Interstitial deletion of (17)(p11.2). A microdeletion syndrome. Another example

Another example of del (17)(p11.2) in a 3-year-old boy with psychomotor retardation, broad face, midface hypoplasia, prognathism, and behavioural anomalies was diagnosed clinically and confirmed by prometaphase analysis. It seems that this new microdeletion syndrome may not be so rare.     

A child with mosaicism for deletion (14)(q11.2q13)

In this case report we describe a child with a de novo deletion in the (q11.2q13) region of chromosome 14. The child presented with dysmorphic features - anophthalmia, microcephaly, and growth retardation. Cytogenetic studies showed mosaicism. The karyotype was 46,XX,del(14)(q11.2;q13) [16] /46,XX [9]. We compared the features observed in this child with that of others with the same deletion reported in scientific literature and found that this is the first report of a child mosaic for this deletion. It is also the first time it has been reported in association with anophthalmia.     

Deletion 11q23-->qter (Jacobsen syndrome). Report of three new patients.

Three unrelated patients with de novo del 11q23-->qter are reported. Clinical features included growth and mental retardation, hypotonia, trigonocephaly, facial dysmorphism with hypertelorism, epicanthal folds, abnormally shaped palpebral fissures, eye globe malformations, depressed nasal bridge, "carp-shaped" mouth, highly arched palate, low set and malformed ears. One patient had congenital heart defect, and reduced platelet count. This syndrome, originally reported by Jacobsen, is now corroborated by more than 35 patients and appears as the most common deletion involving 11q. Since deletion of subband 11q24.1 is critical for full expression of this syndrome, the JBS phenotype could be an example of contiguous gene syndrome.     

Siblings with opposite chromosome constitutions,dup(2q)/del(7q) and del(2q)/dup(7q)

Chromosome 7q36 microdeletion syndrome is a rare genomic disorder characterized by underdevelopment of the brain, microcephaly, anomalies of the sex organs, and language problems. Developmental delay, intellectual disability, autistic spectrum disorders, BDMR syndrome, and unusual facial morphology are the key features of the chromosome 2q37 microdeletion syndrome. A genetic screening for two brothers with global developmental delay using high-resolution chromosomal analysis and subtelomeric multiplex ligation-dependent probe amplification revealed subtelomeric rearrangements on the same sites of 2q37.2 and 7q35, with reversed deletion and duplication. Both of them showed dysmorphic facial features, severe disability of physical and intellectual development, and abnormal genitalia with differential abnormalities in their phenotypes. The family did not have abnormal genetic phenotypes. According to the genetic analysis of their parents, adjacent-1 segregation from their mother's was suggested as a mechanism of their gene mutation. By comparing the phenotypes of our patients with previous reports on similar patients, we tried to obtain the information of related genes and their chromosomal locations.     

Chromosome 3 duplication q21 leads to qter deletion p25 leads to pter syndrome in children of carriers of a pericentric inversion inv(3) (p25q21).

Close phenotypic similarity between two cases carrying a rec(3) dup q,inv(3) (p25q21), 12 additional infants from the same inv (3)(p25q21) kindred who lived less than 1 year, and eight cases studied in other medical centers has led us to postulate the existence of a distinct chromosome 3 duplication-deletion syndrome. In the presence of trisomy for (3)q21 leads to qter and monosomy for (3)p25 leads to pter, the facial dysmorphy is unique: a distorted head shape due to irregular cranial sutures, thick low eyebrows, long eyelashes, persistent lanugo, distended veins on the scalp, hypertelorism, oblique palpebral fissures, a very short nose with a broad depressed bridge and anteverted nares, protruding maxilla, thin upper lip, micrognathia, low-set ears, and a short webbed neck. Port-wine stains, congenital glaucoma, cloudy corneas, cleft palate and harelip also occur frequently. Each infant has difficulty sucking and swallowing. Congenital anomalies of the cardiovascular system, of midgut rotation, and of the urogenital system are noted for the infants who died neonatally. Most frequent is a ventricular septal defect, followed by atrial septal defect, patent ductus arteriosus, patent foramen ovale, and coarctation of the aorta. Omphalocele, umbilical hernia, hyperplastic kidneys, polycystic kidneys, double ureter, hydro-ureter, hydronephrosis, and undescended testes often occur. The extremities are short in proportion to the length of the trunk. Clinodactyly, coxa valga, talipes, and spina bifida are frequently observed.     

