, delineate a fairly distinctive subgroup of individuals with ring 17, whose phenotype consists of growth and mental retardation, seizures, minor dysmorphic features, café-au-lait spots and retinal flecks. This classification of ring 17 into two distinct groups based on the size of the deletion and the phenotypic manifestations should facilitate clinical suspicion of this rare chromosomal abnormality.     

Prenatal diagnosis of inverted duplicated 8p

The phenotype of inverted duplicated 8p, region 8p11.2-p23, reported in children and adults, includes: severe mental retardation, minor facial anomalies, agenesis of corpus callosum, and other malformations including those of heart and kidneys. We report on the prenatal diagnosis of 2 cases of inverted duplication 8p. Both cases were ascertained by abnormal level 2 ultrasound findings. Case 1 presented at 16.5 weeks of gestation with massive distention of the fetal bladder, bilateral hydronephrosis, abnormality of the lower lumbar spine, absence of the sacral spine and a Dandy-Walker variant (interhemispheric cyst and enlarged third ventricle). Case 2 presented at 30 weeks of gestation with agenesis of corpus callosum, slightly enlarged lateral ventricles, interhemispheric cyst and enlarged third ventricle, and possible coarctation of the aorta. The intracranial and cardiac anomalies were confirmed and further defined after delivery. Cytogenetic analysis in both cases showed additional material on 8p. In both cases, fluorescence in situ hybridization (FISH) defined the abnormal chromosome, as a pseudodicentric chromosome with duplication of the short arm from centromere to p23 and deletion from p23 to pter. Our findings support those of prior reports of the inverted duplicated 8p chromosome with multiple anomalies and add prenatal findings to our knowledge.     

Ring chromosome 12

A ring chromosome 12 (p13.3q24.3) was observed in all cells analyzed from skin fibroblasts and the peripheral blood of a 19-year-old man initially referred for developmental delay with expressive language deficiency. Other phenotypic anomalies included growth deficiency, multiple café-au-lait spots, mild pectus excavatum, glandular hypospadias, left esotropia, clinodactyly of the fifth fingers, and hypothyroidism with elevated antithyroid antibodies. The four previously reported cases of r(12) support the theory of a general ring phenotype which is manifested independently of the specific autosome involved and which is characterized by growth failure, moderate mental retardation, and lack of other major phenotypic anomalies. Breakpoints in all cases of r(12) have been assigned to the telomeric regions, suggesting minimal deletion of chromosome material.     

Subtle trisomy 12q24.3 and subtle monosomy 22q13.3: three new cases and review

The high resolution G-bands (850 bands) karyotype have made it possible to identify small chromosome anomalies (5 megabases) which are now microscopically visible. New techniques have been improved, such as the Fluorescent in situ hybridization (FISH) with subtelomeric probes, which can be employed to detect cryptic chromosome alterations not visible microscopically. We present three cases which had been remitted for a high resolution karyotype. The high resolution G-band karyotype and the FISH techniques led us to conclude that the three cases were carriers of a similar subtle chromosomal alteration. Case I is a new born female with developmental and psychomotor delay, hypotonia, and long limbs with arachnodactily. A high resolution G-band karyotype showed an abnormal chromosome 22. FISH techniques confirmed a der(22)t(12;22)(q24.31;q13.3). Case II is a 12-year-old girl, with growth retardation, long shaped face with thick eyebrows, smooth philtrum, and thin upper lip with severe mental retardation (still no language), with a phenotype very similar to that of his sister: long shaped face, thick eyebrows, smooth philtrum, and thin upper lip. A high resolution G-band karyotype also showed in Case II and III an abnormal chromosome 22, studied by FISH techniques which confirmed a der(22)t(12;22)(q24.3;q13.3) in both cases.     

Terminal deletion, del(1)(p36.3), detected through screening for terminal deletions in patients with unclassified malformation syndromes

We report on a 4 year-old girl with a 1p36.3-pter deletion. Clinical findings included minor anomalies of face and distal limbs, patent ductus arteriosus, the Ebstein heart anomaly, and brain atrophy with seizures. Conventional GTG-banded chromosome analysis revealed a normal (46,XX) result. Subsequent analysis by fluorescent in situ hybridization (FISH) using distal probes demonstrated a deletion of 1p36.6-pter. Molecular investigations with microsatellite markers showed hemizygosity at three loci at 1p36.3 with loss of the paternal allele. The deletion of 1p36.3 is difficult to identify by banding alone; indeed, our patient represents the third reported case with a del(1)(p36.3) that was detected only after more detailed analysis. In all three cases the deletion was detected through screening of patients with multiple congenital anomalies/mental retardation syndromes suggestive of autosomal chromosome aberrations for subtelomeric submicroscopic deletions by means of FISH or microsatellite marker analysis. On the basis of these observations we highly recommend that FISH with a subtelomeric 1p probe be routinely performed in patients with similar facial phenotype, severe mental retardation and seizures, and a heart malformation, particularly the Ebstein anomaly.     

