Congenital Alopecia and nail dystrophy associated with severe functional T-cell immunodeficiency in two sibs.

We report on two sisters affected by congenital alopecia, nail dystrophy, and a severe T-cell immunodeficiency, presumably inherited as an autosomal-recessive disorder. The T-cell defect was characterized by severe functional impairment, as shown by the lack of proliferative response and upregulation of activation markers following mitogen stimulation. The functional abnormality occurred in spite of the presence of phenotypically mature of the defect. This is the first observation reported on an ectodermal disorder, characterized by alopecia and nail dystrophy, observed at birth, in association with a primary immunodeficiency. The hypothesis that these two events may be casually related is discussed.

Molecular and cytogenetic characterization of a recurrent unbalanced translocation (4;21)(p16.3;q22.1): relevance to the Wolf-Hirschhorn and Down syndrome critical regions.

We report on an aneuploidy syndrome due to the unbalanced segregation of a familial translocation (4;21)(p16.3;q22.1) causing a partial 4p monosomy and a partial 21q trisomy. The three affected children presented with severe failure to thrive, short stature, microcephaly, profound hypotonia, and mental retardation. The face, very similar in the three children, is characterized by frontal bossing, upslanting of the palpebral fissures, short nose, and deep set ears, giving the overall appearance of the Down syndrome. The molecular study has defined the aneuploid segment on both 4p and 21q. Most of the Down syndrome critical region was found to the trisomic, while only part of the candidate Wolf-Hirschhorn syndrome critical region was deleted, suggesting that this region is not critical for the major malformations characteristic for WHS.

Polysyndactyly and trigonocephaly with partial agenesis of corpus callosum.

Several malformation syndromes which include polysyndactyly and craniofacial anomalies have been described. We report a case of an 11-month-old boy with a pattern of anomalies including polysyndactyly, trigonocephaly, partial agenesis of corpus callosum and dysmorphic facies.

Carotid endarterectomy in community practice: surgeon-specific versus institutional results.

The efficacy of carotid endarterectomy in preventing stroke is clearly related to appropriate patient selection and low surgical morbidity and mortality. It has been suggested that since results at some centers are better than nationwide statistics, perhaps the operation should be limited to those institutions. In this paper we present an experience with carotid endarterectomy over the past twelve years. These 566 consecutive cases were performed by two vascular surgeons in a large metropolitan area using thirteen different hospitals ranging from 150 to 500 beds. Our mortality of 0.5% and permanent stroke incidence of 1.6% did not vary significantly from hospital to hospital. Where the results of surgical audits were available from the individual hospitals, the overall complication rates were significantly higher. We conclude that individual surgeons, not institutions, determine the efficacy of carotid endarterectomy in community practice.

Cost-effective carotid endarterectomy in community practice.

The purpose of this study was to compare hospital charges for carotid endarterectomy on a surgeon-specific basis. The cost of carotid endarterectomy is influenced by preoperative evaluation, operating time, use of the intensive care unit, length of hospital stay, and surgical results. Length of stay and average hospital charges for 18 doctors performing 344 carotid endarterectomies at three hospitals were analyzed. Outcome data were also reviewed. The results demonstrated a wide variation in hospital charges among surgeons. Surgeons using the most cost-effective measures achieved comparable or superior outcomes. In an era of managed care, severe cost constraints mandate that surgeons perform similar studies in their own communities so that cost-effective clinical pathways can be developed. With the use of appropriate guidelines, carotid endarterectomy can be performed at relatively low cost without sacrificing quality.

Isolation of region-specific and polymorphic markers from chromosome 17 by restricted Alu polymerase chain reaction.

We demonstrate that the digestion of template DNAs with restriction endonucleases prior to Alu polymerase chain reaction ("restricted Alu-PCR") reduces the complexity of the Alu-primed amplification patterns of human DNA in somatic cell hybrids and allows a direct informative comparison of these patterns. A comparison of restricted Alu-PCR patterns of a monochromosomal hybrid retaining a human chromosome 17 (MH22-6) and a hybrid retaining a human chromosome 17 deleted for band p11.2 (DH110-D1) revealed four Alu-PCR products that were present in the former but absent in the latter hybrid. Hybridization of these fragments to the total Alu-PCR amplification products of the two hybrids confirmed their absence in DH110-D1 amplification products. Hybridization to a panel of somatic cell hybrids indicated that two of these fragments were deleted in the hybrid DH110-D1 and mapped to 17p11.2, as expected. However, two additional fragments were not deleted in the hybrid DH110-D1 and mapped to other regions of chromosome 17. An insertion-deletion polymorphism was associated with one of the latter fragments, which may be the mechanism for the lack of its amplification in the hybrid DH110-D1. Restricted Alu-PCR should enhance the applications of Alu-PCR and provides a new method for the identification of chromosome-specific polymorphic markers.

Cutis verticis gyrata--mental deficiency syndrome: a patient with drug-resistant epilepsy and polymicrogyria.

