Mutations in the CCN gene family member WISP3 cause progressive pseudorheumatoid dysplasia.

Members of the CCN (for CTGF, cyr61/cef10, nov) gene family encode cysteine-rich secreted proteins with roles in cell growth and differentiation. Cell-specific and tissue-specific differences in the expression and function of different CCN family members suggest they have non-redundant roles. Using a positional-candidate approach, we found that mutations in the CCN family member WISP3 are associated with the autosomal recessive skeletal disorder progressive pseudorheumatoid dysplasia (PPD; MIM 208230). PPD is an autosomal recessive disorder that may be initially misdiagnosed as juvenile rheumatoid arthritis. Its population incidence has been estimated at 1 per million in the United Kingdom, but it is likely to be higher in the Middle East and Gulf States. Affected individuals are asymptomatic in early childhood. Signs and symptoms of disease typically develop between three and eight years of age. Clinically and radiographically, patients experience continued cartilage loss and destructive bone changes as they age, in several instances necessitating joint replacement surgery by the third decade of life. Extraskeletal manifestations have not been reported in PPD. Cartilage appears to be the primary affected tissue, and in one patient, a biopsy of the iliac crest revealed abnormal nests of chondrocytes and loss of normal cell columnar organization in growth zones. We have identified nine different WISP3 mutations in unrelated, affected individuals, indicating that the gene is essential for normal post-natal skeletal growth and cartilage homeostasis.

A phenotype intermediate between Desbuquois dysplasia and diastrophic dysplasia secondary to mutations in DTDST.

We describe a child whose original clinical and radiologic manifestations led to a diagnosis of Desbuquois dysplasia. Subsequent development of features including cervical kyphosis and cystic ears caused us to reconsider the original diagnosis. The new complement of features in this patient fell in a range between Desbuquois dysplasia and diastrophic dysplasia. Molecular testing showed that she is a compound heterozygote for mutations in the diastrophic dysplasia sulfate transporter gene (DTDST). This finding confirms that there is locus heterogeneity in apparent Desbuquois dysplasia. It also expands the phenotypic spectrum of disorders caused by mutations in DTDST.

Somatic mosaicism in Fanconi anemia: molecular basis and clinical significance.

Approximately 25% of patients with Fanconi anemia (FA) have evidence of spontaneously occurring mosaicism as manifest by the presence of two subpopulations of lymphocytes, one of which is hypersensitive to cross-linking agents (e.g. mitomycin C) while the other behaves normally in response to these agents. The molecular basis of this phenotypic reversion has not yet been determined. We have investigated 8 FA patients with evidence of mosaicism. Epstein-Barr virus-immortalized lymphoblastoid cell lines established from these patients exhibited an IC50 for mitomycin C of 25 to > 100 nM compared to a mean of 2 +/- 2 nM for 20 nonmosaic FA patients and 49 +/- 11 nM for 8 healthy controls. In 3 patients who were compound heterozygotes for pathogenic FAC gene mutations the molecular mechanism of the mosaicism was investigated by haplotype analysis. The results indicated that an intragenic mitotic recombination must have occurred leading to a segregation of a wild-type allele in the reverted cells and suggested two patterns of recombination. In 1 patient a single intragenic crossover between the maternally and paternally inherited mutations occurred associated with markers located distally to the FAC gene; in the other 2 patients (sibs) the mechanism appears to have been gene conversion resulting in segregants which have lost one pathogenic mutation. In 6 of the 8 patients the hematological symptoms were relatively mild despite an age range of 9-30 years.

Genetic localization of a new locus for recessive familial spastic paraparesis to 15q13-15.

OBJECTIVE: To characterize a new gene locus for familial spastic paraparesis (FSP). BACKGROUND: FSP is a genetically heterogeneous group of upper motor neuron syndromes. It can be inherited as an autosomal dominant, autosomal recessive, or X-linked disorder. Four loci for autosomal dominant FSP have been genetically mapped, and two genes have been shown responsible for the X-linked type. In addition, two loci for autosomal recessive type have been reported and mapped to chromosomes 8q and 16q. The gene for the 16q locus has been characterized as a mitochondrial protein. METHODS: Eight recessive FSP families from America and Europe were used for genetic linkage analysis. The known recessive loci (8q and 16q) and the X-linked loci (PLP and L1CAM genes) were screened through PCR amplification, followed by linkage analysis, single-strand conformational polymorphism, or both. RESULTS: All the families except one revealed lack of linkage to the known loci for recessive and X-linked types of FSP. One of the eight families showed data consistent with linkage to the previously characterized 8q locus. Analysis of all the families for possible linkage to other candidate loci revealed significant positive lod scores for markers in chromosome 15q. The maximum multipoint combined lod score for the non-8q families was Z = 3.14 for markers D15S1007, D15S971, D15S118, and D15S1012, at a distance of 6.41 cM from the marker D15S1007, in between D15S971 and D15S118. CONCLUSIONS: Our data suggest a new locus for recessive FSP linked to chromosome 15q, and that this may be the most common one.

