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Rib gaps, vertebral ossification defects, hypoplastic ischial bones and large kidneys were present in a newborn. A renal biopsy showed nephroblastomatosis . The observation links two recently described conditions - 'ischiospinal dysostosis' and 'a new syndrome comprising vertebral anomalies and multicystic kidneys' - and shows that nephroblastomatosis may be a manifestation of ischiospinal dysostosis. Ischiospinal dysostosis with nephroblastomatosis is one of a group of disorders characterized by developmental defects of the axial skeleton. It must be added to the conditions predisposing to Wilms tumor formation.

A complex chromosome rearrangement (CCR) involving chromosomes 7, 8, and 13 was detected in a phenotypically normal woman ascertained through her mentally retarded son with abnormal phenotype. He had a karyotype with 47 chromosomes including an extra der(13). In initial banding studies the CCR in the mother was interpreted as a three-way translocation. Fluorescence in situ hybridization with whole chromosome libraries and a telomere-specific probe was used to better characterize the rearrangement. Combined data allowed us to reinterpret the CCR as a translocation and an insertion. A review of 35 familial CCRs involving at least three chromosomes led to the following observations: 1) familial CCRs tend to have fewer chromosomes involved and fewer break-points than do de novo CCRs; 2) familial transmission is mainly observed through female carriers although the origin of de novo cases is paternal; 3) an apparent excess of balanced female carriers among the offspring of index carriers was noted; and 4) meiotic segregation resulting in malformed liveborn infants is most frequently due to adjacent-1 segregation, followed by 4:2 segregation; no adjacent-2 segregation was observed.

The Prospective Study of the Fragile X Syndrome is a large collaborative effort designed to collect prospective data on the pregnancy outcomes of individuals who carry the fragile X mutation. The goal of this 5-year study is to obtain empiric recurrence risks and population parameters for the fragile X syndrome in order to characterize the underlying mechanism of the mutation and the factors that influence its expression. This report presents the DNA results on the first 152 cases of female carriers and their pregnancy outcomes. It was found that the sex ratio of conceptuses was not significantly different from 1.0 and was not associated with mutation status. Thus, there was no evidence for selection against zygotes with full mutations. There was a significant association between the form of the mutation in carrier mothers and the frequency of its transmission. Examination of the segregation ratios from premutation mothers showed that there was a deficit of conceptuses that received the fragile X mutation. The segregation ratio from full mutation carrier mothers did not differ from expected. Several explanations for this observation are discussed. Numbers of cases are too small to estimate recurrence risks; however, the general trend of the data confirm the association of recurrence risks and the repeat number carried by the mother. © 1994 Wiley-Liss, Inc.

Walker-Warburg syndrome (WWS) is a lethal, autosomal recessive disorder characterized by Type II lissencephaly, retinal malformation, cerebellar malformation, and congenital muscular dystrophy. We report on 3 sibs with WWS born to a consanguineous couple. The fetal hydrocephalus associated with this syndrome, while not consistent or necessary for diagnosis, is the key manifestation for its prenatal detection. These sibs illustrate the importance of a careful search for associated malformation(s) in a fetus or newborn infant with hydrocephalus and the potential pitfalls of accurate genetic risk estimation in families of such propositi. © 1994 Wiley-Liss, Inc.

Colony stimulating factor-2 receptor alpha (CSF2RA) and interleukin-3 receptor alpha (IL3RA), two genes from the chromosome Xp and Yp pseudoautosomal region (PAR), have been suggested as candidate genes for short stature in Turner syndrome. We report three girls with X;Y translocation (46,X,der(X)t(X;Y)(p22;q11) initially detected by amniocentesis. The terminal portion of the X chromosome distal to the translocation breakpoint at Xp22 was deleted on the derivative X chromosome in all three patients. Each had normal stature at birth, with greater than expected deceleration of growth velocity by the second year. Using fluorescence in situ hybridisation (FISH), we have shown deletion of the CSF2RA and IL3RA loci on the derivative X chromosomes of all three patients. The role of CSF2RA and IL3RA haploinsufficiency in linear growth and final adult stature is discussed. Additional studies, particularly of molecular deletions within the PAR, are needed to improve our understanding of the role of these and other PAR loci in the genetic control of adult stature.