Molecular analysis of the Smith-Magenis syndrome: a possible contiguous-gene syndrome associated with del(17)(p11.2).

We undertook clinical evaluation (32 cases) and molecular evaluation (31 cases) of unrelated patients affected with Smith-Magenis syndrome (SMS) associated with an interstitial deletion of band p11.2 of chromosome 17. Patients were evaluated both clinically and electrophysiologically for peripheral neuropathy, since markers showing close linkage to one form of Charcot-Marie-Tooth disease (CMT1A) map to this chromosomal region. The common clinical findings were broad flat midface with brachycephaly, broad nasal bridge, brachydactyly, speech delay, and hoarse, deep voice. Fifty-five percent of the patients showed clinical signs (e.g., decreased or absent deep tendon reflexes, pes planus or pes cavus, decreased sensitivity to pain, and decreased leg muscle mass) suggestive of peripheral neuropathy. However, unlike patients with CMT1A, these patients demonstrated normal nerve conduction velocities. Self-destructive behaviors, primarily onychotillomania and polyembolokoilamania, were observed in 67% of the patients, and significant symptoms of sleep disturbance were observed in 62%. The absence of REM sleep was demonstrated by polysomnography in two patients. Southern analysis indicated that most patients were deleted for five 17p11.2 markers--FG1 (D17S446), 1516 (D17S258), pYNM67-R5 (D17S29), pA10-41 (D17S71), and pS6.1-HB2 (D17S445)--thus defining a region which appears to be critical to SMS. The deletion was determined to be of paternal origin in nine patients and of maternal origin in six patients. The apparent random parental origin of deletion documented in 15 patients suggests that genomic imprinting does not play a role in the expression of the SMS clinical phenotype. Our findings suggest that SMS is likely a contiguous-gene deletion syndrome which comprises characteristic clinical features, developmental delay, clinical signs of peripheral neuropathy, abnormal sleep function, and specific behavioral anomalies.     

Trisomy 3 (p23-pter) resulting from maternal translocation, t (3 ; 4)(p23 ; q35).

We describe a patient with partial trisomy 3p resulting from maternal translocation, t(3:4)(p23;q35). The male newborn who died at the age of 22 hours presented with distinct facial features including a square-shaped face with prominent forehead and depressed temporal regions, prominent cheeks, short broad nose, left cleft lip and cleft palate, malformed ears, and a receding mandible. Further findings were flexion deformities of the fingers with finger-like thumbs and mild cutaneous syndactyly 2/3 and 4/5, hypoplastic penis and scrotum with no palpable testes. He probably had a congenital heart defect and situs inversus abdominalis. Many of these features have been reported in other patients with distal trisomy 3p.     

del(X)(p22.1)/r(X)(p22.1q28) Dynamic mosaicism in a Turner syndrome patient

We report on a 16-year-old patient with Turner syndrome who presented a mos 46,X,del(X)(p22.1)[35]/45,X [19]/46,X,r(X)(p22.1q28)[6]GTG-band karyotype. The R-banding showed that the abnormal X-chromosome was inactive in all 61 cells analyzed. Fluorescence in situ hybridization with a Xp/Yp subtelomeric probe revealed that both abnormal chromosomes lacked the complementary sequences, a fact consistent with a terminal deletion. Besides, the molecular analysis of the human androgen receptor gene showed that the rearranged chromosome was paternal in origin. Since the deleted and the ring chromosomes had the same size and banding pattern, and because the former was the predominant cell line, it was inferred that the Xp- formed a ring in some cells apparently without further loss of genetic material. However, the reverse sequence and even a simultaneous origin due to a complex intrachromosomal exchange are also conceivable. The mild Turner syndrome phenotype is explained by the mosaicism and by the size of the deleted segment.     