Ring chromosome 6 in three fetuses: case reports, literature review, and implications for prenatal diagnosis

Prenatal and postnatal findings in three fetuses with a ring chromosome 6 are presented, and the literature of this rare cytogenetic disorder is reviewed. The described fetuses illustrate the broad spectrum of the clinical manifestation of ring chromosome 6. In one fetus, the disorder was diagnosed incidentally by a routine amniocentesis due to advanced maternal age. The other two fetuses were hydrocephalic and had other congenital anomalies. Remarkably, the ring chromosome 6 tends to disappear in cultured amniotic fluid cells; karyotyping revealed complete or nearly complete monosomy 6. In contrast, the ring was preserved in high proportions of fetal leukocytes. Postnatal growth retardation is the only consistent finding of this chromosomal disorder. Maternal age is not significantly above average. An additional review of 20 literature cases revealed a striking tendency to hydrocephalus, either due to deficient brain growth or secondary to an aqueductal stenosis. Children with hydrocephalus and ring chromosme 6 tend to display facial dysmorphism and may have additional malformations, growth failure, eye anomalies, and seizures. In contrast, there are two reports on children with a ring chromosome 6 who had short stature, normal appearance, and a normal or almost-normal psychomotor development. In such patients at the mild end of the clinical spectrum, the phenotype is basically restricted to what Kosztolányi. [1987: Hum Genet 75:174-179] delineated as "ring syndrome," comprising "severe growth failure without major malformations, without a specific deletion syndrome, with only a few or no minor anomalies, and mild to moderate mental retardation." This "ring syndrome" is considered to occur independently of the autosome involved in the ring formation. The overall impression from our cases and from the literature review of cases with ring chromosome 6 is that the karyotype-genotype correlation is poor. This makes prognostic counseling of parents difficult and unsatisfactory. Serial targeted ultrasound examinations, especially of the brain, are decisive factors in elucidating the prognosis.     

22q11.2 duplication syndrome: two new familial cases with some overlapping features with DiGeorge/velocardiofacial syndromes

Twenty-one patients, including our two cases, with variable clinical phenotype, ranging from mild learning disability to severe congenital malformations or overlapping features with DiGeorge/velocardiofacial syndromes (DG/VCFS), have been shown to have a chromosome duplication 22q11 of the region that is deleted in patients with DG/VCFS. The reported cases have been identified primarily by interphase FISH and could have escaped identification and been missed by routine cytogenetic analysis. Here we report on two inherited cases, referred to us, to rule out 22q11 microdeletion diagnosis of VCFS. The first patient was a 2-month-old girl, who presented with cleft palate, minor dysmorphic features including short palpebral fissures, widely spaced eyes, long fingers, and hearing loss. Her affected mother had mild mental retardation and learning disabilities. The second patient was a 7(1/2)-year-old boy with velopharyngeal insufficiency and mild developmental delay. He had a left preauricular tag, bifida uvula, bilateral fifth finger clinodactyly, and bilateral cryptorchidism. His facial features appeared mildly dysmorphic with hypertelorism, large nose, and micro/retrognathia. The affected father had mild mental retardation and had similar facial features. FISH analysis of interphase cells showed three TUPLE1-probe signals with two chromosome-specific identification probes in each cell. FISH analysis did not show the duplication on the initial testing of metaphase chromosomes. On review, band q11.2 was brighter on one chromosome 22 in some metaphase spreads. The paucity of reported cases of 22q11.2 microduplication likely reflects a combination of phenotypic diversity and the difficulty of diagnosis by FISH analysis on metaphase spreads. These findings illustrate the importance of scanning interphase nuclei when performing FISH analysis for any of the genomic disorders.     

Clinical, cytogenetic, and fluorescence in situ hybridization findings in two cases of "complete ring" syndrome

The term "ring syndrome" was proposed to describe a phenotype of growth failure without major malformations due to a ring autosome. The growth failure is thought to be caused by instability of the ring chromosome leading to aneusomy and cell death. Most previous studies of ring chromosomes were based on standard cytogenetic banding techniques and were limited to microscopically detectable deletions in the ring chromosomes. We report on two patients with complete ring (4) and ring (9) chromosomes, respectively. The first was a 15-month-old girl and the second was a 16-month-old boy. They both presented with severe, symmetrical growth failure and normal psychomotor development in the absence of malformations. Their parents had a normal phenotype. The first case had a whorled pattern of hyperpigmentation and hypopigmentation on part of the face and chest, and the second case had a patchy hyperpigmented rash on the trunk. Peripheral blood karyotype of the first patient was 46,XX, r(4)(p16.3q35.2) and of the second 45,XY,-9/46,XY,r(9)(p24q34.3). G-band analysis suggested no loss of material in the ring chromosomes. These findings were confirmed by fluorescence in situ hybridization (FISH) analysis using chromosome-specific subtelomeric probes. The common human telomeric sequences were intact in the first patient but absent in the second patient. The cytogenetic and FISH data in our two cases provide further evidence for the existence of a "complete ring" phenotype independent of the autosome involved. Pigmentary skin changes are a useful clinical sign of mosaicism caused by the ring instability.