Kabuki syndrome and trisomy 10p

Kabuki syndrome (KS) (MIM 147920) is a multiple congenital anomalies/mental retardation syndrome of unknown cause. There is multisystem involvement of anomalies, including 1) unique facial features, 2) postnatal growth retardation, 3) mild-to-moderate mental retardation, 4) skeletal anomalies and 5) dermatoglyphic abnormalities. Kabuki syndrome remains a clinical diagnosis despite significant research on detection of the genetic cause. We present 10 patients with Kabuki syndrome with a brief overview of the syndrome. An additional male patient and his affected aunt, both with trisomy 10p due to unbalanced segregation of a familial translocation, are also discussed for overlapping features and differential clinical diagnosis of the two conditions. Considering a significant overlap in clinical pictures of Kabuki syndrome and trisomy 10p in these two patients, as well as the previous patients with chromosomal abnormalities, we conclude that chromosome analysis is an important step in clinical work-up of patients with Kabuki syndrome.     

Del (13) (q33). Exclusion of esterase D (ESD) from 13q33 and q34]

A de novo del (13) (q33) was found in a 14-month-old boy with hypospadias. Phenotype anomalies included growth retardation, psychomotor retardation (QD = 64), microcephaly with brachycephaly, a round, flat and asymmetrical facies, a normal nose bridge, a small, pointed chin. The patient is heterozygous ESD 2-1. The gene localization may thus be excluded from bands 13q33 and q34 and assigned to bands q31 or q32, if its previous assignment to the q3 region is confirmed.     

Distal duplication 14q: Report of three cases and further delineation of the syndrome

Summary Three cases of distal duplication 14q are presented. The first two cases are cousins in a kindred segregating a balanced translocation t(14;18)(q31;q23). The third case resulted from a maternal translocation t(14;18)(q24;p11). By review of these cases and those previously reported, a distal duplication 14q syndrome is further delineated. Common features include postnatal growth retardation, mental retardation, hypotonia, microcephaly, slanted palpebral fissures, ocular hypertelorism, sparse eyelashes and eyebrows, nasal dysmorphism, tented lip, micrognathia, posteriorly rotated ears, and minor skeletal anomalies.     

Ring chromosome 11. A case report and review of the literature

A female infant with severe growth-weight retardation and with a ring chromosome 11, associated with trisomy X in 15% of metaphases, has been reported. A literature review of cases of r(11) shows that the clinical features of these patients, although showing different frequencies, are similar to those of the del(11q) syndrome. It has been suggested that the variability of the mental retardation in r(11) patients is attributable to the unstability of the ring and to the different break points in these two chromosomal rearrangements. The origin of the r(11) was also addressed by studying fragile sites of the parents at 11p15 and 11q25.     

Phenotypic variability of Cat-Eye syndrome

Cat-Eye syndrome (CES) is a disorder with a variable pattern of multiple congenital anomalies of which coloboma of the iris and anal atresia are the best known. CES is cytogenetically characterised by the presence of an extra bisatellited marker chromosome, which represents an inverted dicentric duplication of a part of chromosome 22 (inv dup(22)). We report on three CES-patients who carry an inv dup(22) diagnosed with FISH studies. They show remarkable phenotypic variability. The cause of this variability is unknown. Furthermore, we review clinical features of 71 reported patients. Only 41% of the CES-patients have the combination of iris coloboma, anal anomalies and pre-auricular anomalies. Therefore, almost 60% of the CES-patients are hard to recognize by their phenotype alone. Mild to moderate mental retardation was found in 32% (16/50) of the cases. Mental retardation occurs more frequently in male CES-patients. There is no apparent phenotypic difference between mentally retarded and mentally normal CES-patients.     

Partial trisomy 14q and familial translocation (2;14) (q12;q13).

A female patient with moderate psychomotor retardation, minor anomalies and proximal trisomy 14q due to segregation of a maternal translocation is reported.     

An r(22)(p11→q13) in a moderately mentally retarded girl

Summary An r(22) was detected in a 6-year-old female patient with growth retardation, IQ of 45, and a lower quotient for verbal performance. She presents some other minor anomalies. The break and fusion points probably were at p11 and q13.     

Partial deletion 10p syndrome. Report of two patients.

Two patients with partial deletion of the short arm of chromosome 10 are described. They showed most of the features observed in twenty other known patients, including growth retardation, mental deficiency, abnormally shaped skull, distinct facial dysmorphisms, cardiac and genitourinary malformations, and limbs anomalies. One of our patients also had features of the DiGeorge sequence, which has been found in five other cases with this imbalance.     

