Two new cases of pure 1q terminal deletion presenting with brain malformations

We describe two new cases of pure 1q terminal deletions. BAC FISH analysis precisely defined the size of deletions. The first is a girl with 10.3-Mb deletion showed typical features of 1q43 deletion as well as a simplified gyral pattern, which was rarely found in 1q43 deletion. The other boy also presented with most of 1q43 deletion features but several atypical symptoms were noted including hydrocephalus, adducted thumbs, and flexion restriction of proximal interphalangeal joints in left hand. A concomitant novel missense mutation in L1CAM was identified in addition to 11.5-Mb deletion. Reviewing all the cases of pure 1q terminal deletion in the literature suggests that it is a clinically recognizable syndrome.     

18p— syndrome with a single central maxillary incisor

A child with a single central maxillary incisor and a deletion of the short arm of chromosome 18 (18p—) is presented. He is the first patient in whom this association has been found.     

Caudal deficiency sequence in 7q terminal deletion

We describe a male infant with signs of caudal deficiency sequence. In addition, he showed growth retardation, microcephaly, prominent forehead, bulbous nose tip, large dysplastic ears, hypospadia, partial sacral agenesis, and neurologic bladder dysfunction. Chromosome examination showed a terminal 7q deletion 46,XY,del(7)(pter----q32:). Four previous reported cases of 7q terminal deletion and signs of caudal deficiency are reviewed. Chromosome aberrations may, at least in some cases, be responsible for developmental defects.     

Single central maxillary incisor and holoprosencephaly

A holoprosencephalic child was born to a mother with a single central maxillary incisor. The infant had a median cleft lip, a flat nose with a single nostril, hypotelorism, and normal chromosomes. The head was brachycephalic and small, and computed tomography (CT) of the brain showed semilobar holoprosencephaly. The mother had mild hypotelorism but no anosmia, and her brain CT was normal. She was of normal intelligence and stature. Other relatives did not have single central maxillary incisors, hypotelorism, or oral clefts. Whether the mother's anomaly was a new mutation or had been inherited is unknown. We show the significance of a single central maxillary incisor as an indicator or potential holoprosencephaly in the next generation, even if other relatives are apparently normal.     

Velocardiofacial syndrome with single central incisor

Three siblings and their mother are reported who all had cytogenetically proven velocardiofacial syndrome (VCFS). One boy had normal dental and craniofacial findings, except for an increased cranial base angle. His sister had only one central incisor in the maxilla. One central incisor had also been missing in the primary dentition. She had no labial frenulum present. Cephalometry showed a small maxillary unit length indicating mild maxillary hypoplasia, an increased anterior face height, steep mandibular plane angle, retruded chin, and a large cranial base angle. Dental measurements showed retroclined lower incisors and increased interincisal angle. A second sister had a cleft of the secondary palate. All permanent teeth were present with the exception of a missing central incisor in the lower jaw: the single lower central incisor was situated in the midline. Her cephalometry showed similar findings as in her sister. All three siblings required palate surgery for speech. Mother was not available for detailed dental and other oral investigations. A single maxillary central incisor has previously been reported in VCFS, but to our knowledge a single central incisor in the mandible has not been reported previously in this entity.     

Currarino triad with a terminal deletion 7q35-->qter.

We describe a de novo terminal deletion of the long arm of chromosome 7 in a 5 year old girl with the Currarino triad, characterised by congenital anorectal stenosis, a sacral defect, and a presacral mass. Recently, this autosomal dominant trait has been shown to be linked to 7q36, the same region as holoprosencephaly (HPE3). The cytogenetic findings in the present patient with the Currarino triad provided further evidence that a gene(s) for the Currarino triad is located in the 7 q terminal segment.     

