Holoprosencephaly and cleidocranial dysplasia in a patient due to two position-effect mutations: case report and review of the literature.

Holoprosencephaly (HPE) is a genetically heterogeneous developmental field defect in which midline cleavage of the forebrain and craniofacial structures is impaired. Based on the analysis of HPE patients with chromosome rearrangements, at least six loci for the disorder have been assigned. The sonic hedgehog gene (SHH) at 7q36 has been identified as the HPE3 locus. Cleidocranial dysplasia (CCD) is an autosomal dominant skeletal disorder characterized by clavicular, pelvic and dental anomalies. It is caused by mutations in the osteoblast-specific transcription factor CBFA1/RUNX2, which maps to 6p21. We report a 20-year-old female with premaxillary agenesis (part of the HPE spectrum), as well as skeletal abnormalities and impacted teeth reminiscent of CCD. She carries a de novo 6;7 reciprocal translocation, with breakpoints at 6p21.1 and 7q36. We have shown previously that the 7q36 breakpoint maps 15 kb telomeric to the 5' end of SHH, which explains the patient's HPE phenotype. Now, using fluorescence in situ hybridization, we have identified a P1 artificial chromosome clone 800 kb upstream of CBFA1/RUNX2 that spans the 6p breakpoint. We propose that the proband's complex phenotype is due to two position-effect (PE) mutations, one at each translocation breakpoint, which have altered the expression of the SHH and CBFA1/RUNX2 genes. The role of PE mutations in human disease is also reviewed.

Velo-cardio-facial syndrome: Implications of microdeletion 22q11 for schizophrenia and mood disorders.

Velo-cardio-facial syndrome (VCFS) is a congenital malformation syndrome with variable phenotypic features that has been associated with chromosomal microdeletion 22q11.2. Psychiatric disorders have been reported to be highly prevalent in individuals with this syndrome, and the objective of this study was to assess the nature and extent of psychopathology among individuals with VCFS. We studied 20 children and adolescents with 22q11 deletions determined by fluorescence in situ hybridization (FISH). Control subjects were 11 nondeleted siblings who were the closest age match to the affected subjects. Both affected and control subjects were assessed using two standardized psychiatric research instruments. The results of this study confirmed the high rate of psychiatric disorders among VCFS subjects (60% of our subjects). Of the specific types of disorders, only mood disorders were significantly more common among VCFS subjects compared to sibling controls, with eight VCFS subjects having mood disorders compared with none of the control subjects (P<0.02). Three affected subjects had schizotypal traits comorbid with a mood disorder. In addition, disruptive behavior disorders were frequently diagnosed among VCFS subjects. Using a dimensional measure of psychopathology, significant differences between VCFS subjects and sibling controls were found on three scales: ADHD (P<0.02), separation anxiety (P<0.02), and depression (P<0.01). VCFS subjects were achieving significantly less well academically and requiring significantly more special educational assistance than sibling controls. Follow-up data were available on two subjects, both of whom had been diagnosed with schizophrenia. Further research on psychopathology in VCFS may provide a model of how a specific genetic defect can lead to the development of psychiatric disorders.

Cutaneous telangiectasias, sparse hair, and type I membranoproliferative glomerulonephritis.

We report the unusual association of normocomplementemic type I membranoproliferative glomerulonephritis in a 10-year-old girl with sparse red hair, absent eyebrows and eyelashes, cutaneous telangiectasias, and an atrial septal defect.

Congenital cytoplasmic body myopathy with survival motor neuron gene deletion or Werdnig-Hoffmann disease.

A 5-week-old boy became rigid and developed cardiac arrest after receiving succinylcholine. He was resuscitated and ventilated but died at 5 months. Muscle biopsy demonstrated no neurogenic features and numerous cytoplasmic bodies, suggesting the possibility of congenital myopathy with cytoplasmic bodies. However, molecular analysis revealed a homozygous deletion of exons 7 and 8 of the survival motor neuron (SMN) gene, suggesting that the patient had Werdnig-Hoffmann disease. We recommend that every patient with congenital cytoplasmic body myopathy be tested for SMN gene deletion.

FGFR2 mutation associated with clinical manifestations consistent with Antley-Bixler syndrome.

