Strychnine therapy in nonketotic hyperglycinemia.

Nonketotic hyperglycinemia is an inborn error of metabolism resulting from a defect in the glycine cleavage enzyme system. It is characterized biochemically by elevated concentrations of glycine in blood, spinal fluid, and urine. Previous therapies which have been directed toward reducing the glycine concentration in plasma and CSF have not been successful in preventing neurological deterioration, which may be the result of the role of glycine as an inhibitory neurotransmitter. Strychnine treatment was initiated because it is a specific antagonist of glycine at postsynaptic membranes. The patient reported here has shown clinical and EEG improvement while taking strychnine in conjunction with sodium benzoate.

The Dubowitz syndrome: the psychological status of ten cases at follow-up.

We report the psychological status of ten people with the Dubowitz syndrome, an autosomal recessive condition characterized by intrauterine and postnatal growth retardation, microcephaly, and high-pitched hoarse voice. Results indicate that the level of intellectual functioning among children with Dubowitz syndrome varies from severe retardation to average intelligence. Our patients have delays in the development of memory, reasoning, expressive vocabulary, fine motor development, and receptive vocabulary, in order of ascending frequency. Data regarding growth status, level of adaptive functioning, and presence of behavioral deficits are also presented.

Linkage analysis in a family with the Opitz GBBB syndrome refines the location of the gene in Xp22 to a 4 cM region.

The Opitz GBBB syndrome (OS) is characterized in part by widely spaced inner ocular canthi and hypospadias. Recently, linkage analysis showed that the gene for the X-linked form to be located in an 18 cM region spanning Xp22. We have now conducted linkage analysis in a family previously published as having the BBB syndrome and found tight linkage to DXS7104 (Z = 3.3, theta = 0.0). Our data narrows the candidate region to 4 cM and should facilitate the identification and characterization of one of the genes involved in midline development.

Type 3 Pfeiffer syndrome with normal thumbs.

We report on a male infant with extremely shallow orbits, spontaneous luxation of the eyes out of the eyelids, hypoplastic midface, broad, medially rotated great toes, and respiratory distress due to severe bilateral posterior choanal stenosis. At 4 days he had open cranial sutures (both by palpation and radiological examination). Subsequent radiologic studies demonstrated: thickening of the skull base, vertebral anomalies, flattening of the olecranon fossae with dislocated radii, and triangular shape of the proximal phalanx of the first toes. Our patient had manifestations of type 3 Pfeiffer syndrome (PS). However, the finding of normal thumbs has not been reported in type 3 PS. Point mutations in fibroblast growth factor receptor-1 (FGFR1) and fibroblast growth factor receptor-2 (FGFR2) have been reported in familial and sporadic cases of PS, but were not found in this patient. Recognizing type 3 PS, despite variability in expression, is important for genetic counseling, prognosis, and decision-making regarding craniofacial surgery.

The Dubowitz syndrome.

The Dubowitz syndrome is an autosomal recessive condition of intrauterine growth retardation, postnatal growth retardation, microcephaly, characteristic facial appearance, high-pitched hoarse voice, and borderline intelligence or mild mental retardation. Cleft palate may occur as well as hypospadias, cryptorchidism in affected males, and mild limb defects. The 13 cases reported in the European literature and eight personally examined patients are reviewed.

High resolution replication banding combined with in situ hybridization for the delineation of a subtle chromosome rearrangement.

Molecular cytogenetic techniques were used to delineate a subtle chromosome rearrangement in an infant with growth and psychomotor retardation, abnormal scalp hair pattern, narrow palpebral fissures, broad nasal bridge, bulbous nose, small nostrils, thin lips in a cupid's bow configuration, bilateral simian creases, and unilateral cryptorchidism. Analysis using GTG-banded chromosomes at about 400 band level showed no obvious abnormality. Prometaphase analysis at about 600 band level showed an extra band at 14q32 on GTG-banding. The father had the same extra band suggesting a reciprocal translocation but the second chromosome involved in the translocation could not be identified. High resolution replication banding on the father's lymphocytes showed a balanced reciprocal translocation 46,XY,rcp(8;14)(q24.1;q32.1). The translocation was confirmed by in situ hybridization with an immunoglobulin heavy chain probe which maps to 14q32.3. The infant therefore had duplication of 8q24.1----qter and deficiency of 14q32.1----qter. His phenotype resembled that of patients with partial duplications of the distal long arm of chromosome 8.