We have studied three children with cutaneous (epidermal nevi), subcutaneous (lipomas, plantar skin thickening), vascular (hemangioma, lymphangioma), skeletal (osteoma, exostosis, localized hypertrophy), and neurological (hydrocephaly, lissencephaly, partial agenesis of the corpus callosum) developmental defects associated with the Proteus syndrome and related hamartoneoplastic conditions. We compared our findings in these three patients with those of 50 others with Proteus syndrome and nine with encephalocraniocutaneous lipomatosis (ECCL) reported in the literature. We found that Proteus syndrome and ECCL have distinct identities even though some clinical manifestations are shared by both and a few patients have manifestations of both conditions.

Deletions or uniparental disomy for human chromosome 15q11q13 result in Prader-Willi Syndrome (PWS) and Angelman Syndrome (AS), depending upon the respective parental origin. Clinical and cytogenetic aspects of the two disorders are covered elsewhere in this book. Molecular studies have indicated that the extent of deletions in PWS and AS do not differ (Knoll et al, 1990). That deletions in PWS occurred predominantly on the paternal chromosome 15 was first demonstrated using cytogenetic polymorphisms (Butler et al, 1986), and we now know that all cases are paternal in origin (Nicholls et al, 1989a; Nicholls et al, 1989b; Butler, 1990). In contrast, deletions in AS always occur on the maternal chromosome 15 (Knoll et al, 1989).

Orofaciodigital syndrome type I (OFD I) includes striking orodental, facial, digital, renal, and central nervous system (CNS) abnormalities. Frequently associated with mental retardation, OFD I is inherited as an X-linked dominant trait, lethal in males. Here, we report the variable expressivity of OFD I in 6 black U.S. females and review findings in 2 previously reported black patients. Only these 8 of over 160 reported cases involve blacks. Abnormalities observed in black patients are similar to those observed in whites, but with specific differences. Only 25% of the blacks had cleft palate and none was observed with midline cleft of the upper lip. Among whites, 80% have cleft palate and 45% midline cleft of the upper lip. These findings suggest that racial genetic factors may protect lip and palate development in blacks, even in the presence of the OFD I gene. CNS abnormalities, including agenesis of the corpus callosum, hydrocephaly, cystic brain lesions, seizures, and mental retardation, were present in 50% of our the cases. This figure is greater than previously reported. Polycystic kidneys were present in 3 of our patients. Including a previously reported patient, 50% of the black OFD I patients show polycystic kidneys. Hyperplastic and supernumerary frenula, with or without brachydactyly, have been shown to be strong diagnostic criteria in our patients. New findings reported here include intracranial berry aneurysm, periodontal disease, and lip pits. Clinicians treating these patients should be aware of the pleiotropic manifestations of the syndrome, which may include renal and CNS anomalies. Ultrasonic and computed tomography scan studies are indicated in patients diagnosed with OFD I.

Ritscher-Schinzel syndrome is also known as the 3C syndrome because it involves principally the cardiac, cerebellar and cranio-facial structures. However, a review of the 29 published cases shows considerable variability in its clinical manifestations. As many as half of all cases may involve only two of the three systems. Here we wish to report on three new cases, two of which were siblings diagnosed prenatally. Cases 1 and 2. Baby R. was identified when autopsy studies following delivery at 31 weeks because of intrauterine fetal demise confirmed prenatally detected Dandy-Walker malformation, large atrial septal defect, cleft palate and hydronephrosis. During the subsequent pregnancy of this non-consanguineous, healthy Caucasian couple with a negative family history of malformations the fetus was found to have Dandy-Walker cyst, hypoplastic left heart, cleft palate and bilateral renal hypoplasia. Both fetuses had normal male karyotypes. Our third case is black male infant born at 38 weeks of gestational age to a 30-year-old primipara mother with no family history of birth defects or consanguinity. The infant weighed 1970 gm. at birth and was noted to have cleft palate, micrognathia, low set ears, tricuspid atresia with hypoplastic right ventricle, Dandy-Walker malformation and hydrocephalus. Other noted anomalies were a single umbilical artery, hypospadias, hemivertebrae and rib anomalies. Chromosomes were normal. The infant died following withdrawal of life support on the eighth day of life and no autopsy was performed. All three cases were seen during a one year period suggesting that the syndrome may be more common than is generally recognized. We will present a detailed review of the 29 published cases and differential diagnosis of the 3C syndrome.