Patient with terminal duplication 3q and terminal deletion 5q: comparison with the 3q duplication syndrome and distal 5q deletion syndrome

Partial duplication of chromosome 3q is a well-described condition of multiple congenital anomalies and developmental delay that resembles the Brachmann-de Lange syndrome. Similarly, an emerging phenotype of a distal 5q deletion syndrome has recently been described. The combination of both chromosome abnormalities has not been previously described. We report on a child with both a de novo duplication of distal 3q (q27 --> qter) and terminal deletion of 5q (q35.2 --> qter). The patient had facial anomalies, hypoplastic toenails, lymphedema of the dorsum of the feet, type I Chiari malformation, a seizure disorder, and moderate developmental delays. The phenotype is compared and contrasted to the few reports of patients with similar terminal 3q duplications and 5q deletions. Our patient did not have the characteristic phenotype of the 3q duplication syndrome, suggesting that the chromosome region responsible for this phenotype is more proximal than the terminal 3q27 region. In addition, comparison with three other reported cases of terminal 5q35 deletions suggests a possible association of terminal 5q deletions with central nervous system (CNS) structural abnormalities.     

Skewed sex ratios in familial holoprosencephaly and in people with isolated single maxillary central incisor

Autosomal dominant holoprosencephaly is a rare but well documented entity and it can be the result of mutations in the Sonic Hedgehog gene (SHH). The transmitting parent may be normal or have a single maxillary central incisor. We describe a skewed sex ratio among the transmitting parents with SHH mutations, with more mothers than fathers having the mutation (p=0.002). The mechanism underlying this skewed sex ratio is not clear; the SHH mutations do not involve triplet repeats, imprinting is plausible but untested, and there is no evidence that the risk of holoprosencephaly is greater among males carrying such a mutation (p=0.15). We considered the possibility that males with such a mutation are at greater risk of other malformations outside the central nervous system, which could reduce their reproductive fitness. To avoid ascertainment bias in identifying children with various malformations in kindreds with familial holoprosencephaly, we reviewed the reports of people with single maxillary central incisor and no other congenital malformations. Of the 16 cases identified, 13 were female (p=0.0085). We suggest that boys with mutations associated with autosomal dominant holoprosencephaly may be at greater risk of major malformations outside the central nervous system than girls.     

DiGeorge syndrome associated with solitary median maxillary central incisor

DiGeorge syndrome is a primary immunodeficiency disease characterized by dysgenesis of the thymus and parathyroid glands, conotruncal cardiac anomalies, and other dysmorphic features. Although most patients have a common microscopic deletion in chromosome 22q11.2, marked clinical variability exists. A solitary median maxillary central incisor (SMMCI) is a rare dental anomaly which may be an isolated occurrence or associated with congenital nasal airway abnormalities or holoprosencephaly. We report a patient with DiGeorge syndrome who was diagnosed at nearly 1 month of age and was later found to have a solitary median central incisor. Initially, the patient presented with recurrent episodes of respiratory distress attributed to partial airway obstruction, one of the phenotypic features of SMMCI. A fluorescence in situ hybridization study showed a chromosome 22q11.2 deletion.     

Single maxillary central incisor and holoprosencephaly]

A holoprosencephalic female was born to a mother with a single central maxillary incisor. The newborn had microcephaly, hypotelorism, cebocephaly, palatoschisis, micrognathia, and normal chromosomes. Her brain computed tomography showed alobar holoprosencephaly. The mother was of normal intelligence and stature, and her brain computed tomography was normal. Other relatives did not have single central maxillary incisors, hypotelorism, or oral clefts. We show a further evidence of a single central maxillary incisor as an indicator of potential holoprosencephaly in the next generation, confirming an autosomal dominant trait with wide variety in penetrance and expressivity.     

Two discrete regions of deletion at 7q in uterine leiomyomas

This study further defines the region of consistent deletion of chromosome 7 in uterine leiomyomas. We have examined 74 leiomyomas for allelic loss of markers spanning the 7q22 region defined by markers D7S518 and D7S471. Forty tumors with cytogenetically defined 7q deletions, twenty-nine tumors without cytogenetically visible 7q deletions, and five tumors with no cytogenetic information were examined for allelic loss of D7S518, D7S666, D7S515, D7S658, D7S496, D7S692, and D7S471. Loss of heterozygosity for one or more of these loci was observed in twenty-eight leiomyomas with cytogenetically defined 7q deletions and in three leiomyomas with a normal karyotype. Allelic loss of D7S666 was common and was observed in all twenty-three informative tumors with 7q deletions and in two tumors with normal karyotypes. This study indicates the presence of a tumor suppressor gene in close proximity to the D7S666 locus. Eight tumors followed an unusual pattern of allelic loss. These tumors showed retention of heterozygosity for at least one locus flanked by deleted loci. These results suggest the possibility that two discrete regions of deletion at 7q22 are involved in the development of a subset of leiomyomas. Genes Chromosom. Cancer 19:156–160, 1997. © 1997 Wiley-Liss Inc.     