Neoplasms in Proteus syndrome.

We report on 2 children with Proteus syndrome who developed neoplasms. Patient 1 had a probable mesothelioma, although papillary carcinoma of the thyroid could not be completely ruled out. Patient 2 had bilateral ovarian serous cystadenomas with nuclear atypia. Other unusual neoplasms in Proteus syndrome are discussed, together with their etiologic and pathogenetic possibilities.

Duplication 6q syndrome.

Duplication (partial trisomy) of the long arm of chromosome 6 has been described in 5 children [Robertson et al, 1975, Chen et al, 1976, Clark, 1977]. We wish to report here an additional case due to a familial translocation in which the proband's karyotype is 46,XX,der(3),rcp(3;6)(p25;q21)mat. The phenotypes of the 6 children with duplication 6q are strikingly similar. Each child has duplication involving approximately the distal 1/3 to 1/2 of the long arm of chromosome 6. Distinctive features present in all 6 children include microcephaly, acrocephaly, prominent forehead, flat facial profile, depressed nasal bridge, flat malar areas, "carp" mouth, micrognathia and mental retardation. The phenotype of the duplication 6q syndrome is distinctive enough to be clinically recognizable.

Hallermann-Streiff syndrome with hypopituitarism contributing to growth failure.

A 35-month-old black boy with Hallermann-Streiff syndrome (HSS) was evaluated for anterior hypopituitarism when he presented with ketotic hypoglycemia, microgenitalia, and short stature. Endocrine evaluation showed a low T4 and TSH levels, suggesting hypothalamic hypothyroidism; this was confirmed by TRH stimulation. Metyrapone test confirmed ACTH deficiency as a contributing factor to the ketotic hypoglycemia. A superagonist GnRH test suggested hypothalamic GnRH deficiency. Growth hormone provocative testing conclusively demonstrated complete growth hormone deficiency. MRI investigation of the brain suggested hypopituitarism. Although facial findings were not completely classical of the HSS, we suggest these may be somewhat altered due to his racial back-ground. We recommend endocrine evaluation of HSS patients with manifestations suggesting hypopituitarism since treatment of this condition will improve the quality of life of these patients.

Deletion of chromosome 15pter-->q11.2 due to t(Y;15) in a boy with Prader-Willi syndrome.

Chromosome analysis of lymphocytes from a patient with the clinical presentation of Prader-Willi syndrome showed the presence of 45 chromosomes, including a der(Y) resulting from an unbalanced t(Y;15)(q12;q11.2). In situ hybridization using DYZ3 and DYZ2 showed positive signals at the paracentromeric region on the short arm and at the heterochromatic region of the long arm of the Y chromosome, respectively. The Prader-Willi syndrome in this patient is caused by the deficiency of a very small region involving 15cen-->q11.2.

Gonadal (ovarian) dysgenesis in 46,XX individuals: frequency of the autosomal recessive form.

Gonadal (ovarian) dysgenesis with normal chromosomes (46,XX) clearly is a heterogeneous condition. In some forms, the defect is restricted to the gonads, whereas other affected females show neurosensory hearing loss (Perrault syndrome). In another form, brothers may have germ cell aplasia [Granat et al., Fertil Steril 1983; 40:215-219]. Nongenetic causes exist as well. To elucidate the proportion of XX gonadal (ovarian) dysgenesis due to autosomal recessive genes, we analyzed published (N = 17) and unpublished (N = 8) families having at least two female offspring. Analysis was restricted to cases in whom ovarian failure was documented by the presence of streak ovaries (published cases) or elevated gonadotropins (unpublished cases). We reasoned that the closer to that segregation ratio expected for an autosomal recessive trait (0.25), the lower the frequency of nongenetic forms. Segregation analysis utilized standard correction for single ascertainment, with only females included in the preliminary analysis. The segregation ratio estimate was 0.16. Our results suggest that many 46,XX females with gonadal (ovarian) dysgenesis represent a disorder segregating as an autosomal recessive trait, placing sisters of these cases at a 25% risk for this disorder.

