Ehlers-Danlos syndrome type VIIA and VIIB result from splice-junction mutations or genomic deletions that involve exon 6 in the COL1A1 and COL1A2 genes of type I collagen.

Ehlers-Danlos syndrome (EDS) type VII results from defects in the conversion of type I procollagen to collagen as a consequence of mutations in the substrate that alter the protease cleavage site (EDS type VIIA and VIIB) or in the protease itself (EDS type VIIC). We identified seven additional families in which EDS type VII is either dominantly inherited (one family with EDS type VIIB) or due to new dominant mutations (one family with EDS type VIIA and five families with EDS type VIIB). In six families, the mutations alter the consensus splice junctions, and, in the seventh family, the exon is deleted entirely. The COL1A1 mutation produced the most severe phenotypic effects, whereas those in the COL1A2 gene, regardless of the location or effect, produced congenital hip dislocation and other joint instability that was sometimes very marked. Fractures are seen in some people with EDS type VII, consistent with alterations in mineral deposition on collagen fibrils in bony tissues. These new findings expand the array of mutations known to cause EDS type VII and provide insight into genotype/phenotype relationships in these genes.

Femoral-facial syndrome--prenatal diagnosis--autosomal dominant inheritance.

Fetal micrognathia and short, bowed femora were found on a routine prenatal ultrasonogram. At birth, a cleft palate and the characteristic facial appearance confirmed the diagnosis of the femoral-facial syndrome. (The femoral-facial syndrome [McKusick 137840] was first delineated by Daentl et al. [1975: J Pediatr 86:197-211] and called the "femoral hypoplasia-unusual facies syndrome." We prefer the "femoral-facial syndrome" because it is shorter, more easily translated, and because the McKusick catalog is the most widely recognized standard of nomenclature.) A paternal great uncle, deceased at age 4 years, seems to have had the same condition.

The Robinow (fetal face) syndrome: a continuing puzzle.

The history of the Robinow (fetal face) syndrome and the evolution of the phenotype are presented. Non-specific and syndrome-specific abnormalities are listed, discussed and illustrated. Existence of an autosomal dominant and an autosomal recessive type has been well documented. The two forms can be distinguished phenotypically. Hypogenitalism, especially micropenis, is a constant feature in males, while females show only hypoplasia of clitoris and labia minora and are functionally normal. No biochemical or molecular anomaly has been identified.

Autosomal recessive cerebellar hypoplasia and endosteal sclerosis: a newly recognized syndrome.

We describe a brother and sister and an unrelated boy with congenital cerebellar hypoplasia and endosteal sclerosis. All 3 children presented with ataxia and developmental delay, and were found to have microcephaly, short stature, oligodontia, strabismus, nystagmus, and congenital hip dislocation. A previously published case is reviewed. The disorder appears to represent a newly recognized autosomal recessive syndrome.

Respiratory obstruction and cor pulmonale in the Hallermann-Streiff syndrome.

The risk of respiratory death in the Hallermann-Streiff syndrome is not insignificant, particularly in the neonatal period and in infancy. Upper airway obstruction may result from small nares and glossoptosis secondary to micrognathia, which sometimes lead to cor pulmonale. I report on a patient with such problems.

New clinical aspects of hereditary mucoepithelial dysplasia.

Hereditary mucoepithelial dysplasia (HMD) is a multiepithelial disorder. It is transmitted as an autosomal dominant trait (McKusick: Mendelian Inheritance in Man-Catalogs of Autosomal Dominant, Autosomal Recessive, and X-Linked Phenotypes, 8th edition. Baltimore: The Johns Hopkins University Press, pp 499, 1988). HMD is characterized by variable combinations of lesions of skin, hair, orificial mucosa, gingiva, eyes, and lungs. In some previously described patients, the corneal and pulmonary lesions were progressive and led to blindness, recurrent pneumonia, and/or premature death. On light microscopy, the lesion is characterized by dyskeratosis, and, on electron microscopy, by a paucity of gap junctions and desmosomes. Here, we describe a new 5-generation kindred in which affected individuals had the same histologic characteristics but a somewhat different clinical spectrum and a more benign course. HMD should be considered in the differential diagnosis of childhood alopecia, follicular hyperkeratosis, keratoconjunctivitis, juvenile cataracts, gingival hyperemia, restrictive lung disease, and esophageal stenosis or webs.

