Additional copies of the proteolipid protein gene causing Pelizaeus-Merzbacher disease arise by separate integration into the X chromosome.

The proteolipid protein gene (PLP) is normally present at chromosome Xq22. Mutations and duplications of this gene are associated with Pelizaeus-Merzbacher disease (PMD). Here we describe two new families in which males affected with PMD were found to have a copy of PLP on the short arm of the X chromosome, in addition to a normal copy on Xq22. In the first family, the extra copy was first detected by the presence of heterozygosity of the AhaII dimorphism within the PLP gene. The results of FISH analysis showed an additional copy of PLP in Xp22.1, although no chromosomal rearrangements could be detected by standard karyotype analysis. Another three affected males from the family had similar findings. In a second unrelated family with signs of PMD, cytogenetic analysis showed a pericentric inversion of the X chromosome. In the inv(X) carried by several affected family members, FISH showed PLP signals at Xp11.4 and Xq22. A third family has previously been reported, in which affected members had an extra copy of the PLP gene detected at Xq26 in a chromosome with an otherwise normal banding pattern. The identification of three separate families in which PLP is duplicated at a noncontiguous site suggests that such duplications could be a relatively common but previously undetected cause of genetic disorders.

Fryns syndrome: neurologic findings in a survivor.

Fryns syndrome, a multiple congenital anomaly syndrome associated with diaphragmatic defects, craniofacial dysmorphism, distal digital hypoplasia, and neurologic abnormalities, was first described in 1979. This autosomal recessive disorder is usually associated with stillbirth or death immediately after birth. Detailed neurologic findings in the third survivor beyond the neonatal period are reported, and neurologic abnormalities in other cases are reviewed. Initially, hypotonia, areflexia, and weakness were seen. Myoclonus developed immediately after birth and was well controlled with high-dose valproate. Electroencephalography revealed slowing and irregular paroxysmal discharges with spikes and sharp waves that disappeared with time and treatment. Magnetic resonance imaging demonstrated partial agenesis of the corpus callosum, a Dandy-Walker malformation, and progressive cerebral and brainstem atrophy. This syndrome should be considered in patients with unusual facial features and digital abnormalities associated with frequent early myoclonus.

Blepharophimosis, ptosis, and epicanthus inversus syndrome (BPES) associated with interstitial deletion of band 3q22: review and gene assignment to the interface of band 3q22.3 and 3q23.

We report on a child with blepharophimosis, ptosis, and epicanthus inversus (BPES), developmental delay and an interstitial deletion of band q22 of chromosome 3. A review of chromosome 3q anomalies associated with eye abnormalities, specifically blepharophimosis and ptosis, strongly suggests that a locus for eyelid development is present at the interface of bands 3q22.3 and 3q23.

Najjar syndrome revisited.

We describe 2 brothers with cardiomyopathy and hypergonadotropic hypogonadism and conclude that this is the first description of the Najjar syndrome in the United States. The inheritance may be autosomal recessive.

Williams syndrome: autosomal dominant inheritance.

Williams syndrome (WS) usually occurs sporadically. Few familial cases of Williams syndrome have been described, and those reports have often lacked photographic documentation. We describe 3 families, including a 3-year-old boy and his 34-year-old father, a 2-year-old girl and her 30-year-old mother, and a 3-year-old girl and her 31-year-old mother. None of these patients has supravalvular aortic stenosis or chromosome abnormalities. In all 3 families, the parent with Williams syndrome was diagnosed after the identification of the syndrome in the affected child.

Inversion (X)(p11.4q22) associated with Norrie disease in a four generation family.

We report on a 4-generation family in which Norrie disease occurs together with a pericentric inversion of the X chromosome in all affected males and carrier females. The breakpoint in the short arm of the X chromosome appears to be at the purported location of the Norrie disease gene. This is the second report of an association between Norrie disease and a chromosome aberration involving Xp11, and the first report of a specific gene disruption, thus physical gene location, due to a pericentric chromosome inversion.

Holzgreve syndrome: recurrence in sibs.

