Purpose: The Center for Jewish Genetics provides genetic education and carrier screening to individuals of Jewish descent. Carrier screening has traditionally been performed by targeted mutation analysis for founder mutations with an enzyme assay for Tay–Sachs carrier detection. The development of next-generation sequencing (NGS) allows for higher detection rates regardless of ethnicity. Here, we explore differences in carrier detection rates between genotyping and NGS in a primarily Jewish population. Methods: Peripheral blood samples or saliva samples were obtained from 506 individuals. All samples were analyzed by sequencing, targeted genotyping, triplet-repeat detection, and copy-number analysis; the analyses were carried out at Counsyl. Results: Of 506 individuals screened, 288 were identified as carriers of at least 1 condition and 8 couples were carriers for the same disorder. A total of 434 pathogenic variants were identified. Three hundred twelve variants would have been detected via genotyping alone. Although no additional mutations were detected by NGS in diseases routinely screened for in the Ashkenazi Jewish population, 26.5% of carrier results and 2 carrier couples would have been missed without NGS in the larger panel. Conclusion: In a primarily Jewish population, NGS reveals a larger number of pathogenic variants and provides individuals with valuable information for family planning. Genet Med 18 12, 1214–1217.

A large Filipino-American family with progressive matrilineal hearing loss, premature graying, depigmented patches, and digital anomalies was ascertained through a survey of a spina bifida clinic for neural crest disorders. Deafness followed a matrilineal pattern of inheritance and was associated with the A1555G mutation in the 12S rRNA gene (MTRNR1) in affected individuals as well as unaffected maternal relatives. Several other malformations were found in carriers of the mutation. The proband had a myelocystocele, Arnold-Chiari type I malformation, cloacal exstrophy, and severe early-onset hearing loss. Several family members had premature graying, white forelock, congenital leukoderma with or without telecanthus, somewhat suggestive of a Waardenburg syndrome variant. In addition to the patient with myelocystocele, two individuals had scoliosis and one had segmentation defects of spinal vertebrae. The syndromic characteristics reported here are novel for the mitochondrial A1555G substitution, and may result from dysfunction of mitochondrial genes during early development. However, the mitochondrial A1555G mutation is only rarely associated with neural tube defects as it was not found in a screen of 218 additional individuals with spina bifida, four of whom had congenital hearing loss.

Neural tube defects (NTD) are common findings in the 13q deletion syndrome, but the relationship between the 13q- syndrome and NTDs is poorly understood. We present a child with a 13q deletion and lumbosacral myelomeningocele. This was a boy with microcephaly, telecanthus, minor facial anomalies, and ambiguous genitalia. Cytogenetic and fluorescence in situ hybridization analysis showed a de novo 46,XY,del(13)(q33.2-->qter) with no visible translocation. By using microsatellite markers, the deletion breakpoint was mapped to a 350-kb region between D13S274 and D13S1311 and was paternal in origin. An analysis of 13q deletions with NTDs, including the present case, suggests that a deletion in 13q33-34 is sufficient to cause an NTD. The deletions associated with NTDs are distal to and nonoverlapping with the previously defined critical region in 13q32 for the major malformation syndrome [Brown et al., 1999: Am J Hum Genet 57: 859-866]. Our analysis also suggests that one or more genes in 13q33-34 produces NTDs by haploinsufficiency.

Optic pathway gliomas and brainstem gliomas are the predominant intracranial neoplasms associated with neurofibromatosis type 1 (NF1). Before the past 15 years, studies of optic pathway gliomas in NF1 were hampered by the inaccurate diagnosis of NF1, the unavailability of noninvasive neuroimaging techniques, and the frequent rendering of what would now be considered unnecessary, overly aggressive therapy. When studied systematically, these tumors behave in a much more benign fashion than their counterparts in children who do not have NF1. While they may cause symptoms in as many of 50% of cases, progression to the point where specific intervention is deemed necessary is unusual. Consequently, screening neuroimaging of asymptomatic patients is unwarranted. Because optic pathway tumors universally arise in children younger than 7 years of age, all such children should undergo yearly ophthalmologic evaluations and annual assessments of growth to monitor for signs of precocious puberty. Am. J. Med. Genet. (Semin. Med. Genet.) 89:38–44, 1999. © 1999 Wiley-Liss, Inc.

Symptomatic optic pathway tumors (OPT) occur in 7% of children with neurofibromatosis type-1 (NF-1). Although tumor progression following diagnosis is unusual in such children, specific therapy may be necessary for patients with either severe or progressive disease. We reviewed the records of 9 children (6 girls, 3 boys) with NF-1 associated OPT who were treated with the second generation platinum compound carboplatin. Carboplatin was given at a dose of 560 mg/mm2 every 4 weeks for a mean of 15 cycles. The mean age at presentation of the OPT was 3.4 years. Eight children had abnormal ophthalmologic examinations at the time of diagnosis. Only 4 patients had documented evidence of progressive disease prior to the institution of therapy. No patient had evidence of progressive disease following therapy. Four patients had radiologic evidence of tumor shrinkage and 2 patients had definite improvement in vision. There was only minimal toxicity. In conclusion, carboplatin is a safe and effective treatment for OPT in children with NF-1. However, as disease stabilization of NF-1 associated OPT often occurs following clinical presentation, the clinician should document tumor progression or visual deterioration prior to the institution of therapy.

