A recurrent mutation in the tyrosine kinase domain of fibroblast growth factor receptor 3 causes hypochondroplasia.

Hypochondroplasia (MIM 146000) is an autosomal dominant skeletal dysplasia with skeletal features similar to but milder than those seen in achondroplasia. Within the past year, the achondroplasia locus has been mapped to 4p 16.3 (refs 5-7) and mutations in the fibroblast growth factor receptor 3 (FGFR3) gene have been identified in patients with the disorder. More than 95% of 242 cases reported so far are accounted for by a single Gly380Arg mutation. McKusick et al. proposed that achondroplasia and hypochondroplasia are allelic based on the similarities in phenotype between the two disorders and the identification of a severely dwarfed individual whose father had achondroplasia and whose mother had hypochondroplasia. There is also genetic linkage evidence that hypochondroplasia and achondroplasia map to the same locus. We therefore began a systematic screening of FGFR3 to detect mutations in patients with hypochondroplasia. We now report a single FGFR3 mutation found in 8 out of 14 unrelated patients with hypochondroplasia. This mutation causes a C to A transversion at nucleotide 1620, resulting in an Asn540Lys substitution in the proximal tyrosine kinase domain.

New chromosome 11p15 epigenotypes identified in male monozygotic twins with Beckwith-Wiedemann syndrome.

Beckwith-Wiedemann syndrome (BWS) is an overgrowth syndrome demonstrating heterogeneous molecular alterations of two imprinted domains on chromosome 11p15. The most common molecular alterations include loss of methylation at the proximal imprinting center, IC2, paternal uniparental disomy (UPD) of chromosome 11p15 and hypermethylation at the distal imprinting center, IC1. An increased incidence of female monozygotic twins discordant for BWS has been reported. The molecular basis for eleven such female twin pairs has been demonstrated to be a loss of methylation at IC2, whereas only one male monozygotic twin pair has been reported with this molecular defect. We report here two new pairs of male monozygotic twins. One pair is discordant for BWS; the affected twin exhibits paternal UPD for chromosome 11p15 whereas the unaffected twin does not. The second male twin pair is concordant for BWS and both twins of the pair demonstrate hypermethylation at IC1. Thus, this report expands the known molecular etiologies for BWS twins. Interestingly, these findings demonstrate a new epigenotype-phenotype correlation in BWS twins. That is, while female monozygotic twins with BWS are likely to show loss of imprinting at IC2, male monozygotic twins with BWS reflect the molecular heterogeneity seen in BWS singletons. These data underscore the need for molecular testing in BWS twins, especially in view of the known differences among 11p15 epigenotypes with respect to tumor risk.

ASPP2 deficiency causes features of 1q41q42 microdeletion syndrome.

Chromosomal abnormalities are implicated in a substantial number of human developmental syndromes, but for many such disorders little is known about the causative genes. The recently described 1q41q42 microdeletion syndrome is characterized by characteristic dysmorphic features, intellectual disability and brain morphological abnormalities, but the precise genetic basis for these abnormalities remains unknown. Here, our detailed analysis of the genetic abnormalities of 1q41q42 microdeletion cases identified TP53BP2, which encodes apoptosis-stimulating protein of p53 2 (ASPP2), as a candidate gene for brain abnormalities. Consistent with this, Trp53bp2-deficient mice show dilation of lateral ventricles resembling the phenotype of 1q41q42 microdeletion patients. Trp53bp2 deficiency causes 100% neonatal lethality in the C57BL/6 background associated with a high incidence of neural tube defects and a range of developmental abnormalities such as congenital heart defects, coloboma, microphthalmia, urogenital and craniofacial abnormalities. Interestingly, abnormalities show a high degree of overlap with 1q41q42 microdeletion-associated abnormalities. These findings identify TP53BP2 as a strong candidate causative gene for central nervous system (CNS) defects in 1q41q42 microdeletion syndrome, and open new avenues for investigation of the mechanisms underlying CNS abnormalities.

Familial spontaneous pneumothorax.

A family is described in which four persons in three generations suffered spontaneous pneumothoraces: a newborn, an infant, an adolescent, and an adult. Review of the literature reveals 61 reports of familial spontaneous pneumothorax in 22 families. The ratio of male to female cases is approximately 1.8. Affected parents and affected children (including affected fathers and sons) are seen in ten families, while affected siblings with unaffected parents are noted in 13 families. Consanguinity has not been reported. Although autosomal dominant inheritance has been suggested as an explanation of familial spontaneous pneumothorax, available pedigree data are not adequate for statistical analysis. Physicians should be aware of the familial occurrence of spontaneous pneumothorax so that members of such families may be appropriately managed when problems arise.