We report on 2 sibs with cardiac and renal abnormalities. The first had hypoplastic left heart sequence and renal hypoplasia; the second had a complex congenital heart defect, renal agenesis, and cleft lip and palate. We suggest that these cases represent the first familial examples of the Holzgreve syndrome. As such, they demonstrate the phenotypic variability seen in sibs, and may serve to further delineate the syndrome.

Unbalanced mosaic karyotypes with different structural abnormalities involving a common chromosome region: report of two cases.

We report on 2 cases with different de novo unbalanced mosaic karyotypes in which each cell line had a different structural abnormality involving a common chromosome region: 46,XX,del(11)(q23.3)/46,XX.-11, + der(11)t(11;?)(q23.3;?) and 46,X,idic(Xq)/46,X,idic(Xq),-12, + der(12)t(X;12)(p11.2;p13.3). Molecular-cytogenetic analysis confirmed the origin of the derivative 12 chromosome in the latter. We present a literature review of reports with mosaic cell lines of structural chromosome abnormalities that share the same chromosome breakpoint.

Molecular cytogenetic analysis of a familial 8p23.1 deletion associated with minimal dysmorphic features, seizures, and mild mental retardation.

We report a family in which three members presented with minimal phenotypic abnormalities, normal intelligence to mild mental retardation, and a cytogenetically terminal chromosome deletion at band 8p23.1 Whole chromosomal painting with a chromosome 8-specific DNA library confirmed this familial chromosome abnormality as a deletion, while fluorescence in situ hybridization with telomeric probes demonstrated the presence of telomeres at the deletion site. Coagulation studies were additionally performed to evaluate the purported location of the coagulation factor VII regulator gene at 8p23.1. A review of the clinical findings of seven cases of del(8)(p23.1) is presented.

De novo inv(2)(p21q31) associated with isolated bilateral microphthalmia and cataracts.

We report on a patient with bilateral microphthalmia and unusual cataracts with a de novo pericentric inversion of chromosome (2)(p21q31). A literature review of previous associations of eye abnormalities and anomalies of chromosome 2 suggests probable gene locations for eye development.

Radiographic features of craniometadiaphyseal dysplasia, wormian bone type.

We describe the radiographic findings in two siblings with a previously unrecognized craniotubular bone dysplasia. We call this condition craniometadiaphyseal dysplasia, wormian bone type. Because the parents of the siblings are consanguineous, this is probably a genetically determined condition with an autosomal recessive type of transmission. The findings in the siblings are compared with those of a woman with the same condition, previously reported as an example of craniometaphyseal dysplasia. The combination of findings in these patients seems diagnostic: characteristic skull changes including multiple wormian bones; wide long tubular bones without normal metaphyseal flaring; wide short tubular bones without normal diaphyseal constriction and sometimes actual diaphyseal expansion; and wide ribs and clavicles.

Unusual cytogenetic mosaicism involving chromosome 14 abnormalities in a child with an MR/MCA syndrome and abnormal pigmentation.

An 8-year-old female child with mental retardation (MR), multiple congenital anomalies (MCA) and irregular pigmentation was shown to have karyotypic mosaicism involving chromosome 14 abnormalities. Four cell lines were found in both peripheral blood lymphocytes and skin fibroblasts and were represented by: a normal karyotype, an isopseudodicentric 14q [iso psu dic(14)], a ring 14 [r(14)], and a monosomy 14 [mono(14)]. Our results are compared with reported cases involving multiple abnormalities of specific chromosomes. Karyotypic mosaicism of comparable chromosome 14 abnormalities is rare, with only one known previous case. Detailed analysis of karyotypic mosaicism of rare chromosomal abnormalities is essential to determine meaningful correlations with specific patterns of malformation.

Association of pigmentary anomalies with chromosomal and genetic mosaicism and chimerism.