Maternal and fetal sequelae of anticoagulation during pregnancy.

Review of published cases of pregnancies in which coumarin derivatives or heparin were administered demonstrates that use of either class of anticoagulant carries substantial risks. Of 418 reported pregnancies in which coumarin derivatives were used, one-sixth resulted in abnormal liveborn infants, one-sixth in abortion or stillbirth and, at most, two-thirds in apparently normal infants. In addition to the expected hemorrhagic complications, fetal effects of coumarin derivative administration include a specific embryopathy and central nervous system abnormalities. All available cases (including unpublished ones) of warfarin embryopathy and central nervous system abnormalities following gestational exposure to coumarin derivatives are reviewed, various complications are tabulated, critical periods of teratogenesis are discussed and possible mechanisms proposed. The use of heparin during gestation does not result in a significantly better outcome of pregnancy. In 135 published cases, the infants in one-eighth were stillborn, in one-fifth premature (a third of whom died) and, again at most, in two-thirds apparently normal. Because of the substantial risks of both clases of anticoagulants, and the inherent risks of pregnancy complicated by the indications for anticoagulation, prevention of pregnancy is usually indicated. If pregnancy occurs, a relatively normal outcome can be anticipated in about two-thirds of the pregnancies regardless of the anticoagulant used. Heparin does not appear to be a clearly superior alternative to coumarin derivatives.

Lower mesodermal defects: a common cause of fetal and early neonatal death.

Among the first 1,130 referrals to the Wisconsin Stillbirth Service Program 17 infants have been recognized to share phenotypic characteristics involving the genital, urinary, lower gastrointestinal, and axial skeletal systems. The pattern of abnormalities identified appears to be limited to structures sharing a common embryologic origin. These features, for the most part, are shown to be non-randomly associated. No clearly definable sub-groups within this population are demonstrable. The pattern of abnormalities is defined to include abnormalities of the following structures as pathogenetically primary features: lumbosacral vertebrae, kidneys, ureters, uterus/fallopian tubes, vagina, bladder, urethra, adrenals, gonads, anorectum, external genitalia, and umbilical arteries. An embryologic mechanism is proposed which explains this non-random association as arising secondary to disruption of structures derived from the lower portion of the primitive intraembryonic mesoderm. The Lower Mesodermal Defects Sequence appears to be a rather common (and under-recognized) cause of stillbirth and immediate neonatal death.

Cranial nerve abnormalities in CHARGE association.

Many children with the CHARGE association have facial paralysis and feeding and swallowing difficulties. Indeed, facial paralysis and pharyngeal incoordination may be important diagnostic indicators of CHARGE association [Davenport et al., 1986a; Mitchell et al., 1985]. We describe an individual with dysfunction of multiple cranial nerves (Möbius sequence) and CHARGE association, a previously unrecognized combination. Our review of 150 patients from the literature and 13 patients from this center with CHARGE association documented that dysfunction of cranial nerves is frequent in CHARGE association, and that often cranial nerve abnormalities are multiple. Such multiple cranial nerve abnormalities may be the primary underlying cause for the facial paralysis, feeding difficulties and sensorineural hearing loss seen in many individuals with CHARGE association.

Wisconsin Stillbirth Service Program: II. Analysis of diagnoses and diagnostic categories in the first 1,000 referrals.

The Wisconsin Stillbirth Service Program has provided a mechanism for the collection and analysis of unbiased and representative information concerning stillborn infants. Generated diagnoses and diagnostic categories within the first 1,000 referrals (including 789 stillbirths) is summarized here. Among all referred stillborns, 24.5% were found to have an identifiable intrinsic fetal cause of death. Specific diagnoses were extraordinarily heterogeneous, with about 85 different processes identified with this group. No single diagnosis was found in more than 1 1/2% of the evaluated stillborns. Distribution by classes of fetal causes (as a percent of all fetal causes in stillborns) included malformation syndromes in 44%, single malformations and defined sequences in 34%, disruptions in 10%, and dysplasias in 3%. The heterogeneity of syndromic causes is illustrated, examples of previously undescribed syndromic processes provided and the problems experienced in generating specific diagnoses discussed. Specific single malformations, sequences, disruptions, and dysplasias are also tabulated and illustrated. Distribution by etiologic categories (as a percent of all fetal causes in stillborns) included defined sporadic conditions in 29%, cytogenetic aberration in 25%, presumed multifactorial processes in 12%, Mendelian disorders in 5%, and environmental events in less than 4%. A fourth of all fetal causes could not be sufficiently defined to allow for certainty in assigning a specific etiologic category. The materials summarized provide reference data regarding the frequency of classes and categories of fetal diagnoses generated from an unbiased and non-selected series of stillborns.