Modeling del(17)(p11.2p11.2) and dup(17)(p11.2p11.2) contiguous gene syndromes by chromosome engineering in mice: phenotypic consequences of gene dosage imbalance

Contiguous gene syndromes (CGS) are a group of disorders associated with chromosomal rearrangements of which the phenotype is thought to result from altered copy numbers of physically linked dosage-sensitive genes. Smith-Magenis syndrome (SMS) is a CGS associated with a deletion within band p11.2 of chromosome 17. Recently, patients harboring the predicted reciprocal duplication product [dup(17)(p11.2p11.2)] have been described as having a relatively mild phenotype. By chromosomal engineering, we created rearranged chromosomes carrying the deletion [Df(11)17] or duplication [Dp(11)17] of the syntenic region on mouse chromosome 11 that spans the genomic interval commonly deleted in SMS patients. Df(11)17/+ mice exhibit craniofacial abnormalities, seizures, marked obesity, and male-specific reduced fertility. Dp(11)17/+ animals are underweight and do not have seizures, craniofacial abnormalities, or reduced fertility. Examination of Df(11)17/Dp(11)17 animals suggests that most of the observed phenotypes result from gene dosage effects. Our murine models represent a powerful tool to analyze the consequences of gene dosage imbalance in this genomic interval and to investigate the molecular genetic bases of both SMS and dup(17)(p11.2p11.2).     

A second case of inv(4)pat with both recombinants in the offspring: rec dup(4q) in a girl with Wolf-Hirschhorn syndrome and rec dup(4p)

In a girl presenting with features of Wolf-Hirschhorn syndrome, cytogenetic and molecular cytogenetic analysis revealed a rearranged chromosome 4 with monosomy of the distal bands 4pter-->4p16.2 and trisomy of the distal bands 4q35.1-->4qter [rec dup(4q)] due to a large, paternal pericentric inversion. In the following two pregnancies, prenatal diagnosis showed the same imbalance in one fetus and a reverse segmental imbalance [rec dup(4p)] in the other. We discuss the recombination risk of the given inversion with respect to the size of the inverted segment and the viability of the recombinants. The high frequency of recombinants in this family and others suggests a high recurrence risk in similar cases with large pericentric inversions comprising almost entire chromosomes.     

A duplication dup(4)(q28q35.2) de novo in a newborn

We report here a case of a newborn with hypotrophy and somatic stigmatization: microcephaly, facial dysmorphism, heart defect and immunodeficiency syndrome. The proband's karyotype was 46,XY,dup(4)(q28q35.2) de novo with chromosomal breaks in 4% of metaphases. We demonstrate the usefulness of a combination of physical examination, classical cytogenetics, FISH and PCR techniques in order to establish correct diagnosis because of overlap of some clinical and cytogenetic features of Nijmegen breakage syndrome (NBS) and duplication 4q in our patient. Although FISH technique detected translocation t(14q;21q) in 4 metaphases, deletion 657del5 in exon 6 of the NBS1 gene associated with NBS in Slavic population was not confirmed. We compare in this report similarity of the clinical picture of our patient, NBS cases and other patients carrying a duplication of the distal part of 4q as described in the literature.     

De novo del(6)(q25) associated with macular degeneration

An eight-month-old girl with a de novo del(6)(q25) is described. She and other previous cases of 6q deletion showed concordance for developmental retardation associated with multiple unspecific congenital abnormalities, which do not yet allow the delineation of a syndrome. However, bilateral macular degeneration was found in the proposita and had been observed in another similar case, so it probably represents a distinctive feature of 6q terminal monosomy. This observation also suggests the existence of a dominant macular degeneration locus within 6q25----qter.     