Hypertrichosis, pigmentary retinopathy, and facial anomalies: a new syndrome?

We report on a 22-month-old male with congenital hypertrichosis of the face, arms, legs, shoulders, back, and buttocks, abnormal facial appearance, dolichocephaly, and pigmentary retinopathy. Symmetrical hyperpigmentation is present on the sideburn areas of his face, and hyperpigmented streaks are seen on arms and legs. Biopsy of the hyperpigmented' skin showed many separate bundles of smooth muscles in the dermis. No relative had hypertrichosis or other birth defects. To our knowledge, the syndrome of facial anomalies, pigmentary retinopathy, and congenital hypertrichosis has not been reported previously.

Identification of the origin of ring/marker chromosomes in patients with Ullrich-Turner syndrome using X and Y specific alpha satellite DNA probes.

Fluorescent in situ hybridization (FISH) using X and Y chromosome-specific alpha satellite DNA probes hybridizing to loci DXZ1 and DYZ3 was performed to identify the origin of ring/marker chromosomes in 6 patients with Ullrich-Turner syndrome (UTS). All patients had a mosaic karyotype, 5 with 45,X/46,X,r(?) and one with 45,X/46,X,mar. We demonstrated that the marker/ring chromosome in each of these 6 patients originated from the X. A timely knowledge of the X or Y origin of ring and marker chromosomes can be crucial in genetic counseling and medical management since the presence of Y chromosome material in phenotypic females is known to increase the risk for developing gonadoblastoma.

Identification of the origin of centromeres in whole-arm translocations using fluorescent in situ hybridization with alpha-satellite DNA probes.

We detected 2 patients with whole-arm translocations resulting in a derivative chromosome consisting of 18q and 21q. Because the breakpoints were near the centromere, classical cytogenetic techniques could not determine the centromeric origin of the derivative chromosomes. Using nonradioactive in situ hybridization with a chromosome 18 alpha-satellite DNA probe (D18Z1), the centromeres in the abnormal chromosomes were determined to be from chromosome 18. The abnormality in one patient resulted in monosomy 18p with a karyotype 45,XX, -18, -21, + der(18)t(18;21) (p11;q11)mat complement. The second patient with a 46,XX, -21, + der(18)t(18;21)(p11;q11) de novo karyotype had complete trisomy of 18q. In both cases the appropriate phenotype was observed.

Characterization of an unbalanced de novo rearrangement by microsatellite polymorphism typing and by fluorescent in situ hybridization.

Unbalanced de novo rearrangements, difficult to characterize by conventional cytogenetic techniques, may be elucidated by molecular approaches. By dinucleotide repeat polymorphism typing and fluorescence in situ hybridization (FISH), we have defined the composition of an unbalanced de novo translocation (46,XX,15p+) in a child with multiple congenital anomalies. Use of a microsatellite repeat D5S208 (localized to 5p15) and polymerase chain reaction (PCR) analysis confirmed that the extra segment originated from the short arm of chromosome 5. Amplification of the patient's DNA with primers for dinucleotide repeats D5S350 and D5S118 showed that the entire 5p (from 5pter to 5q11) was present in 3 copies. FISH confirmed the trisomic status of 5p, and further revealed the presence of centromeres of both chromosomes 5 and 15 on the rearranged chromosome thus delineating its dicentric nature. This information allowed us to redefine the de novo rearrangement in this patient as 46,XX,dic der(15)t(5;15)(q11;p11).

Ring chromosome 6: variability in phenotypic expression.

We present four children with a ring chromosome 6. Clinically, these cases are quite variable. A review of ten previously reported cases also suggests difficulty of phenotype-karyotype correlation in patients with a ring 6.

Adjacent-2 disjunction of a maternal t(9;22) leading to duplication 9pter----q22 and deficiency of 22pter----q11.2.