The Antley-Bixler syndrome (ABS) is a rare syndrome with synostosis of cranial sutures and elbow joints as minimal diagnostic criteria. The inheritance has been suggested to be autosomal recessive based on two families with sib recurrence with both sexes being affected, and two cases born to consanguineous parents. We report the first case of ABS associated with an apparent dominant de novo mutation in the fibroblast growth factor receptor 2 (FGFR2) gene. The patient was found to be heterozygous for a C-->G transversion at nucleotide 1064, which predicts a Ser351Cys amino acid substitution in the IgIII domain of FGFR2. Apart from the craniosynostosis and elbow ankylosis, our patient also presented with severe spinal dysraphism, the first report of such a finding in association with ABS. This suggests that FGFR2 is expressed as early as the fourth week of embryogenesis when somite formation occurs. We propose that the Antley-Bixler syndrome is an autosomal dominant condition with possible gonadal mosaicism. Alternatively, there may be two types of ABS: an autosomal dominant form and an autosomal recessive form. In light of our findings, FGFR mutations should be looked for in other craniosynostosis patients with elbow synostosis.

Familial ileal perforation: prenatal diagnosis and postnatal follow-up.

We report sibs (a brother and a sister) who presented prenatally with ultrasound findings of meconium peritonitis and postnatally were found to have perforation of the terminal ileum. The sister presented with fetal ultrasound findings of severe ascites and peritoneal calcifications. She had no prenatal intervention and was born at 38 weeks' gestation. Laparatomy revealed perforation of the terminal ileum with meconium peritonitis. Her post-surgical course was uncomplicated and at 30 months of age her growth and development are normal. Her brother presented prenatally with signs of meconium peritonitis including severe ascites and peritoneal calcifications. Prenatal aspiration of the ascitic fluid was performed and unlike his sister he was born prematurely, was operated on at 8 days, and developed bronchopulmonary dysplasia. He is currently 1 year old and has normal growth and development. The aetiology of the ileal perforation is not known. There were no findings suggesting connective tissue disorder and the aetiology of the intestinal perforation is not known. The occurrence of the same rare abnormality in sibs of different sexes points towards an autosomal recessive disorder.

MRI findings in macrocephaly-cutis marmorata telangiectatica congenita.

We describe a child with macrocephaly-cutis marmorata telangiectatica congenita (M-CMTC), cherry red macules, megalencephaly with hemifacial and segmental overgrowth, macrosomia, and cutis marmorata telangiectasia congenita of the trunk, and visceral and subcutaneous cavernous hemangiomas. The megalencephaly is accompanied by MRI findings of CNS dysgenesis with protrusion of the cerebellar tonsils through the foramen magnum (Chiari I), lumbar syrinx, and hydrops of the optic nerves. The report of this additional patient further confirms the newly described macrocephaly-cutis marmorata telangiectatica congenita as a distinct clinical phenotype.

Cytogenetic rearrangements involving the loss of the Sonic Hedgehog gene at 7q36 cause holoprosencephaly.

Holoprosencephaly (HPE) is a genetically heterogeneous disorder that affects the midline development of the forebrain and midface in humans. As a step toward identifying one of the HPE genes, we have set out to refine the HPE3 critical region on human chromosome 7q36 by analyzing 34 cell lines from families with cytogenetic abnormalities involving 7q, 24 of which are associated with HPE. Genomic clones surrounding the DNA marker D7S104, which has previously been shown to be in the HPE3 critical region, have been examined by fluorescent in situ hybridization and microsatellite analysis of our panel of patient cell lines. We report the analysis of a cluster of four translocation breakpoints within a 300-kb region of 7q36 that serves to define the minimal critical region for HPE3 and that has directed the search for candidate genes. The human Sonic Hedgehog (hSHH) gene maps to this region and has been shown to be HPE3 on the basis of mutations within the coding region of the gene. We present evidence that cytogenetic deletions and/or rearrangements of this region of chromosome 7q containing Sonic Hedgehog, and translocations that may suppress Sonic Hedgehog gene expression through a position effect are common mechanisms leading to HPE.

Computerized videokeratography of keratoconus kindreds.

OBJECTIVE: To assess the role of heredity in the development of keratoconus. DESIGN: Prospective study. SETTING: Eye clinic providing secondary and tertiary ophthalmic care in Toronto. PATIENTS: Thirty-nine patients with keratoconus (57 eyes) and 48 relatives of 11 patients with keratoconus. The corneal topography of the family members was compared with that of a group of 68 volunteer control subjects (136 eyes) without clinical evidence or a family history of keratoconus. OUTCOME MEASURES: Three quantitative measures derived from computerized videokeratography: the relative steepness of the inferior cornea versus the superior cornea, central corneal power and the difference in central corneal power between the two eyes. All the data were statistically analysed with the use of nonparametric discriminant analysis. RESULTS: Fifteen family members who were believed to be clinically normal on the basis of refraction, keratometry and slit-lamp examination has statistically significant topographic abnormalities suggestive of early or mild keratoconus. CONCLUSIONS: The presence of these findings in family members of patients with keratoconus may represent the incomplete expression of a gene contributing to the development of the condition. Pedigree analysis suggested an autosomal dominant inheritance pattern in 9 of the 11 families. Our results underline the value of videokeratography for accurate family pedigree analysis and the diagnosis of keratoconus.

