FGFR2 exon IIIa and IIIc mutations in Crouzon, Jackson-Weiss, and Pfeiffer syndromes: evidence for missense changes, insertions, and a deletion due to alternative RNA splicing.

Fibroblast growth factor receptor 2 (FGFR2) mutations have been associated with the craniosynostotic conditions Crouzon, Jackson-Weiss, and Pfeiffer syndromes. Previously, mutations were described in the exons IIIa and IIIc, which form the extracellular, third immunoglobulin-like domain (IgIII) and adjacent linker regions, both of which are normally involved in ligand binding. For all three conditions, mutations were found in exon IIIc. Only in Crouzon syndrome were mutations identified in exon IIIa. In this study, 39 cases with one of these three conditions were screened for exon IIIa or IIIc mutations. Eleven mutations are reported in 17 unrelated cases. Mutations in exon IIIa are identified for not only Crouzon but also Jackson-Weiss and Pfeiffer syndromes. Four mutations in either exon IIIa or exon IIIc reported only in Crouzon syndrome are present also in one of the other two syndromes. Two insertions, one in exon IIIa in a Crouzon syndrome patient and the other in exon IIIc in a Pfeiffer syndrome patient, were observed. The latter mutation has the same alternative RNA splicing effect as a reported synonymous mutation for Crouzon syndrome. A missense mutation was detected in one Pfeiffer syndrome family in which two members had craniosynostosis without limb anomalies. The inter- and intrafamilial variability in expression of FGFR2 mutations suggests that these three syndromes, presumed to be clinically distinct, are instead representative of a spectrum of related craniosynostotic and digital disorders.

Autosomal dominant familial spastic paraplegia: report of a large New England family.

A large New England family with autosomal dominant familial spastic paraplegia is described. In a pedigree of 173 individuals, 71 affected individuals are identified. Seventeen cases examined by the authors are described with regard to the natural history of FSP in this family. A staging system for following progress and planning interventions is proposed. Three illustrative cases are presented. In this family, FSP is found to have a homogeneous clinical course with nearly complete penetrance. Onset occurs at or before 3 years of age with involvement limited to the lower extremities. After the initial onset, no significant progression was noted. Early aggressive habilitative care may result in more functional ambulation.

Trisomy 20 mosaicism confirmed in a phenotypically normal liveborn.

Prenatal diagnosis of trisomy 20 mosaicism in this case was based on cytogenetic analysis of cultured amniotic fluid cells (23/252 cells were trisomy 20 representing cells from each of four primary cultures). The pregnancy continued to term and the mosaicism was confirmed in the phenotypically normal male neonate by analysis of cultured foreskin fibroblasts (7/49 cells + 20) and placental cells 20/20 cells + 20) whereas the peripheral lymphocytes were cytogenetically normal (20/20 cells were 46,XY). This represents the first confirmation of trisomy 20 mosaicism in a phenotypically normal full-term neonate.

Triploidy: pregnancy complications and clinical findings in seven cases.

Seven cases of triploidy were encountered by the Prenatal Diagnosis Program at Dartmouth-Hitchcock Medical Center over an 8-year period through associated pregnancy complications. We describe the characteristic findings that facilitate prenatal diagnosis and management. Our experience includes fetuses with major central nervous system abnormalities (spina bifida aperta, holoprosencephaly) and anterior abdominal wall defects, which are detectable with routine prenatal diagnostic screening examinations (ultrasound and AFP). In addition, we stress the importance of recognizing obstetric complications and associated cystic placental changes, which are quite common among triploid conceptuses. Molar changes associated with triploidy have a more benign prognosis than that associated with diploid moles. Such molar changes may relate to the presence of a diploid paternal chromosome complement. The usefulness of cytofluorometric DNA determinations in helping to confirm a clinical suspicion of triploidy is emphasized. These cases are presented in an effort to facilitate prenatal recognition and management of this common cytogenetic condition and prevent unnecessary Caesarean section deliveries.

Prenatal diagnosis of a new syndrome: holoprosencephaly with hypokinesia.

Markedly decreased fetal activity (akinesia/hypokinesia) is usually readily apparent to experienced mothers, and frequently this concern leads to attempts at prenatal diagnosis. We report prenatal diagnosis of two fetuses with congenital contractures, markedly decreased fetal movement, and microcephaly due to severe holoprosencephaly. Such familial recurrence to phenotypically normal parents suggests a newly recognized autosomal recessive or X-linked syndrome that is readily detectable by prenatal ultrasonography.

Bilateral renal agenesis in three consecutive siblings.

We report here an unusual recurrence of bilateral renal agenesis (BRA) in three consecutive siblings. Chromosome analysis was normal, as were renal ultrasound studies on both parents and their surviving child. Ultrasound was employed prenatally to diagnose Potter's syndrome in both of the recurrences, and autopsy confirmed BRA in otherwise normal fetuses. Recurrence of BRA points to the usefulness of ultrasound in monitoring subsequent pregnancies in couples who have had one such occurrence. Ultrasound studies should also be performed in non-affected family members to detect the presence of asymptomatic anomalies of the genitourinary system, but a negative family study does not preclude recurrence of BRA.

Enhanced visualization of soft tissues in the study of aborted fetuses through the use of xeroradiography.

As part of the diagnostic workup following an episode of fetal loss, it is generally recommended that fetal tissue be submitted for chromosome analysis and that the fetus be photographed and radiographed. Our recent clinical experience has suggested that, in those fetuses where size is compatible, xeroradiography may be superior to standard radiography. Xeroradiography utilizes principles similar to those in film radiology, with low-energy photon beams and relatively long exposure times. The physical characteristics of the beam and imaging system provide optimal soft tissue visualization. We have found this technique to be of use in studying a broad variety of abortuses with abnormalities. Examples of fetal abnormalities in which we have used this technique include acardia, neural tube defects, nuchal cystic hygroma, and arthrogryposis. In fetuses weighing 500-1,000 gm, the exposure settings are 25 MA, 1 second, 40 KVP. For larger fetuses the KVP should be increased by 1 or 2. This technique has not been useful for a complete body view of large fetuses due to the size limitations of the xeroradiographic cassette itself.