The proposita presented at birth with multiple congenital anomalies including craniofacial anomalies, bilateral cleft lip and palate, abnormalities of the urogenital system, talipes equinovarus, and the DiGeorge sequence. Cytogenetic investigation showed a 46,XX,-22,+der(9)t(9;22)(q22;q11.2) karyotype. The mother, maternal uncle, and maternal grandmother of the infant are carriers of a reciprocal balanced translocation involving chromosomes 9 and 22 at regions q22 and q11.2, respectively. The unbalanced karyotype seen in the proposita arose due to an adjacent-2 disjunction of the quadrivalent in the mother. Prenatal diagnosis of the second pregnancy of this woman showed a similar karyotype. Review of the literature shows that adjacent-2 disjunction may occur preferentially when certain chromosomes are involved in translocations.

Localization of SRY by primed in situ labeling in XX and XY sex reversal.

Primed in situ labeling (PRINS) can be used to localize DNA segments too small to be detected by fluorescence in situ hybridization. By PRINS we identified the SRY gene in two XX males, a woman with XY gonadal dysgenesis, and an azoospermic male with Xp-Yp interchange. Because PRINS has been used generally in the study of repetitive sequences, we modified the technique for study of the single copy 2. 1-kb SRY sequence. SRY signals were identified at band Yp11.31p11.32 in normal XY males and in the woman with XY gonadal dysgenesis. SRY signals were identified on Xp22 in one XX male but not in the other. They were identified in the corresponding region (Xp22) of the der(X) in the azoospermic male with Xp-Yp interchange. SRY signals were not observed in normal XX females. Presence of SRY in DNA samples from the various subjects was confirmed by polymerase chain reaction. We conclude that PRINS is ideal for rapid localization of single copy genes and small DNA segments in general.

Most Jacobsen syndrome deletion breakpoints occur distal to FRA11B.

Recent studies have identified a (CCG)n repeat in the 5' untranslated region of the CBL2 protooncogene (11q23.3) and have demonstrated that expansion of this repeat causes expression of the folate-sensitive fragile site FRA11B. It has also been demonstrated that FRA11B is the site of breakage in some cases of Jacobsen syndrome (JS) involving terminal deletions of chromosome 11q. We report on 2 patients with JS and a 46,XX,del(11)(q23.3) karyotype. In both cases, microsatellite and fluorescence in situ hybridization analyses indicated that the deletion breakpoint was approximately 1.5-3 Mb telomeric to FRA11B. There was no evidence of expansion of the CBL2 (CCG)n repeat in the parents of either patient. The deleted chromosome was of paternal origin in both cases, although it was of maternal origin in the cases reported to be caused by FRA11B. These findings and those in previously reported patients suggest that the breakpoint for most 11q deletions in JS patients is telomeric to FRA11B, which raises the possibility that there may be other fragile sites in 11q23.3 in addition to FRA11B. These findings also support previous evidence that there may be a propensity for breakpoints to differ depending on the parental origin of the deleted chromosome.

Genetic amniocentesis: a twelve years' experience.

The first 2,013 fetuses in 2,000 patients undergoing genetic amniocentesis at our institution were analyzed for the incidence of abnormal findings and for the safety and accuracy of the procedure. One percent of the patients were found to have aneuploid fetuses and another 1% were found to have elevated amniotic fluid concentrations of alpha-fetoprotein. Advanced maternal age was the indication for amniocentesis in 84% of the women with aneuploid fetuses. Thirty-two (1.6%) of the pregnancies ended in spontaneous abortion and 35 (1.7%) were terminated because of abnormal results of the prenatal diagnostic procedure. Our error rate was 0.15%, and tissue culture was successful in 97.7% of the procedures. During the latter part of our experience concurrent ultrasonography was utilized with the amniocentesis, resulting in a reduction in blood-tinged specimens from 15.0% to 5.2%. In experienced hands, midtrimester amniocentesis for the purpose of prenatal diagnosis of genetically determined defects is a safe, accurate, and valuable procedure for the identification of fetal abnormalities.