We have evaluated eight patients with pigmentary anomalies reminiscent of incontinentia pigmenti or hypomelanosis of Ito. All demonstrated abnormal lymphocyte karyotypes with chromosomal mosaicism in lymphocytes and/or skin fibroblasts. In seven the skin was darkly pigmented, and in all of these seven cases the abnormal pigmentation followed Blaschko lines. The literature contains at least 36 similar examples of an association between pigmentary anomalies and chromosomal mosaicism, as well as five examples of an association with chimerism. The pigmentary anomalies are pleomorphic, and the chromosomal anomalies involve autosomes and sex chromosomes. The pigmentation patterns are reminiscent of the archetypal paradigm seen in allophenic mice and demonstrate the clonal origin of melanoblasts from neural crest precursors. Patients with anomalous skin pigmentation, particularly when it follows a pattern of Blaschko lines, should be appropriately evaluated for a possible association with chromosomal or genetic mosaicism or chimerism.

New methods for quantitative and qualitative facial studies: an overview.

The clinical study of birth defects has traditionally followed the Gestalt approach, with a trend, in recent years, toward more objective delineation. Data collection, however, has been largely restricted to measurements from X-rays and anthropometry. In other fields, new techniques are being applied that capitalize on the use of modern computer technology. One such technique is that of remote sensing, of which photogrammetry is a branch. Cartographers, surveyors and engineers, using specially designed cameras, have applied geometrical techniques to locate points on an object precisely. These techniques, in their long-range application, have become part of our industrial technology and have assumed great importance with the development of satellite-borne surveillance systems. The close-range application of similar techniques has the potential for extremely accurate clinical measurement. We are currently evaluating the application of remote sensing to facial measurement using three conventional 35 mm still cameras. The subject is photographed in front of a carefully measured grid, and digitization is then carried out on 35-mm slides specific landmarks on the cranioface are identified, along with points on the background grid and the four corners of the slide frame, and are registered as xy coordinates by a digitizer. These coordinates are then converted into precise locations in object space. The technique is capable of producing measurements to within 1/100th of an inch. We suggest that remote sensing methods such as this may well be of great value in the study of congenital malformations.

Magnetic resonance imaging in the assessment of medullary compression in achondroplasia.

Children with achondroplasia may be at increased risk of developing apneic episodes and of dying unexpectedly. The risks seem to be related to neural axis compression by an abnormal cranial base and may be complicated by the development of hydrocephalus. We used magnetic resonance imaging to study five children with achondroplasia. All of them demonstrated a discrepancy between the size of the brain stem and the foramen magnum. Comprehensive prospective assessment of infants with achondroplasia, including the use of new imaging techniques, will provide important information concerning the natural history of the relationship of the neural axis to the bony posterior fossa and upper cervical spine in this condition. It may also help to identify those patients at risk before the development of life-threatening medullary compression.

Teratogens and teratogenesis: general principles of clinical teratology.

Numerous factors hinder our ability to recognize fully human teratogens. Among these are the limitations of animal and epidemiologic studies, the lack of understanding of the mechanisms of action of most teratogens, and the variability in expression of the clinical manifestation. Dose and timing of exposure, interactions with other environmental agents, and host susceptibility influence this variable expressivity. Recent studies suggest the genetic constitution of the mother and the fetus play a central role in the teratogenic response. Techniques currently being developed may help in a near future to identify susceptible individuals and to prevent specific types of drug-induced birth defects.

The cardiovascular manifestations of genetic disorders of collagen metabolism.

Current research in the biochemistry and molecular genetics of collagen metabolism has produced a sophisticated level of understanding of the mechanisms involved in the pathogenesis of a number of inherited diseases of connective tissue. Nowhere is this better exemplified than in the cardiovascular disorders associated with certain genetic disorders of collagen metabolism. For instance, the life-threatening vascular complications of Ehlers-Danlos syndrome IV, the Sack-Barabas type, appears to be related to a number of defects in the production of Type III procollagen. The large size of the collagen genes and the complexity of the biochemistry of collagen have not made research a simple task. Nevertheless, the location of certain genes is now known with a reasonable degree of accuracy and a few have been cloned in their entirety. The future investigation of these genetic mutations holds great excitement for those engaged in research in this fascinating field.