Presence of telomeric and subtelomeric sequences at the fusion points of ring chromosomes indicates that the ring syndrome is caused by ring instability

In situ hybridization of a telomeric (TTA-GGG) _n sequence to metaphases from three cases of ring chromosome, involving respectively chromosomes 4, 16, and 20, showed the presence of the cognate sequences in all three rings. To investigate whether these ring chromosomes originated by telomere-telomere fusion, we determined, by in situ hybridization, whether telomere-associated sequences and/or specific distal sequences were still present in the ring chromosomes. The finding that these sequences were preserved in all the ring chromosomes strongly indicates that they originated by telomere-telomere fusion. All three subjects carrying the ring chromosomes are affected by the so-called ring syndrome, with failure to thrive, minor dysmorphic signs and no major anomalies. The r(4) patient has the ring in mosaic form with a normal cell line and has normal intelligence. The r(16) and the r(20) patients have moderate mental retardation and suffer from seizures. We conclude that the ring syndrome, even in its more severe manifestation, is caused by ring chromosome instability.     

11q- syndrome: three cases and a review of the literature.

We report on three children with de novo terminal deletions of the long arm of chromosome 11 (11q-) and breakpoints in 11q23-q24. Eighty-nine other patients with partial monosomy 11q have been reported and were reviewed by us. Salient features of 11q- syndrome are psychomotor retardation, trigonocephaly, telecanthus/hypertelorism, broad depressed nasal bridge, micrognathia, low set abnormal ears, cardiac anomalies and hand/foot anomalies. Renal agenesis and anal atresia are reported first here. Supratentorial white matter abnormality on CT and MRI present in our second patient was reported in three patients. Increased mortality is caused by cardiac anomalies. A third of all patients with partial monosomy 11q had thrombocytopenia or pancytopenia and this seems to be related to the absence of band 11q23-q24. Seventy-six percent of patients have de novo deletions with breakpoints in 11q21-q25. There is no obvious correlation between the length of the deleted segment and the severity of the symptoms. In unbalanced chromosomal patterns with deletions of 11q involving bands 11q23-q24 the typical phenotype of 11q- syndrome remains recognizable. Deletions distal to 11q24.1 do not produce the typical 11q- syndrome.     

Ring chromosome 14 in monozygotic twins]

An r(14) is observed in monozygotic twins, with psychomotor retardation and no obvious somatic malformation.     

Ring chromosome 8 associated with microcephaly.

A two-year-old mental defective girl with microcephaly and minor dysmorphic features had a 46,XX,r(8) karyotype. Low birth weight, short stature, and mental retardation were common features in the four known patients with r(8).     

Thrombocytopenia-absent radius (tar) syndrome: a case with agenesis of corpus callosum, hypoplasia of cerebellar vermis and horseshoe kidney

The thrombocytopenia-absent radius (TAR) syndrome (MIM 274000) is a congenital malformation syndrome characterised by bilateral absence of the radii with present thumbs, hypomegakaryocytic thrombocytopenia and a number of additional features including skeletal and cardiac anomalies. Mental retardation, reported in about 7% of patients, is usually secondary to intracranial hemorrhage. In 1994 there was a single report of a girl with TAR syndrome and hypoplasia of the cerebellar vermis and corpus callosum and in 2003 another case of TAR syndrome with cerebellar dysgenesis has been reported. In 2000 there was first report of horseshoe kidney in association with TAR syndrome followed by a clinical study of 34 cases with TAR syndrome in 2002 where horseshoe kidney was noted in two cases. Here we report of a girl with TAR syndrome, severe mental retardation, agenesis of corpus callosum, hypoplasia of cerebellar vermis and horseshoe kidney. There is no previous report of a child with TAR syndrome and all those associated anomalies in the same patient.     

Interstitial deletion of the long arm of chromosome 7 46,XX,del(7)(pter→q2200::q3200→qter)

Summary We present a boy with the karyotype 46,XY,r3 and a phenotype with psychomotor and growth retardation, craniofacial anomalies, syndactyly of the toes, and edema of the feet. The karyotypes and phenotypes of both parents are normal.     

Trisomy 4q syndrome: presentation of a new case and review of the literature

We describe the 11th case of a de novo partial trisomy of the long arm of chromosome 4, with the extra segment spanning from 4q27 to 4q35. The aberration resulted from an unbalanced translocation of material from 4q to the short arm of chromosome 7, as evident from fluorescent in situ hybridization. Microsatellite analysis revealed the extra material to originate from the father. The karyotype was interpreted as 46,XX,der(7)t(4;7)(q27;p22). The patient is a 13-year-old girl with severe mental retardation, growth retardation, hearing impairment as well as minor foot, thumb and facial anomalies. Although the extent of the aberration varies between the reported patients, there are nevertheless features in common, suggestive of a trisomy 4q syndrome. The clinical findings most frequently reported are: mental retardation, seizures, microcephaly, hearing impairment and growth retardation, as well as epicanthic folds, high/broad/depressed nasal bridge, malformed ears, tooth and thumb anomalies. Almost the entire long arm of chromosome 4, except band q11, has been involved in trisomies/duplications, but 4q27 and 4q31 seem to be preferentially engaged in the trisomy 4q syndrome.     

