Molecular genetic advances in understanding craniosynostosis.
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Craniosynostoses↗
Biomedical subjects
N H Robin
Publications and source records attributed to N H Robin.
Nonpenetrance in FGFR3-associated coronal synostosis syndrome.
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Adult↗
Severe oculocerebrocutaneous (Delleman) syndrome: overlap with Goldenhar anomaly.
Oculocerebrocutaneous syndrome (OCCS), or Delleman syndrome, is a multiple congenital anomaly syndrome characterized by orbital cysts, cerebral malformations, and focal dermal hypoplasia [Delleman and Oorthuys, 1981, Clin Genet 19:191-198; Delleman et al., 1984, Clin Genet 25:470-472]. Two previous reports presented children having what is suggested as the more severe form of the OCCS syndrome who also had anophthalmia, congenital hydrocephalus, and cleft lip and palate [Leichtman et al., 1994, Am J Med Genet 50:39-41; Angle and Hersh, 1997, Am J Med Genet 68:39-42]. We report on a third case of severe OCCS, an infant girl with a similar constellation of findings and additional anomalies including lateral facial cleft, vertebral anomaly, and ventricular septal defect. The additional findings in our patient highlight the phenotypic overlap of OCCS and the Goldenhar anomaly, an overlap previously noted by Delleman and Oorthuys [1981], and others [Al-Gazali et al., 1988, J Med Genet 25: 773-778]. We suggest that the minimal diagnostic criteria for Delleman syndrome include central nervous system cyst or hydrocephalus, orbital cysts or microphthalmia, and focal skin defects.
Abnormalities, Multiple↗
Favorable prognosis for children with Pfeiffer syndrome types 2 and 3: implications for classification.
Pfeiffer syndrome (PS) is an autosomal dominant condition comprising bilateral coronal craniosynostosis, midface hypoplasia with a beaked nasal tip, and broad and medially deviated thumbs and great toes. It is a clinically variable disorder and has been divided into three subtypes [Cohen, 1993: Am J Med Genet 45:300-307]. Type 1 represents the less severe cases, while types 2 and 3 are the more severe cases. These latter types tend to have a higher risk for neurodevelopmental problems and a reduced life expectancy. Here we review the clinical course of seven children with PS type 3. All of these children had severe manifestations of PS; however, development was essentially normal in three, mild delay was noted in two, and moderate delay in one. Favorable outcomes in children with types 2 and 3 PS were also documented by Moore et al. [1995: Cleft Pal-Craniofac J 32:62-70]. These cases illustrate that while children with PS types 2 and 3 have an increased risk for neurodevelopmental difficulties, a favorable outcome can be achieved in some cases with aggressive medical and surgical management. Finally, although such management should be the rule for PS types 2 and 3, it needs to be remembered that normal outcome is not the rule. The prognosis for favorable neurodevelopmental outcome and/or life expectancy remains guarded in most cases.
Acrocephalosyndactylia↗
Pendular nystagmus in patients with peroxisomal assembly disorder.
BACKGROUND: Pendular nystagmus commonly occurs in congenital and acquired disorders of myelin. OBJECTIVE: To characterize the nystagmus in 3 siblings with an infantile form of an autosomal recessive peroxisomal assembly disorder causing leukodystrophy. DESIGN: We examined visual function and measured eye movements using infrared oculography. We noted changes in eye speed and frequency before and after the administration of gabapentin to 1 patient. RESULTS: All 3 siblings showed optic atrophy and pendular nystagmus that was predominantly horizontal, at a frequency of 3 to 6 Hz, with phase shifts of 45 degrees to 80 degrees between the oscillations of each eye. Gabapentin administered to 1 child caused a modest improvement of vision and the reduction of the velocity and frequency of oscillations in the eye with worse nystagmus. CONCLUSION: The pendular nystagmus in these patients was due to their leukodystrophy and may have a similar pathogenesis to the oscillations seen in other disorders affecting central myelin.
Adolescent↗
Picture of the month. Fragile X syndrome.
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Child↗
Deletion 22q11: a newly recognized cause of behavioral and psychiatric disorders.