The Langer-Giedion syndrome: report of a 22-year old woman.

A 22-year-old woman with the Langer-Giedion syndrome and delayed puberty is presented. Pertinent features include a bulbous nose, sparse hair, protruding ears, multiple cartilaginous exostoses, cone-shaped phalangeal epiphyses, short stature, microcephaly, and mental retardation. She is the oldest patient thus far described with this condition, and is compared to the ten previously published cases. The clinical course of patients with the Langer-Giedion syndrome and the possibility of malignant change in the exostoses have not been established.

Vascular basis for neural tube defects: a hypothesis.

A hypothesis is set forth that neural tube defects are produced by inadequate nutrient supply to the rapidly growing neural folds. According to this hypothesis, a delay in establishing blood flow or an aberration of blood supply to neural tissue may interfere with nutrition and prevent neural tube closure. The hypothesis was tested by examining the vasculature of fetuses with spinal neural tube defects. In each case, the arterial supply to the region of the neural tube defect was disturbed. Because development of arterial supply to the neural folds predates neural tube closure, these vascular abnormalities are considered to be primary malformations that lead to neural tube defects rather than secondary morphologic disturbances resulting from neural tube defects.

Clinical aspects of defects in the determination of laterality.

Of individuals in the human population, 99.99% have developed identical thoracoabdominal asymmetry with the cardiac apex, a bilobed lung, the stomach, and the spleen on the left side of the midline, and the vena cavae, a trilobed lung, the appendix, and the larger liver lobe on the right. This arrangement of organs is situs solitus. Occasionally, individuals have a complete, mirror-image reversal of this asymmetry called situs inversus, and 20-25% of those individuals have an autosomal recessive condition, Kartagener syndrome, with ciliary dyskinesia, bronchiectasis, sinusitis, and infertility. Between these extremes of situs solitus and situs inversus lies the spectrum of situs ambiguus, characterized by isomerism, heterotaxy, and multiple malformations in one or more thoracic or abdominal organs. Although most abnormal situs in humans occurs sporadically, growing evidence suggests that interference with normal genetic mechanisms and pathways may be responsible for most cases. Familial cases suggest major effects of both autosomal and X-linked genes with both dominant and recessive expression. Situs inversus and situs ambiguus (SI/SA) occurring in probands who have close relatives with "isolated," nonsyndromic birth defects suggests that some of the pathways important in situs determination may also be involved in causing sporadic malformations not obviously associated with a defect in laterality determination. Human phenotypes of interest include the association of SI/SA with short rib-polydactyly syndromes and renal-hepatic-pancreatic dysplasia, and with agnathia and holoprosencephaly. Further elucidation of the developmental pathways involved in left-right axis determination should shed light on the causes of and relationships among these human phenotypes.

Townes-Brocks syndrome in two mentally retarded youngsters.

We report on 2 children with Townes-Brocks syndrome (TBS) and mental retardation. One child had mild hearing loss, but the other only had hearing loss at 8000 Hz. These cases suggest that there may be an increased incidence of mental retardation in individuals with TBS.

Nager acrofacial dysostosis: male-to-male transmission in 2 families.

We describe 2 unrelated families with male-to-male transmission of Nager syndrome. All 5 affected individuals have moderate expression of the phenotype. One affected boy also has Hirschsprung disease. Although Nager acrofacial dysostosis usually occurs sporadically, both recessive and dominant inheritance have been suggested on the basis of reported familial cases. The 2 families described here with father-to-son transmission strongly support the hypothesis that some cases of Nager acrofacial dysostosis occur in individuals who are heterozygous for dominantly expressed, autosomal mutations.

Neurological aspects of del(1q) syndrome.

We have studied three children with de novo terminal deletion of the long arm of chromosome 1 (46,XX,del(1)(q43)). They all have minor anomalies and neurological signs (severe psychomotor developmental delay, generalized hypotonia, and seizures) that have been described previously. In addition, all of these three patients have autistic-like behavior. They avoid eye contact, show no interest in people, express little emotion, and repeat stereotypic movements such as head nodding and purposeless finger manipulation. They also spend excessive time in making unusual sounds consisting of a high-pitched shrill cry with little intonation in infancy and a harsh, strained, and glottal stridency in later life. They make no labial, lingual, or nasal sounds. We suggest that these observations may be unique clinical manifestations of certain terminal 1q deletions.

A mild autosomal recessive form of osteopetrosis.