We report a case of cutis verticis gyrata-mental deficiency syndrome (CVG-MD) which was associated with drug-resistant epilepsy and bilateral occipital polymicrogyria. Genetic analysis showed an increased number of breaks at the 3p14 and 16q23 sites. We hypothesize that a deleterious factor acting at a critical period of intrauterine development could result in the cerebral malformation and in the development of CVG. Neuroradiological investigation is warranted in cases of CVG-MD.

Surgical treatment of aneurysm of the persistent sciatic artery.

Persistent sciatic artery (PSA) is a rare congenital malformation that is complicated by aneurysm formation in more than 25% of the reported cases. Two cases of aneurysm of the PSA are presented. Twenty-six aneurysms of the PSA, including our two cases, have been reported in the English literature in the last three decades. Early surgical treatment is warranted to decrease the 25% amputation rate associated with thromboembolic complications. The posterior, transgluteal repair of this aneurysm affords excellent exposure and avoids a long bypass graft, multiple incisions, and staged procedures. Magnetic resonance imaging may be helpful in preoperative evaluation of the feasibility of proximal, extrapelvic vascular control.

Control of lactase in human adult-type hypolactasia and in weaning rabbits and rats.

Lactase is an enterocyte brush-border membrane beta-glycosidase that splits lactose, the sugar of milk. In mammals, including many human populations, intestinal lactase activity is very high in the suckling and declines to low levels after weaning. There are two human adult lactase phenotypes, one in which high lactase activity persists and another in which it declines. Two alleles have been postulated to explain these different phenotypes. In the present study lactase mRNA levels have been investigated in the small intestine (a) of rabbits and rats, at different ages, considered as models for mammals, and (b) of human adults with the two lactase phenotypes. In rabbits and rats, high levels of lactase mRNA are present up to the weaning period, a time at which a consistent decrease of this mRNA is found, a decrease that parallels that of lactase activity. It is surprising that after this period adult animals of both species express again high levels of lactase mRNA, whereas lactase activity remains at very low levels. Our results suggest that in the adult rabbits and rats the main control of lactase gene expression is likely to be at a posttranscriptional level. Similarly, in man no clear difference was found at the RNA level between adults with hypolactasia and adults with persistent high lactase activity, a result that also indicates a posttranscriptional control of lactase expression.

Charcot-Marie-Tooth disease: molecular characterization of patients from central and southern Italy.

The syndrome of peroneal muscular atrophy, or Charcot-Marie-Tooth (CMT), disease represents the most common inherited peripheral neuropathy, with a prevalence of about 1 per 2500. The disease is usually transmitted in an autosomal dominant fashion, although it can display all the mendelian patterns of inheritance. The chromosome 17-linked form (CMT1a) appears to be the most common form of the disease in all the ethnic groups studied so far, Italians included, and is due to a tandem duplication in 17p11.2. In order to study the distribution of CMT types and to establish a genotype-phenotype correlation in patients from Central and Southern Italy, we collected 19 CMT pedigrees diagnosed in the years 1992-1993. Simple tandem repeats (STR) polymorphism analysis with the marker RM11-GT and Southern blotting with the probes pVAW409R3 and pVAW412 were performed, demonstrating a high prevalence (about 60%) of 17p duplication in the families studied. No clinical or electrophysiological differences were noted between CMT1 patients with or without 17p duplication, respectively. Two families affected by CMT2 showed no evidence of rearrangement at the D17S122 locus. These data are consistent with the hypothesis of a different molecular basis for CMT2.

Clinical and biochemical screening for Smith-Lemli-Opitz syndrome. Italian SLOS Collaborative Group.

Smith-Lemli-Opitz syndrome (SLOS) is a multiple congenital anomalies/mental retardation disorder possibly due to a defect of delta 7-sterol reductase, leading to low plasma cholesterol levels and to the accumulation of 7-dehydrocholesterol (7-DHC) and other cholesterol precursors. This study aimed to identify clinical features that could potentially be specific indicators for the clinical diagnosis of SLOS, and to test the reliability of ultraviolet spectrophotometry (UVS) as a biochemical screening procedure for the syndrome. Twenty patients with clinical suspicion of SLOS, referred to 11 Italian paediatric and clinical genetic centres, were collected during 1994. In 10 patients the diagnosis was confirmed biochemically by gas chromatography/mass spectrometry (GC/MS) analysis of serum sterols, whereas in the other 10 patients the serum sterol profiles were normal. A comparison between confirmed SLOS patients and biochemically negative subjects did not show clinical signs specific for the syndrome. UVS measurement of 7-DHC correlated well with GC/MS profiles, showing 100% sensitivity and specificity. Four out of five patients had serum bile acid concentrations below the normal range of controls.

Phenylketonuria in Italy: distinct distribution pattern of three mutations of the phenylalanine hydroxylase gene.