Secondary trisomy or mosaic "tetrasomy" 8p.

We report on two patients with mosaic tetrasomy of 8p[46,XY/47,XY,+i(8p)], a previously unreported cytogenetic anomaly. The first patient had a low percentage of tetrasomic (secondary trisomic) cells in lymphocytes and fibroblasts, an only mildly abnormal phenotype, and a rather benign clinical course. The second patient had a considerably larger percentage of tetrasomic cells in lymphocytes and fibroblasts, and had more severe congenital anomalies that led to his death at 8 months. A characteristic phenotype +i(8p) is suggested but not yet established. The manifestations of these two patients resemble those of mosaic trisomy 8 and mosaic trisomy 8p, with rib and vertebral abnormalities, absent corpus callosum, and enlarged cerebral ventricles.

Diagnostic criteria for Walker-Warburg syndrome.

Walker-Warburg syndrome (WWS) is an autosomal recessive disorder manifest by characteristic brain and eye malformations. We reviewed data on 21 of our patients and an additional 42 patients from the literature. From this review, we expand the phenotype to include congenital muscular dystrophy (CMD) and cleft lip and/or palate (CLP), and revise the diagnostic criteria. Four abnormalities were present in all patients checked for these anomalies: type II lissencephaly (21/21), cerebellar malformation (20/20), retinal malformation (18/18), and CMD (14/14). We propose that these comprise necessary and sufficient diagnostic criteria for WWS. Two other frequently observed abnormalities, ventricular dilatation with or without hydrocephalus (20/21) and anterior chamber malformation (16/21), are helpful but not necessary diagnostic criteria because they were not constant. All other abnormalities occurred less frequently. Congenital macrocephaly with hydrocephalus (11/19) was more common than congenital microcephaly (3/19). Dandy-Walker malformation (10/19) was sometimes associated with posterior cephalocele (5/21). Additional abnormalities included slit-like ventricles (1/21), microphthalmia (8/21), ocular colobomas (3/15), congenital cataracts (7/20), genital anomalies in males (5/8), and CLP (4/21). Median survival in our series was 9 months. A related autosomal recessive disorder, Fukuyama congenital muscular dystrophy, consists of similar but less severe brain changes and CMD. It differs from WWS because of consistently less frequent and severe cerebellar and retinal abnormalities. We think that WWS is identical to "cerebro-oculo-muscular syndrome" and "muscle, eye, and brain disease."

The Weismann-Netter syndrome.

The Weismann-Netter syndrome is a rare, heritable dysplasia of anterior bowing of tibiae and fibulae, often with lateral bowing of femora, short stature, and mild mental retardation. The condition is probably due to a primary metabolic abnormality of bone. The disease process is inactive in the adult. The pathogenesis is unknown. The patient reported here is the only child described in the Anglo-American literature.

Autosomal dominant ectrodactyly and absence of long bones of upper or lower limbs: further clinical delineation.

The association of ectrodactyly and absence of long bones of the upper or lower extremities has been recognized previously in nine families. We report 24 additional individuals in four families who are similarly affected. Two of these families manifest the unusual feature of unilateral preaxial polydactyly of a lower extremity. Data from these four families plus the nine previously reported suggest that ectrodactyly associated with absence of long bones of the upper or lower limbs is a genetically determined disorder, inherited as an autosomal dominant trait with widely variable expression or nonpenetrance.

Metacarpophalangeal pattern profile analysis in Robinow syndrome.

We analyzed the metacarpophalangeal pattern profile (MCPP) on 15 individuals with Robinow syndrome and calculated a mean Robinow syndrome profile. Correlation studies confirm clinical homogeneity of the hand profile in the Robinow syndrome. Discriminant analysis of individuals with Robinow syndrome compared with a sample of normal individuals produces a function of 6 MCPP variable that may provide a useful tool for diagnosis.

Robin sequence and oligodactyly in mother and son.

A combination of the Robin sequence with pre- and postaxial oligodactyly was observed in a mother and her son. This familial association has not been reported before and probably represents a previously unrecognized heritable malformation syndrome.

Hemifacial microsomia, ipsilateral facial palsy, and malformed auricle in two families: an autosomal dominant malformation.

Hemifacial microsomia, ipsilateral facial palsy and anomalies of the auricle were observed in father and son in two families. This combination of anomalies is a causally heterogeneous developmental field defect which may occur rarely as an autosomal dominant trait.