We undertook a comprehensive study of children with neurofibromatosis type 1 (NF-1) cared for in a large multidisciplinary clinic to determine the prevalence of precocious puberty and its relationship to optic pathway tumors (OPTs), Precocious puberty was diagnosed in 7 of 219 children with NF-1 (5 boys and 2 girls) examined between Jan. 1, 1985, and April 20, 1993, All seven children had OPTs involving the optic chiasm; they represented 39% of children with NF-1 and chiasmal tumors (95% confidence interval, 17% to 64%), Eleven prepubertal children (aged 2 to 10 years) with NF-1 and OPTs, and age- and sex-matched NF-1 control subjects without OPTs, underwent luteinizing hormone-releasing hormone (LH-RH) stimulation tests. Two boys with OPTs had pubertal luteinizing hormone (LH) responses, and testosterone levels >10 ng/dl, Basal LH levels were also elevated in these two boys when tested with a very sensitive immunochemiluminometric assay. None of the children without an OPT had either a pubertal response to LH-RH or an elevated basal LH level. We conclude that precocious puberty in children with NF-1 is found exclusively in those who have OPTs involving the optic chiasm; it is a common complication in those children, With the use of a highly sensitive LH assay, biochemical evidence of hypothalamic-pituitary-gonadal axis activation may be demonstrated, even without provocative testing.

To assess the natural history of optic pathway tumors (OPT) in children with neurofibromatosis type 1 (NF-1), from January 1985 through May 1993 we performed a prospective, longitudinal study of OPT in an unselected population of children with NF-1. Of 227 children with NF-1 seen in a specialty clinic, 176 (77%) underwent neuroimaging. Children in whom tumors were identified were followed closely by both repeated neuroimaging and ophthalmologic examinations to detect tumor growth or visual deterioration. Thirty-three children (19%) were found to have OPT at a median age of 4.2 years. The median age of children who had ophthalmologic complaints was significantly lower than that of children who had no such complaints (1.9 vs 5.3 years; p < 0.001). Although eight tumors were discovered because of ophthalmologic complaints or evidence of precocious puberty, 25 children (76%) were free of symptoms at the time of diagnosis. Twenty-one children (64%) had normal ophthalmologic findings at diagnosis; six children, all with chiasmal tumors, had previously unrecognized decreased visual acuity. Only three children (9%) had evidence of either tumor growth or deteriorating vision after diagnosis; the median duration of neuroimaging follow-up was 2.4 years (range, 0.2 to 7.2 years) and of ophthalmologic examinations 3.4 years (range, 0.2 to 8.1 years). All symptomatic OPT were diagnosed before 6 years of age. We conclude that OPT rarely progress during the next few years in children with NF-1 once the OPT have been discovered. The utility of screening neuroimaging for OPT in symptom-free children with NF-1 appears very limited.

Multiple café-au-lait spots have been observed in successive generations of several families without any other manifestations of neurofibromatosis (NF) or any other systemic disorder. The café-au-lait spots in these families segregate as an autosomal dominant trait. The relationship (if any) between the gene for this trait and the NF-1 gene has previously been unknown. We describe a family with five individuals spanning four generations with dominantly inherited café-au-lait spots, without any other stigmata of NF-1. Linkage analysis with probes proximal, distal, and within the NF-1 gene indicate that the trait in this family is not linked to NF-1. We propose that this condition be called Familial Café-Au-Lait Spots (FCAL) to distinguish it from the neurofibromatosis syndromes.

Optic pathway tumors are common in children with neurofibromatosis-1 (NF-1). The optimal management of these tumors is unknown, particularly when the optic chiasm and other brain structures are involved. We report the dramatic response to carboplatin in a 10-year-old girl with NF-1 and a progressive optic pathway tumor. Tumor shrinkage was accompanied by striking improvement in visual fields, return of color discrimination, and marked improvement in visual acuity. No significant toxicity was observed. One year following completion of chemotherapy the glioma remains as small or smaller than it was at the conclusion of therapy, and there has been no deterioration of vision. Carboplatin is a promising agent for the treatment of optic pathway tumors in children with NF-1.

We did compare the two groups of infants with respect to their birth weight, as mentioned in the Results section.There were no statistical differences (control group, 2899 • 562 gm; treatment group, 3119 • 546 gm); both groups contained only a few premature babies with, again, no statistical differences between them.We were well aware of the different management of premature babies, which can be recognized from Fig. 1.I Neither the treatment nor the control group contained very low birth weight babies, which is likely to differ in countries such as India.It would be of major interest ifa study similar to ours could be performed in India, where the incidence of both Rh hemolytic disease and prematurity is probably much higher than in Germany.The lgG levels in the infants in our study were not measured.However, because the birth weights did not differ among groups, we assumed that IgG levels were similar.Nevertheless, lgG levels are of interest because Kelton et al. 2 showed that IgG competes with immune complexes (and IgG-sensitized erythrocytes?) for macrophage Fc receptors in vivo, and thus might influence the clearance of sensitized erythrocytes.Future studies should take this into consideration.Our decisions for exchange transfusions were not based on a single determination of bilirubin levels.Fig. 2, in our publication, depicts only the last values before blood exchange.

We report the appearance of gliomas of the optic nerve or chiasm in four young children with neurofibromatosis type 1 whose previous neuroimaging studies showed no abnormalities; the age range of the children was 1 year 8 months to 5 years 9 months at the time the tumors were detected. Normal neuroimaging findings in an infant or young child with neurofibromatosis type 1 does not provide assurance that the optic nerves and chiasm will remain healthy.

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.