Clinical phenotype associated with terminal 2q37 deletion

Three children with deletions of the terminal portion of the long arm of chomosome 2 [del (2) (q37)] are described and their clinical findings compared to published cases of 2q terminal deletions. Common clinical findings include development delay, macrocephaly, frontal bossing, depressed nasal bridge and cardiac anomaly. Hypotonia and repetitive behavior are also seen during different times of development. The facial characteristics of children with 2q terminal deletions are not uniform, but development delay is a constant finding. Chromosomal analysis of such children using high resolution banding may uncover the diagnosis of a small chromosomal deletion.     

Prenatal diagnosis of terminal deletion 7q and partial trisomy 3p in fetuses with holoprosencephaly

Chromosome aberrations, mendelian mutations and exogenous agents can cause holoprosencephaly. Therefore, etiologic evaluation of holoprosencephaly is necessary for obstetricians and genetic counselors, once a prenatal diagnosis of holoprosencephaly has been made. We present four pregnancies in three women in which routine sonographic examinations led to the prenatal diagnosis of holoprosencephaly. Prenatal cytogenetic analysis and fluorescence in situ hybridization demonstrated a 46, XY, del(7)(pter→q32:) and a 46, XY, der(2)t(2;3)(q37;p21)pat karyotype respectively in two fetuses with cyclopia, and a 46, XX, der(2)t(2;3)(q37;p21)pat and a 46, XX, der(7)t(3;7)(p23;q36) karyotype respectively in two fetuses with premaxillary agenesis. In conclusion, terminal deletion 7q and partial trisomy 3p in holoprosencephalic fetuses indicates that genes contributing to craniofacial development reside in these critical regions. Proper prognostic evaluation in further pregnancies requires expertise in cytogenetics and genetic counseling.     

The 11q terminal deletion disorder: a prospective study of 110 cases

We performed a prospective study of 110 patients (75 not previously published) with the 11q terminal deletion disorder (previously called Jacobsen syndrome), diagnosed by karyotype. All the patients have multiple dysmorphic features. Nearly all the patients (94%) have Paris-Trousseau syndrome characterized by thrombocytopenia and platelet dysfunction. In total, 56% of the patients have serious congenital heart defects. Cognitive function ranged from normal intelligence to moderate mental retardation. Nearly half of the patients have mild mental retardation with a characteristic neuropsychiatric profile demonstrating near normal receptive language ability, but mild to moderate impairment in expressive language. Ophthalmologic, gastrointestinal, and genitourinary problems were common, as were gross and fine motor delays. Infections of the upper respiratory system were common, but no life-threatening infections were reported. We include a molecular analysis of the deletion breakpoints in 65 patients, from which genetic "critical regions" for 14 clinical phenotypes are defined, as well as for the neuropsychiatric profiles. Based on these findings, we provide a comprehensive set of recommendations for the clinical management of patients with the 11q terminal deletion disorder.     

Microphthalmia with single central incisor and hypopituitarism.

A patient is described with a new association of microphthalmia, single central incisor, and hypopituitarism believed to represent a holoprosencephaly malformation. In view of the genetic ramifications of this malformation and its variable manifestations, we would like to alert the clinician to consider holoprosencephaly whenever midline malformations are detected.     

9q34.3 deletion syndrome in three unrelated children

We described three unrelated children with cryptic 9q34.3 rearrangements and similar clinical manifestations: two with 9q34.3 terminal deletions and the other with an unbalanced translocation involving 9q34.3-qter monosomy and 6p25-pter trisomy. Common features among the three we studied and the other six patients with 9q34.3 deletions in the literature include microcephaly, mental retardation (MR), hypotonic, and epileptic seizures. Their facial characteristics included flat face, arched eyebrows, synophrys, hypertelorism, short nose, anteverted nostrils, carp mouth, protruding tongue, micrognathia, and pointed chin. Other frequent abnormalities were cardiac abnormalities, cryptorchidism or hypospadias, and abnormal toes. These findings are characteristic enough to be a clinically recognizable syndrome.