Limb deficiency and splenogonadal fusion.

We report a 10-year-old boy with tetramelic limb deficiencies, splenogonadal fusion, and mild mandibular and oral abnormalities. This patient is quite typical of 14 reported cases with this combination of findings. This association must be nosologically closely related to the Hanhart syndrome and other syndromes of limb deficiency and orofacial abnormalities. Recent experience does not support the idea that limb reduction with splenogonadal fusion is an invariably lethal dominant disorder.

Hajdu--Cheney syndrome: evolution of phenotype and clinical problems.

Hajdu-Cheney syndrome is a rare, autosomal dominant disorder comprising acroosteolysis of the distal phalanges with associated digital abnormalities, distinctive craniofacial and skull changes, dental anomalies, and proportionate short stature. The clinical and radiologic characteristics of Hajdu-Cheney syndrome develop and progress with age. Many of the medical problems that arise in this syndrome cluster in specific age ranges. Case reports of six affected individuals in two additional families and a summary of the English literature is presented with emphasis on the changing physical findings and medical sequelae over time.

Absence of correlation between infantile hypotonia and foramen magnum size in achondroplasia.

Virtually all infants with achondroplasia exhibit variably severe hypotonia in infancy. This hypotonia contributes to delays in motor development and risks for sudden death. Some have proposed that this hypotonia is a direct result of impaired function of long tracts of the spinal cord, secondary to the intrinsic narrowing of the foramen magnum, which also is present in variable severity in all children with achondroplasia. We postulated that if foraminal constriction causes infantile hypotonia, then there should be a strongly positive correlation between foraminal size and severity of hypotonia. Therefore, clinical and computed tomographic data in 71 infants were retrospectively reviewed. We found no correlation. These results suggest that there is no direct relationship and foraminal size does not affect severity of hypotonia. Other potential explanations for this infantile hypotonia are considered.

Natural history study of hereditary multiple exostoses.

Hereditary multiple exostosis (EXT) is an autosomal dominant disorder in which the clinical hallmark is the growth of bony protuberances from long bones and which can cause a variety of orthopedic deformities. This study sought to further delineate the natural history of EXT. In addition, since previous studies have suggested that there are deviations from Mendelian expectations in EXT, including incomplete penetrance and a skewed sex ratio, we attempted to confirm or refute these suggestions. Both portions of the study were carried out through retrospective review of 43 affected probands and 137 of their affected relatives. Data are presented concerning frequency and severity of complications of EXT including short stature, sequelae of exostoses, occurrence of malignant degeneration of exostoses, and problems in pregnancy and delivery of affected females. Only 2.8% of the total affected population had experienced exostosis-related malignancy, an estimate which is considerably less than earlier reports would suggest. Penetrance was 100%. There was an excess of males within the entire affected population (104:76) and within identified probands (28:15). However, the male to female ratio was unskewed in nuclear families (probands, affected sibs, and parents). The excess of males appears to be related to males having more severe and more frequent complications of EXT than having any primary genetic origin.

Familial agnathia-holoprosencephaly.

Two stillborn sisters had characteristics of both agnathia and holoprosencephaly. Familial occurrence implies that agnathia-holoprosencephaly may be determined by a single recessive gene, something to be taken into account when counseling such families. Evidence from human experience and various animal models suggests that agnathia-holoprosencephaly represents a causally heterogeneous single developmental field defect. Anatomical studies of these two stillborn sisters support the view that they shared a developmental field defect which affected structures in the face, cranial cavity, and upper neck. The pathogenesis of these variably expressed defects probably relates to defects in neural crest cells of cranial origin and/or to underlying mesodermal support elements of these cells.

Gardner syndrome and periampullary malignancy.

In a family with colonic polyposis and the typical associated findings of Gardner syndrome (osteomas and soft-tissue tumors), two and possibly four of the affected members developed periampullary malignancy. A review indicates that individuals with Gardner syndrome may have a 100- to 200-fold increased risk of developing periampullary carcinoma when compared to the general population. While certain families and certain individuals (those with other duodenal involvement, males and those with all of the characteristics of Gardner syndrome expressed) may be most susceptible, all patients with Gardner syndrome should be periodically endoscopically evaluated for the presence of upper gastrointestinal tract disease.

Mild hypophosphatasia mimicking severe osteogenesis imperfecta in utero: bent but not broken.