BACKGROUND: Chromosome 22q11 deletion (del22q11), the most common microdeletion syndrome, causes a wide spectrum of clinical disorders. Recent studies have suggested that significant psychiatric and behavioral disturbances occur in up to 60% of these individuals. OBJECTIVE: To illustrate the spectrum of behavioral and psychiatric abnormalities associated with del22q11 and the subtle nature of its associated physical findings. PATIENTS AND METHODS: Case series describing psychiatric and behavioral findings in 3 patients with del22q11. RESULTS AND CONCLUSIONS: Behavioral and psychiatric problems are common in patients with del22q11 syndrome. Because the physical manifestations of the disorder are so variable and may be subtle, the behavioral and psychiatric manifestations may be the presenting problem. Providers must therefore consider del22q11 as a potential diagnosis in children and adults with behavioral and psychiatric problems. Furthermore, behavioral and psychiatric problems need to be looked for when caring for children and adolescents with a known diagnosis of del22q11.
Adolescent↗
Molecular characterization and delineation of subtle deletions in de novo "balanced" chromosomal rearrangements.
To test the hypothesis that the phenotypic abnormalities seen in cases with apparently balanced chromosomal rearrangements are the result of the presence of cryptic deletions or duplications of chromosomal material near the breakpoints, we analyzed three cases with apparently balanced chromosomal rearrangements and phenotypic abnormalities. We characterized the breakpoints in these cases by using microsatellite analysis by polymerase chain reaction and fluorescence in situ hybridization analysis of yeast artificial chromosome clones selected from the breakpoint regions. Molecular characterization of the translocation breakpoint in patient 1 [46,XY,t(2;6)(p22.2;q23.1)] showed the presence of a 4- to 6-Mb cryptic deletion between markers D6S412 and D6S1705 near the 6q23.1 breakpoint. Molecular characterization of the proximal inversion 7q22.1 breakpoint in patient 2 [46,XY,inv(7)(q22.1q32.1)] revealed the presence of a 4-Mb cryptic deletion between D7S651 and D7S515 markers. No deletion or duplication of chromosomal material was found near the breakpoints in patient 3 [46,XX,t(2;6)(q33.1;p12.2)]. Our study suggests that a systematic molecular study of breakpoints should be carried out in cases with apparently balanced chromosomal rearrangements and phenotypic abnormalities, because cryptic deletions near the breakpoints may explain the phenotypic abnormalities in these cases.
Abnormalities, Multiple↗
Stickler syndrome without eye involvement is caused by mutations in COL11A2, the gene encoding the alpha2(XI) chain of type XI collagen.
Eye involvement has been considered a principal component feature in Stickler syndrome. However, families lacking eye involvement have been reported. We describe such a family and show that their phenotype is due to a heterozygous 27 basepair deletion in the gene COL11A2, which encodes the alpha2(XI) chain of type XI collagen. This is the second family in whom a COL11A2 mutation has been found to cause Stickler syndrome without eye involvement. This result confirms the role of COL11A2 in the etiopathogenesis of this disorder.
Child, Preschool↗
Disorganization in mice and humans and its relation to sporadic birth defects.
Disorganization (Ds) is a mouse mutant best known for producing an exceptional variety of unusual developmental anomalies, such as mirror-limb duplications and hamartomatous skin papillae. So great is the range of malformations that no two affected mice are identical. Several patients with a similar variety of exceptional anomalies have been reported, raising the possibility of the existence of a human homologue of Ds. However, although these human cases represent the most striking findings seen in Ds mice, they do not represent the full range of defects. Most affected mice have only a single malformation, and most of these malformations are similar to both common (neural tube defects, orofacial clefting, gastroschisis, limb reductions) and rare (anophthalmia, duplicated rectum) human birth defects. It is therefore possible that the full spectrum of the human homologue of Ds includes not only patients with the unusual combination of anomalies but also common sporadic birth defects. We suggest that the low penetrance (approximately 0-30%) and highly variable expression of Ds make it a paradigm for understanding the genetic basis for many seemingly sporadic birth defects.
Abnormalities, Multiple↗
Duplication 14(q24.3q31) in a father and daughter: delineation of a possible imprinted region.