Deletion 4q21/4q22 syndrome: two patients with de novo 4q21.3q23 and 4q13.2q23 deletions.

We report on 2 patients with de novo proximal interstitial deletions of the long arm of chromosomes 4: in one the deletion resulted in monosomy (4)(q21.3q23), in the other it produced monosomy (4)(q13.2q23). Review of 9 cases of deletions involving the 4q21/4q22 region reported previously detected a characteristic phenotype in 8 patients. This phenotype was present in our patients. We conclude that the deletion in the 4q21/4q22 region results in a specific clinical syndrome associated with central nervous system overgrowth that may be a result of anomalous imprinting in the 4q21/4q22 region.

Hirschsprung disease, postaxial polydactyly, and atrial septal defect.

We report on an infant girl with Hirschsprung disease, postaxial polydactyly, and atrial septal defect who was born to a consanguineous Iraqi couple. A similar condition of aganglionic megacolon, postaxial polydactyly, and ventricular septal defect with a presumed autosomal recessive (AR) inheritance was reported by Laurence in two sibs [Laurence et al.; J Med Genet 12: 334-338, 1975].

Cloning and characterization of a novel bicoid-related homeobox transcription factor gene, RIEG, involved in Rieger syndrome.

Rieger syndrome (RIEG) is an autosomal-dominant human disorder that includes anomalies of the anterior chamber of the eye, dental hypoplasia and a protuberant umbilicus. We report the human cDNA and genomic characterization of a new homeobox gene, RIEG, causing this disorder. Six mutations in RIEG were found in individuals with the disorder. The cDNA sequence of Rieg, the murine homologue of RIEG, has also been isolated and shows strong homology with the human sequence. In mouse embryos Rieg mRNA localized in the periocular mesenchyme, maxillary and mandibular epithelia, and umbilicus, all consistent with RIEG abnormalities. The gene is also expressed in Rathke's pouch, vitelline vessels and the limb mesenchyme. RIEG characterization provides opportunities for understanding ocular, dental and umbilical development and the pleiotropic interactions of pituitary and limb morphogenesis.

Identification of Sonic hedgehog as a candidate gene responsible for holoprosencephaly.

Holoprosencephaly (HPE) is a genetically and phenotypically heterogenous disorder involving the development of forebrain and midface, with an incidence of 1:16,000 live born and 1:250 induced abortions. This disorder is associated with several distinct facies and phenotypic variability: in the most extreme cases, anophthalmia or cyclopia is evident along with a congenital absence of the mature nose. The less severe form features facial dysmorphia characterized by ocular hypertelorism, defects of the upper lip and/or nose, and absence of the olfactory nerves or corpus callosum. Several intermediate phenotypes involving both the brain and face have been described. One of the gene loci, HPE3, maps to the terminal band of chromosome 7. We have performed extensive physical mapping studies and established a critical interval for HPE3, and subsequently identified the sonic hedgehog (SHH) gene as the prime candidate for the disorder. SHH lies within 15-250 kilobases (kb) of chromosomal rearrangements associated with HPE, suggesting that a 'position effect' has an important role in the aetiology of HPE. As detailed in the accompanying report, this role for SHH is confirmed by the detection of point mutations in hereditary HPE patients.

FISH detection of chromosome 15 deletions in Prader-Willi and Angelman syndromes.

We have evaluated fluorescence in situ hybridization (FISH) analysis for the clinical laboratory detection of the 15q11-q13 deletion seen in Prader-Willi syndrome (PWS) and Angelman syndrome (AS) using probes for loci D15S11, SNRPN, D15S10, and GABRB3. In a series of 118 samples from patients referred for PWS or AS, 29 had deletions by FISH analysis. These included two brothers with a paternally transmitted deletion detectable with the probe for SNRPN only. G-banding analysis was less sensitive for deletion detection but useful in demonstrating other cytogenetic alterations in four cases. Methylation and CA-repeat analyses of 15q11-q13 were used to validate the FISH results. Clinical findings of patients with deletions were variable, ranging from newborns with hypotonia as the only presenting feature to children who were classically affected. We conclude that FISH analysis is a rapid and reliable method for detection of deletions within 15q11-q13 and whenever a deletion is found, FISH analysis of parental chromosomes should also be considered.

Infantile lethal variant of Simpson-Golabi-Behmel syndrome associated with hydrops fetalis.