We describe a fifth instance of hypophosphatasia presenting with prenatal findings suggestive of a very severe bone dysplasia but with a subsequently benign course. Spontaneous improvement of long-bone angulation began prenatally. The postnatal course has been encouraging. This sixth clinical form of hypophosphatasia, which we suggest should be called the benign prenatal form of hypophosphatasia, should be added to the differential diagnostic possibilities considered when angulation or bowing of long bones is discovered prenatally.

Achondroplasia: unexpected familial recurrence.

We review six families in which recurrence of achondroplasia, inexplicable through autosomal dominant inheritance, has occurred. The clinical and radiographic characteristics of affected individuals in these families are identical to those usually seen in achondroplasia. Family histories and parental characteristics likewise seemed not to set this group apart from others with achondroplasia. While various mechanisms for these occurrences of achondroplasia in family members related through unaffected relatives can be postulated, the hypothesis that these recurrences were simply the result of two independent chance events cannot, at least for the moment, be excluded.

Atelosteogenesis type III: long term survival, prenatal diagnosis, and evidence for dominant transmission.

We describe two additional instances of atelosteogenesis, type III, in a woman and her son. Clinical and radiographic information concerning these individuals allows further definition of this rare skeletal dysplasia. This is the first documentation of survival to adulthood of an individual with this disorder, of prenatal diagnostic assessment of an affected individual, and of vertical transmission suggestive of autosomal dominant inheritance. The clinical and radiologic phenotype of atelosteogenesis, type III overlaps with that of another skeletal dysplasia, autosomal dominant Larsen syndrome; these most likely represent allelic conditions.

Temperament in Williams syndrome.

Anecdotal reports suggest that children with Williams syndrome are loquacious, affectionate, charming, open, and gentle. The temperament, or behavioral style, of individuals with Williams syndrome was assessed using standard temperament scales of parental response. Children with Williams syndrome appear, on average, to display higher activity, lower rhythmicity, greater approach, lower adaptability, greater intensity, more negative mood, less persistence, greater distractibility, and lower threshold to arousal than will average children. Older children with Williams syndrome will likely be viewed as "difficult." Despite this overrepresentation in the "difficult" cluster, on average, this population differs from the usual population of "difficult" children in being approaching, rather than displaying a tendency to withdraw. Parents of a child with Williams syndrome should be apprised of potentially negative temperament characteristics, relieved of the burden of responsibility for having a difficult child who "should" be easy, and counselled, when appropriate, regarding the efficacy of modification of parent-child interactions with children having the difficult temperament.

Fetal disruptions: assessment of frequency, heterogeneity, and embryologic mechanisms in a population referred to a community-based stillbirth assessment program.

The Wisconsin Stillbirth Service Project (WiSSP) is a community-based program for the investigation of the cause of fetal death. From its inception in 1983 through July 1988, 629 referrals were made to WiSSP. All referrals were assessed for the presence of disruptional characteristics, and 23 were found to have major or primary disruptive effects. Most of these were either early amnion disruption/limb-body wall disruption (treated as a single group, since analysis suggests a continuum of clinical characteristics) and twin-twin disruptions. Therefore, disruptions accounted for 3.6% of all referrals (including liveborn and miscarriage referrals) to WiSSP. When only stillborn fetuses are considered, approximately 2.4% appear to have died because of disruptions. This makes disruptions one of the most frequent, identifiable causes of late intrauterine death. We estimate that 0.6-1.4% of all stillborn fetuses die because of early amnion disruption/limb-body wall disruption which, when taken with previous estimates of the frequency of such problems in early miscarriages and liveborn infants, suggests that these disruptions result in a 95% prenatal mortality rate. We suggest a unified model of likely pathogenetic mechanisms which may help explain the continuum of multisystem involvement seen in those with early amnion disruption/limb body wall disruption. In addition, 3 patients with atypical disruptions are reviewed who exemplify the difficulty and importance of differentiating disruptional and malformational processes.

Wisconsin Stillbirth Service Program: I. Establishment and assessment of a community-based program for etiologic investigation of intrauterine deaths.

Although stillbirth is a common event, few programs have previously been established for the comprehensive etiologic investigation of intrauterine death. Fewer still have been prospective, unbiased in ascertainment, and consistent in protocol utilization. The Wisconsin Stillbirth Service Program was established in 1983 as a unique model for the investigation of the causes of stillbirth. This community-based, University-supported model for health care delivery is here described. Through it more than a thousand infants have been etiologically investigated. We demonstrate that a community-based program of stillbirth assessment can succeed, that compliance with recommended protocols is high and that a specific primary cause of fetal death can be demonstrated in about 40% of referrals. A majority of the established causes of intrauterine death are fetal etiologies. Furthermore, it appears that there are no substantial referral biases. Lack of such biases, together with the prospective, protocol driven nature of the program provides a unique population upon which to base estimates of the frequency of various etiologic diagnoses and classes and categories of cause.