A number of clinical reports have described children with a variety of congenital anomalies in association with uniparental disomy (upd) of chromosome 14, suggesting that at least some genes on chromosome 14 are subject to parent of origin, or imprinting, effects. However, little else is known about this putative imprinting of chromosome 14. Both maternal and paternal upd have been observed, but a consistent phenotype has only been suggested for the former. Here we report on a child with developmental delay, microcephaly, distinct facial findings, and who has a duplication of 14q24.3q31. The same cytogenetic abnormality was found in her phenotypically normal father. We hypothesize that this segment of chromosome 14 contains maternally silenced genes, and that this duplicated segment defines an imprinted region on chromosome 14. Alternatively, this cytogenetic duplication may be unrelated to the girl's phenotypic anomalies, and this duplication may contain genes that are not subject to dosage effect.
Abnormalities, Multiple↗
Sibs with cleidocranial dysplasia born to normal parents: germ line mosaicism?
Cleidocranial dysplasia (CCD) is classically an autosomal dominant disorder. However, the possibility of an autosomal recessive form of CCD has been suggested based on a report of 2 consanguineous families, one with a single affected child, the second with affected sibs, born to normal parents. We present a family with sibs with CCD born to normal parents, and suggest germ line mosaicism as the more likely mechanism for this occurrence.
Cleidocranial Dysplasia↗
Clinical and locus heterogeneity in brachydactyly type C.
Brachydactyly type C is characterized by shortness of the second and fifth middle phalanges and the first metacarpal. It is inherited as an autosomal dominant trait, and is noted for its widely variable clinical phenotype both within and between families. In most families involvement is limited to the hands. However, in some families additional skeletal and non-skeletal findings have been reported. We report on 12 affected members from a 5 generation kindred that segregates a brachydactyly type C phenotype. All affected individuals had shortness principally affecting the second and fifth phalanges and first metacarpal. However, the metacarpal-phalangeal profile indicated that other digital elements were short as well. In addition, one affected individual had a bilateral Madelung deformity, but none had foot involvement. No other non-skeletal findings cosegregated with brachydactyly in this family. Recently, a gene for brachydactyly type C has been localized to 12q24. This was done by studying a large kindred first reported by Haws [1963], which manifests both hand and foot anomalies. Here we present linkage data which excludes the 12q24 locus in our kindred, indicating locus heterogeneity as one explanation for the interfamilial variability described in brachydactyly type C.
Adolescent↗
Recurrent immune cytopenias in two patients with DiGeorge/velocardiofacial syndrome.
We describe two patients with clinical and cytogenetic findings consistent with DiGeorge/velocardiofacial syndrome who had recurrent cytopenias at presentation. Our observations suggest that recurrent cytopenias may be part of the clinical spectrum of deletion 22q11.2. We also suggest that the diagnosis of DG/VCF syndrome be considered in patients with unexplained recurrent immune cytopenias in association with cardiac lesions, subtle craniofacial dysmorphisms, and/or learning or behavioral impairments.
Adolescent↗
Mutations in CDMP1 cause autosomal dominant brachydactyly type C.
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Base Sequence↗
A novel phenotypic pattern in X-linked inheritance: craniofrontonasal syndrome maps to Xp22.
Craniofrontonasal syndrome (CFNS, OMIM 304110) is a distinctive genetic disorder whose main clinical manifestations include coronal synostosis, widely spaced eyes, clefting of the nasal tip and various skeletal anomalies. CFNS originally was thought to be transmitted as an autosomal dominant trait, but recent studies suggest that it is X-linked dominant, whereby all daughters of males are affected, whereas none of their sons are affected. Here we report data confirming that CFNS is X-linked, mapping to a 13 cM interval in Xp22 with a maximum two-point lod score of 3.9 (theta = 0) at DXS8022 and a multipoint lod score of 5.08 at DXS1224. Detailed phenotypic analysis shows that females are more severely affected than males, a highly unusual characteristic for an X-linked disorder. CFNS represents the first multiple congenital anomaly syndrome with this unusual phenotypic pattern of X-linked inheritance.
Chromosome Mapping↗