Phenylketonuria (PKU) is an autosomal recessive disease caused by the deficiency of a liver-specific enzyme, phenylalanine hydroxylase (PAH). The pattern of PAH mutations in Mediterranean populations appears to be different from that observed in northern Europe and Asia. Our aim was to study the molecular basis of PKU in Campania and Calabria, two regions of southern Italy. We studied 99 unrelated alleles, detecting 75.8% of the mutations. Our results show that 57% of all the PKU alleles are caused by three different mutations: IVS10nt-546, R261Q and L48S, which display significant differences in their relative distribution across Italy. A novel mutation, a G-to-T transversion at the codon 257 (G257C), was also identified. This mutation results in a Gly-to-Cys change in the catalytic domain of the protein.

DNA duplication associated with Charcot-Marie-Tooth disease type 1A.

Charcot-Marie-tooth disease type 1A (CMT1A) was localized by genetic mapping to a 3 cM interval on human chromosome 17p. DNA markers within this interval revealed a duplication that is completely linked and associated with CMT1A. The duplication was demonstrated in affected individuals by the presence of three alleles at a highly polymorphic locus, by dosage differences at RFLP alleles, and by two-color fluorescence in situ hybridization. Pulsed-field gel electrophoresis of genomic DNA from patients of different ethnic origins showed a novel SacII fragment of 500 kb associated with CMT1A. A severely affected CMT1A offspring from a mating between two affected individuals was demonstrated to have this duplication present on each chromosome 17. We have demonstrated that failure to recognize the molecular duplication can lead to misinterpretation of marker genotypes for affected individuals, identification of false recombinants, and incorrect localization of the disease locus.

Somatic cell hybrids, sequence-tagged sites, simple repeat polymorphisms, and yeast artificial chromosomes for physical and genetic mapping of proximal 17p.

Somatic cell hybrids retaining the deleted chromosome 17 from 15 unrelated Smith-Magenis syndrome (SMS) [del(17)(p11.2p11.2)] patients were obtained by fusion of patient lymphoblasts with thymidine kinase-deficient rodent cell lines. Seventeen sequence-tagged sites (STSs) were developed from anonymous markers and cloned genes mapping to the short arm of chromosome 17. The STSs were used to determine the deletion status of these loci in these and four previously described human chromosome 17-retaining hybrids. Ten STSs were used to identify 28 yeast artificial chromosomes (YACs) from the St. Louis human genomic YAC library. Four of the 17 STSs identified simple repeat polymorphisms. The order and location of deletion breakpoints were confirmed and refined, and the regional assignment of several probes and cloned genes were determined. The cytogenetic band locations and relative order of six markers on 17p were established by fluorescence in situ hybridization mapping to metaphase chromosomes. The latter data confirmed and supplemented the somatic cell hybrid results. Most of the hybrids derived from [del(17)(p11.2p11.2)] patients demonstrated a similar pattern of deletion for the marker loci and were deleted for D17S446, D17S258, D17S29, D17S71, and D17S445. However, one of them demonstrated a unique pattern of deletion. This patient is deleted for several markers known to recognize a large DNA duplication associated with Charcot-Marie-Tooth (CMT) disease type 1A. These data suggest that the proximal junction of the CMT1A duplication is close to the distal breakpoint in [del(17)(p-11.2p11.2)] patients.

Molecular analysis of the Smith-Magenis syndrome: a possible contiguous-gene syndrome associated with del(17)(p11.2).

We undertook clinical evaluation (32 cases) and molecular evaluation (31 cases) of unrelated patients affected with Smith-Magenis syndrome (SMS) associated with an interstitial deletion of band p11.2 of chromosome 17. Patients were evaluated both clinically and electrophysiologically for peripheral neuropathy, since markers showing close linkage to one form of Charcot-Marie-Tooth disease (CMT1A) map to this chromosomal region. The common clinical findings were broad flat midface with brachycephaly, broad nasal bridge, brachydactyly, speech delay, and hoarse, deep voice. Fifty-five percent of the patients showed clinical signs (e.g., decreased or absent deep tendon reflexes, pes planus or pes cavus, decreased sensitivity to pain, and decreased leg muscle mass) suggestive of peripheral neuropathy. However, unlike patients with CMT1A, these patients demonstrated normal nerve conduction velocities. Self-destructive behaviors, primarily onychotillomania and polyembolokoilamania, were observed in 67% of the patients, and significant symptoms of sleep disturbance were observed in 62%. The absence of REM sleep was demonstrated by polysomnography in two patients. Southern analysis indicated that most patients were deleted for five 17p11.2 markers--FG1 (D17S446), 1516 (D17S258), pYNM67-R5 (D17S29), pA10-41 (D17S71), and pS6.1-HB2 (D17S445)--thus defining a region which appears to be critical to SMS. The deletion was determined to be of paternal origin in nine patients and of maternal origin in six patients. The apparent random parental origin of deletion documented in 15 patients suggests that genomic imprinting does not play a role in the expression of the SMS clinical phenotype. Our findings suggest that SMS is likely a contiguous-gene deletion syndrome which comprises characteristic clinical features, developmental delay, clinical signs of peripheral neuropathy, abnormal sleep function, and specific behavioral anomalies.