Simpson-Golabi Behmel syndrome (SGBS) is an X-linked disorder characterized by pre- and postnatal macrosomia, minor facial anomalies, and variable visceral, skeletal, and neurological abnormalities. Since its first description by Simpson et al. [1975: BD:OA XI(2):18-24], a wide clinical range of cases has been reported. There is great variability in severity, ranging from a mild form associated with long-term survival to an early lethal form with multiple congenital anomalies and severe mental retardation. In 8 reported families, affected individuals died in infancy. Here we present 4 maternally related, male cousins with a severe variant of SGBS. One of these males was aborted therapeutically at 19 weeks of gestation following the detection of multicystic kidneys on ultrasound. The 3 liveborn males were hydropic at birth with a combination of craniofacial anomalies including macrocephaly; apparently low-set, posteriorly angulated ears; hypertelorism; short, broad nose with anteverted nares; large mouth with thin upper vermilion border; prominent philtrum; high-arched or cleft palate; short neck; redundant skin; hypoplastic nails; skeletal defects involving upper and lower limbs; gastrointestinal and genitourinary anomalies. All 3 patients were hypotonic and neurologically impaired from birth. With the exception of a trilobate left lung in one patient, the cardiorespiratory system was structurally normal. All patients died within the first 8 weeks of life of multiple complications including pneumonia and sepsis. Two SGBS kindreds, with moderate expression of the condition, have been mapped to Xq27. It is not known whether severe, familial cases, such as ours, are genetically distinct from and map to another locus. Final resolution of the genetic basis of the phenotypic variability in SGBS must await cloning and mutation analysis of the SGBS gene(s).

A 4-megabase YAC contig that spans the Langer-Giedion syndrome region on human chromosome 8q24.1: use in refining the location of the trichorhinophalangeal syndrome and multiple exostoses genes (TRPS1 and EXT1).

We have constructed a physical map covering over 4 Mb of human chromosome 8q24.1 and used this map to refine the locations of the genes responsible for Langer-Giedion syndrome. The map is composed of overlapping YAC clones that were identified and ordered in relation to sequence tagged sites mapped to the Langer-Giedion chromosomal region on somatic cell hybrids. The minimal region of overlap of Langer-Giedion syndrome deletions, previously identified by analysis of 15 patients, was placed on the map by analysis of 2 patients whose deletions define the endpoints. The chromosome 8 breakpoint of a balanced t(8;9)(q24.11;q33.3) translocation from a patient with trichorhinophalangeal syndrome (TRPS I) was found to be located just within the proximal end of the minimal deletion region. A deletion of 8q24.11-q24.3 in a patient with multiple exostoses was found to overlap the distal end of the LGS deletion region, indicating that the EXT1 gene is distal to the TRPS1 gene and supporting the hypothesis that Langer-Giedion syndrome is due to loss of functional copies of both the TRPS1 and the EXT1 genes.

A gene for cleidocranial dysplasia maps to the short arm of chromosome 6.

Cleidocranial dysplasia (CCD) is an autosomal dominant generalized bone dysplasia characterized by mild-to-moderate short stature, clavicular aplasia or hypoplasia, supernumerary and ectopic teeth, delayed eruption of secondary teeth, a characteristic craniofacial appearance, and a variety of other skeletal anomalies. We have performed linkage studies in five families with CCD, with 24 affected and 20 unaffected individuals, using microsatellite markers spanning two candidate regions on chromosomes 8q and 6. The strongest support for linkage was with chromosome 6p microsatellite marker D6S282 with a two-point lod score of 4.84 (theta = .03). Furthermore, the multipoint lod score was 5.70 in the interval between D6S282 and D6S291. These data show that the gene for autosomal dominant CCD is located within a 19-cM interval on the short arm of chromosome 6, between D6S282 and D6S291.

Molecular characterization of the marker chromosome associated with cat eye syndrome.

Cat eye syndrome (CES) is associated with a supernumerary bisatellited marker chromosome which is derived from duplicated regions of 22pter-22q11.2. In this study we have used dosage and RFLP analyses on 10 CES patients with marker chromosomes, by using probes to five loci mapped to 22q11.2. The sequences recognized by the probes D22S9, D22S43, and D22S57 are in four copies in all patients, but the sequences at the more distal loci, D22S36 and D22S75, are duplicated only in some individuals. D22S36 is present in three copies in some individuals, and D22S75 is present in two copies in the majority of cases. Only three individuals have a duplication of the most distal locus examined (D22S75), and these individuals have the largest marker chromosomes identified in this study. From the dosage analysis it was found that the marker chromosomes are variable in size and can be asymmetric in nature. There is no obvious correlation between the severity of the phenotype and the size of the duplication. The distal boundary of the CES critical region (D22S36) is proximal to that of DiGeorge syndrome, a contiguous-gene-deletion syndrome of 22q11.2.