The cytogenetics of 90 patients with idiopathic mental retardation/malformation syndromes and of 90 normal subjects

Summary A cytogenetic study, done on randomized coded slides, of 90 patients with idiopathic mental retardation and at least 3 other developmentally independent congenital anomalies and of 90 normal subjects is reported. Audiatorography, Q-banding and C-staining were used in the analysis of chromosomally abnormal cases. Eight patients were found to have chromosome abnormalities. Four had substantial chromosome aberrations that would be expected to cause abnormal phenotype. These were CD165 (46,18q-); CD25 (46,18q+) (partial trisomy of 10q); CD175 (46,4q+) and CD95 (46,mar22). In addition, 4 patients were found to have chromosomal anomalies that could not account for their conditions. Three of these were considered to have heterochromatic variants. Patient CD167 had an 9qh+ chromosome which had been inherited from her mother. Case CD137 had a No. 19 chromosome with additional centric heterochromatin. A similar chromosome was found in her mother, maternal grandmother and 2 of 3 half sibs. In patient CD125 a telocentric No. 13 was found. In addition, CD80 was shown to have an XYY constitution.In the normal subjects, no unbalanced chromosome rearrangements were found. Four persons, however, had minor chromosome anomalies. Three were considered to have heterochromatic variants. These were CD54 (46,22p+); CD149 (46,21p+) and CD19 (46,tel22). One normal subject (CD51) was found to be a balanced t(13q14q) carrier. The translocation chromosome had been inherited from his father.     

Distal 4p microdeletion in a case of Wolf-Hirschhorn syndrome with congenital diaphragmatic hernia

BACKGROUND: Wolf-Hirschhorn syndrome (WHS) is a well-known genetic condition characterized by typical facial anomalies, midline defects, skeletal anomalies, prenatal and postnatal growth retardation, hypotonia, mental retardation, and seizures. Affected patients with a microdeletion on distal 4p present a milder phenotype that lacks congenital malformations. WHS is rarely associated with congenital diaphragmatic hernia (CDH), and only 8 cases are reported in the literature. In almost all cases of CDH and WHS a large deletion of the short arm of chromosome 4 is present. CASE: A microdeletion of 2.6 Mb on distal 4p associated with CDH and multiple congenital malformations (i.e., cleft palate) is reported for the first time. CONCLUSIONS: Such a microdeletion should prompt a molecular study for WHS when in a fetus/newborn with CDH the association with cleft lip/palate and typical facial appearance (flat facial profile, hypertelorism) is found.     

Partial 4q duplication due to inherited der(20), t(4;20)(q25;q13)mat.

A boy with mental and growth retardation associated with congenital anomalies has a partial duplication of the distal 4q chromosome region as a result of inheritance of a t(4:20) from his mother. Comparison with twelve other patients from the literature indicates that similar clinical features may be associated with this chromosome change suggesting a partial 4q duplication syndrome.     

Molecular analyses of 17p11.2 deletions in 62 Smith-Magenis syndrome patients.

Smith-Magenis syndrome (SMS) is a clinically recognizable, multiple congenital anomalies/mental retardation syndrome caused by an interstitial deletion involving band p11.2 of chromosome 17. Toward the molecular definition of the interval defining this microdeletion syndrome, 62 unrelated SMS patients in conjunction with 70 available unaffected parents were molecularly analyzed with respect to the presence or absence of 14 loci in the proximal region of the short arm of chromosome 17. A multifaceted approach was used to determine deletion status at the various loci that combined (i) FISH analysis, (ii)PCR and Southern analysis of somatic cell hybrids retaining the deleted chromosome 17 from selected patients, and (iii) genotype determination of patients for whom a parent(s) was available at four microsatellite marker loci and at four loci with associated RFLPs. The relative order of two novel anonymous markers and a new microsatellite marker was determined in 17p11.2. The results confirmed that the proximal deletion breakpoint in the majority of SMS patients is located between markers D17S58 (EW301) and D17S446 (FG1) within the 17p11.1-17p11.2 region. The common distal breakpoint was mapped between markers cCI17-638, which lies distal to D17S71, and cCI17-498, which lies proximal to the Charcot Marie-Tooth disease type 1A locus. The locus D17S258 was found to be deleted in all 62 patients, and probes from this region can be used for diagnosis of the SMS deletion by FISH. Ten patients demonstrated molecularly distinct deletions; of these, two patients had smaller deletions and will enable the definition of the critical interval for SMS.     

Localization of the gene for a syndrome of X-linked skeletal dysplasia and mental retardation to Xq27-qter

Summary An Indiana family segregating a syndrome of X-linked mental retardation and skeletal anomalies was tested for linkage of the mutant gene to X-chromosome molecular markers. Lod scores of 3.27 and 3.06 (-0) for the molecular probes St14-1 (DXS52) and Dx13 (DXS15), respectively, indicate that the disease gene is located in the terminal portion of Xq.