We report on four individuals in one kindred with relative or absolute short stature; increased upper/lower segment ratio with decreased arm span; mandibular prognathism and dental abnormalities; fractures following minimal trauma; mild to moderate anemia with extramedullary hematopoiesis; and radiographic changes of osteopetrosis, including sclerosis of the cranial base, generally increased bone density, sclerosis of the vertebral end plates, and transverse bands and poor diaphyseal modelling of the long bones. There is intrafamilial variability of clinical and radiographic findings in individuals with this mild, autosomal recessive form of osteopetrosis. We summarize ten families from the literature, which include 18 cases of mild recessive osteopetrosis. The manifestations of many are similar to those of the individuals reported here. Two other types of recessive osteopetrosis have been reported previously: osteopetrosis associated with renal tubular acidosis, and severe osteopetrosis with hepatosplenomegaly, pancytopenia, and early death. Autosomal dominant osteopetrosis is variable but usually mild. Pedigree analysis is currently the only reliable method of determining the pattern of inheritance in mild osteopetrosis.

Prenatal diagnosis of a severe deforming type of osteogenesis imperfecta.

A pregnancy at risk for a severe deforming type of osteogenesis imperfecta (OI) was monitored by ultrasonography and radiography. Long bone measurements were normal at 15 1/2 weeks gestation, but ultrasound detected an abnormality of one femur that appeared to be a fracture. The ultrasound study at 19 weeks revealed severe shortness of the femora, and radiographs showed only vertebral bodies with no other fetal skeletal parts clearly visible. These studies indicate the feasibility of prenatal diagnosis before 20 weeks for the more severe handicapping types of OI that are compatible with survival past the newborn period and that can result in death during later infancy.

Holoprosencephaly in an infant with a minute deletion of chromosome 21(q22.3).

We evaluated an infant because holoprosencephaly had been detected by prenatal ultrasound examination and magnetic resonance imaging (MRI). Postnatally, high-resolution cytogenetic studies showed a minute deletion of chromosome 21(q22.3). This patient lacks many of the characteristics associated with monosomy 21, partial monosomy 21, and ring 21 chromosome patients. She also lacks the midline facial abnormalities often seen with holoprosencephaly. The similarity in facial appearance between this case and one previously reported patient with holoprosencephaly and a ring chromosome 21 suggests a causal relationship between holoprosencephaly and deletion of chromosome 21(q22.3). These findings also suggest that infants and children with developmental delay and apparently normal facial appearance should be examined for holoprosencephaly and that all identified patients with holoprosencephaly need high-resolution cytogenetic studies with careful attention to the terminal portion of 21q.

Type I diabetes mellitus in a patient with chromosome 22q11.2 deletion syndrome.

We describe a patient with type I diabetes, clinical findings consistent with velocardiofacial syndrome, and a chromosome 22q11.2 deletion. A nine-year-old boy presented with a history of polyuria, polydipsia, weight loss, hyperglycemia, ketosis, serum insulin antibodies, and a low C-peptide level. He had distinctive facial features, learning disabilities, short stature, and a history of glottic web and clubfoot. Although a normal karyotype was obtained, fluorescence in situ hybridization (FISH) revealed a submicroscopic deletion in the DiGeorge/velocardiofacial syndrome critical region at 22q11.2. His maternal half-brother also carried a chromosome 22q11.2 deletion. His mother has similar facial features and hypoparathyroidism. Autoimmune problems associated with chromosome 22q11.2 deletions have been reported. We suggest that the defects in immune regulation due to T-cell deficiency in chromosome 22q11.2 deletion syndrome may predispose to autoimmune disorders, including type I diabetes mellitus.

Preliminary phenotypic map of chromosome 4p16 based on 4p deletions.

We have collected and analyzed clinical information from 11 patients with chromosome 4p deletions or rearrangements characterized by various molecular techniques. Comparing the extent of these patients' deletions with their respective clinical presentations led to the proposal of a preliminary phenotypic map of chromosome 4p. This map consists of regions which, when deleted, are associated with specific clinical manifestations. Nonspecific changes such as mental and growth retardation are not localized, and probably result from the deletion of more than one gene or region. The region associated with most of the facial traits considered typical in Wolf-Hirschhorn syndrome (WHS) patients coincides with the currently proposed WHS critical region (WHSCR), but some anomalies commonly seen in WHS appear to map outside of the WHSCR. The observation of clinodactyly in 2 patients with nonoverlapping deletions allows assignment of these defects to at least 2 separate regions in 4p16. These initial observations and attempts at genotype/phenotype correlation lay the groundwork for identifying the genetic basis of these malformations, a common objective of gene mapping efforts and chromosome deletion studies.

Oculoauriculovertebral abnormalities in children of diabetic mothers.