Currently, standard methods of chromosome banding detect an abnormality in some 10%--15% of all patients referred for a cytogenetic study. Higher resolution by the study of the less contracted chromosomes with or without cell synchronization techniques may yield higher frequencies in the future. On the other hand, use of more complicated methodology adds to the time and expense needed for the study. The method of 5' bromodeoxyuridine pretreatment of cells in culture is commonly used to study the replication behavior of X chromosomes, and is known to demonstrate R bands along the other chromosomes. We have modified this technique with the addition of a cell synchronization step and evaluated several variables that are of importance in a clinical service laboratory setting. The method offers a simple way to obtain quality R-banded karyotypes. The advantages and limitations, based on our study of 120 consecutive cultures, are described.

Idiopathic multicentric osteolysis is a rare skeletal disorder, usually presenting in early childhood with a clinical picture mimicking juvenile rheumatoid arthritis. Progressive destruction of the carpal and tarsal bones usually occurs and other bones may also be involved. Chronic renal failure is a frequent component of this syndrome. Mental retardation and minor facial abnormalities have been noted in some patients. We report on 2 unrelated, sporadic cases, one with facial anomalies and the other with nephropathy. Our second patient is the first black child to be diagnosed with this disease. The mode of presentation, differential diagnosis, and natural history of this disorder are briefly reviewed.

Hashimoto thyroiditis, Addison disease, and diabetes mellitus occurs with a greater than normal frequency among patients with Turner syndrome. Most studies demonstrating this have been of patients over 20 years old. Therefore, 20 pediatric patients with Turner syndrome were recalled to obtain subjective and objective data reflecting thyroid function. Thyroxine (T4) and thyroid-stimulating hormone (TSH) were measured in serum samples by radioimmunoassay, and the serum antithyroid antibody titer (Thab) obtained by the tanned red cell agglutination method. Hypothyroidism was diagnosed in the presence of a decreased T4 and an elevated TSH. Hashimoto thyroiditis was presumed when a hypothyroid patient had an elevated Thab. Ten patients with Turner syndrome had structural abnormalities of the X chromosome. Three were hypothyroid, four had elevated serum Thab titers, and one had a goiter and low T4 without other evidence of thyroid dysfunction. Ten patients with Turner syndrome did not have structural abnormality of the X chromosome. None of these were hypothyroid, although five were considered to be at risk by virtue of an elevated serum Thab. One of these had a goiter. The Thab titer was elevated in nine of 15 patients over 10 years old, but in only one of five under 10 years. The three hypothyroid patients were over 10 years of age. Screening of children with Turner syndrome for evidence of thyroid dysfunction is clearly indicated.

Sir .—A 28-year-old gravida II, para I woman was referred for genetic counseling because of a Wilms' tumor in her previous child. Her daughter had been born at term, weighed 4.2 kg, and had a purplish birthmark over her forehead. Her neonatal course was uncomplicated. At age 1 year, her left leg and foot were found to be smaller than the right. At age 5 years, the finding of a large abdominal mass during a routine examination led to the diagnosis of bilateral Wilms' tumor. At age 9 years, the girl weighed 65 kg, was 139 cm tall, and had a faint fan-shaped midline nevus flammeus on her forehead. She had mild macroglossia but no dental malocclusion, earlobe creases, umbilical hernia, or diastasis recti. Her left foot was 1.5 cm shorter than the right. Her mother was 174 cm tall, weighed 122 kg, and had diastema between her upper central