Duplication 5q and deletion 9p due to a t(5;9)(q34;p23) in 2 cousins with features of Hunter-McAlpine syndrome and hypothyroidism

We report on 2 similarly affected cousins with a compound imbalance resulting from a familial t(5;9)(q34;p23) and entailing both an ～17-Mb 5q terminal duplication and an ～12-Mb 9p terminal deletion as determined by G-banding, subtelomere FISH, and aCGH. The proband's karyotype was 46,XX,der(9)t(5;9)(q34;p23)mat.ish der(9)t(5;9)(q34;p23)(9pter-,5qter+).arr 5q34q35(163,328,000-180,629,000)×3, 9p24p23(194,000-12,664,000)×1. Her cousin had the same unbalanced karyotype inherited from his father. The clinical phenotype mainly consists of a distinct craniofacial dysmorphism featuring microcephaly, flat facies, down slanting palpebral fissures, small flat nose, long philtrum, and small mouth with thin upper lip. Additional remarkable findings were craniosynostosis of several sutures, craniolacunia and preaxial polydactyly in the proband and hypothyroidism in both subjects. The observed clinical constellation generally fits the phenotypic spectrum of the 5q distal duplication syndrome (known also as Hunter-McAlpine syndrome), except for the thyroid insufficiency which can likely be ascribed to the concurrent 9p deletion, as at least 4 other 9pter monosomic patients without chromosome 5 involvement had this hormonal disorder. The present observation further confirms the etiology of the HMS phenotype from gain of the 5q35→qter region, expands the clinical pictures of partial trisomy 5q and monosomy 9p, and provides a comprehensive list of 160 patients with 5q distal duplication.     

Partial trisomy 10q occurring in a family with a reciprocal translocation t(10;18)(q25;q23).

Partial trisomy 10q was observed in an eighteen year old girl with severe mental and physical retardation, microcephaly, a high forehead, microphthalmia, antimongoloid slants, low set ears and severely malformed extremities. A balanced translocation t(10q-;18q+), present in several family members, was identified by fluorescence and thermic denaturation techniques; the break points were 10q25 and 18q23. A comparison made with seven similar cases suggests a common, phenotypical appearance which may be of diagnostic value.     

Complex translocation t(9;21)(9;22)(q12p13)(q12q11) in the family of a child with 9p trisomy syndrome

Summary Leukocyte peroxidase activity was estimated in 5 patients with the juvenile form of neuronal ceroid lipofuscinosis (Spielmeyer-Vogt's disease) and in 15 healthy controls. In contradiction to recent reports normal activity of p-phenylene diamine mediated peroxidase was found in the patients. The possible role of contamination of the white cell preparation with hemoglobin is discussed.     

Duplication 8 [inv dup(8)(p12p23)] with macrocephaly.

A 10-month old female is described with inv dup(8)(p12p23) who had macrocephaly with subtle changes in facial appearance and no structural birth defects. Her findings, together with those of 37 reported cases with inv dup (8), define a syndrome that emphasizes the importance of genes on the 8p region for brain development.     

A new case of monosomy for 17q25----qter due to a maternal translocation [t(3;17)(p12;q24)]

An 18-month-old girl was found to have monosomy for 17q25----qter which resulted from an unequal crossing-over in the mother carrying an apparently balanced translocation 46, XX, t(3;17) (p12;q24). Clinical features of the proband included: cleft palate, micrognathia and glossoptosis. It seems to be the first reported case where a single band deletion in the long arm of chromosome 17 has ever been noted.     

Congenital hyperthyroidism with reciprocal translocation t(1;17)(q25;q21)

Summary The authors report a case of 1;17 translocation and request contact with colleagues who have observed similar cases.