Maternal diabetes is known to have teratogenic effects. Malformations including neural tube defects, caudal dysgenesis, vertebral defects, congenital heart defects, femoral hypoplasia, and renal anomalies are described in infants of diabetic mothers. However, craniofacial anomalies have rarely been reported in such infants. Here we document craniofacial anomalies of patients born to diabetic mothers. We describe two patient populations: individuals evaluated through our genetics services for multiple malformations and individuals identified through a database search in our craniofacial clinic. The first group consists of 14 individuals evaluated in our genetics clinics who were born to diabetic mothers and had craniofacial anomalies. The second group consists of seven individuals who were identified from a craniofacial database search of patients with hemifacial microsomia and who were born to diabetic mothers. Thus, both groups were born to diabetic mothers and had hemifacial microsomia (67%), microtia (52%), hearing loss (43%), epibulbar dermoids (24%), and fused cervical vertebrae (24%). Therefore, the teratogenic effects of maternal diabetes probably include such craniofacial malformations as the oculoauriculovertebral/Goldenhar complex. Infants of diabetic mothers should be evaluated for craniofacial anomalies. Conversely, mothers of infants with craniofacial anomalies should be evaluated for diabetes to aid in counseling concerning cause and recurrence risks.

Fragile X phenotype in a patient with a large de novo deletion in Xq27-q28.

A 2-year-old boy with manifestations of the fragile X syndrome was found to have a cytogenetically visible deletion of Xq27-q28 including deletion of FMR-1. Molecular analysis of the patient was recently described in Tarleton et al. [1993: Hum Mol Genet 2(11): 1973-1974] and the deletion was estimated to be at least 3 megabases (Mb). His mother had 2 FMR-1 alleles with normal numbers of CGG repeats, 20 and 32, respectively. Thus, the deletion occurred as a de novo event. The patient does not appear to have clinical or laboratory findings other than those typically associated with fragile X syndrome, suggesting that the deletion does not remove other contiguous genes. This report describes the phenotype of the patient, including psychological studies.

Radiological findings in Hallermann-Streiff syndrome: report of five cases and a review of the literature.

Hallermann-Streiff syndrome (HSS) is a rare disorder with an associated constellation of radiological findings that may aid in the diagnosis of affected individuals. We reviewed the skeletal surveys of 5 affected individuals and noted some characteristic and constant findings. Radiological findings can include a large, poorly ossified skull with decreased ossification in the sutural areas. There was an increase in the number of Wormian bones. Severe mid-facial hypoplasia was present along with a prominent nasal bone. The skull films also showed an abnormally obtuse or nearly straight gonial angle. The teeth appeared small. The long bones were thin and gracile in appearance and often showed poor demarcation of the cortex from the medullary portion. Abnormal bowing of the radius and ulna was seen neonatally in 2 cases. There was widening at the metaphyseal ends of the long bones. The ribs were thin, but normal in length. The vertebral bodies were noted to be small and 3 cases had platyspondyly. There was a decreased number of sternal ossification enters. The metacarpals were also thin and gracile in appearance with metaphyseal widening. We conclude that these characteristic radiological findings in the newborn with HSS can aid in the diagnosis, and a skeletal survey in suspected individuals may be valuable in confirming the diagnosis.

Monozygotic twins discordant for partial trisomy 1.

A 25-year-old primigravida delivered monozygotic twins discordant for multiple anomalies and partial trisomy 1 mosaicism. The phenotype of partial trisomy 1 includes craniofacial, central nervous system, and ocular anomalies. The most likely explanation for these findings is that the translocation occurred after twinning occurred. This observation emphasizes that monozygotic twins are not necessarily genetically identical. They are identical at conception, but subsequent mutation and rearrangement of the genome may cause substantial phenotypic differences.

Similarities of EEG and seizures in del(1q) and benign rolandic epilepsy.

We studied the seizure disorders manifested by three previously reported children with "de novo" terminal deletions of the long arm of chromosome 1 (46,XX,del(1)(q43)) and similar clinical phenotypes. In late infancy, two of these children developed partial seizures characterized by tonic-clonic movements of the ipsilateral face and arm with occasional involvement of the leg. In both children, the seizure frequency decreased with increasing age. Electroencephalograms of these two children demonstrated centrotemporal spike discharges morphologically similar to rolandic spikes. Although these cases present significant similarities to benign rolandic epilepsy, they also express many manifestations not detected in benign rolandic epilepsy that may reflect the extensive deletion of chromosome 1. Based on the seizure semiology and centrotemporal epileptiform discharges, we suggest that the distal portion of the long arm of chromosome 1 is a potential site for a candidate gene for benign rolandic epilepsy.