Excess of deletions of maternal origin in the DiGeorge/Velo-cardio-facial syndromes. A study of 22 new patients and review of the literature

We have determined the parental origin of the deleted chromosome 22 in 29 cases of DiGeorge syndrome (DGS) using a CA-repeat mapping within the commonly deleted region, and in one other case by using a chromosome 22 short arm heteromorphism. The CA-repeat was informative in 21 out of 29 families studied and the deleted chromosome was of maternal origin in 16 cases (72%). When these data are pooled with recent results from the literature, 24 de novo DGS, velo-cardio-facial syndrome (VCFS) and isolated conotruncal cardiac disease deletions are found to be of maternal origin and 8 of paternal origin, yielding a ² of 8 with a probability level lower than 0.01. These data, and review of the literature on familial DGS/VCFS and isolated conotruncal cardiopathies suggest that there is a strong tendency for the 22q11.2 deletions to be of maternal origin.     

Genomic analysis identifies candidate pathogenic variants in 9 of 18 patients with unexplained West syndrome

West syndrome, which is narrowly defined as infantile spasms that occur in clusters and hypsarrhythmia on EEG, is the most common early-onset epileptic encephalopathy (EOEE). Patients with West syndrome may have clear etiologies, including perinatal events, infections, gross chromosomal abnormalities, or cases followed by other EOEEs. However, the genetic etiology of most cases of West syndrome remains unexplained. DNA from 18 patients with unexplained West syndrome was subjected to microarray-based comparative genomic hybridization (array CGH), followed by trio-based whole-exome sequencing in 14 unsolved families. We identified candidate pathogenic variants in 50 % of the patients (n = 9/18). The array CGH revealed candidate pathogenic copy number variations in four cases (22 %, 4/18), including an Xq28 duplication, a 16p11.2 deletion, a 16p13.1 deletion and a 19p13.2 deletion disrupting CACNA1A. Whole-exome sequencing identified candidate mutations in known epilepsy genes in five cases (36 %, 5/14). Three candidate de novo mutations were identified in three cases, with two mutations occurring in two new candidate genes (NR2F1 and CACNA2D1) (21 %, 3/14). Hemizygous candidate mutations in ALG13 and BRWD3 were identified in the other two cases (14 %, 2/14). Evaluating a panel of 67 known EOEE genes failed to identify significant mutations. Despite the heterogeneity of unexplained West syndrome, the combination of array CGH and whole-exome sequencing is an effective means of evaluating the genetic background in unexplained West syndrome. We provide additional evidence for NR2F1 as a causative gene and for CACNA2D1 and BRWD3 as candidate genes for West syndrome.     

A rare case report of polyangiitis overlap syndrome: granulomatosis with polyangiitis and eosinophilic granulomatosis with polyangiitis

Background

Granulomatosis with polyangiitis (GPA) is a systemic ANCA-associated vasculitis characterized by necrotizing granulomatous inflammation and a predilection for the upper and lower respiratory tract. Eosinophilic granulomatosis with polyangiitis (EGPA) is also a systemic ANCA-associated vasculitis, but EGPA is characterized by eosinophilic as well as granulomatous inflammation and is more commonly associated with asthma and eosinophilia.Polyangiitis overlap syndrome is defined as systemic vasculitis that does not fit precisely into a single category of classical vasculitis classification and/or overlaps with more than one category. Several polyangiitis overlap syndromes have been identified, however, there are very few case reports of an overlap syndrome involving both GPA and EGPA in the medical literature.

Case presentation

We conducted a PUBMED literature review using key words ‘granulomatosis with polyangiitis,’ ‘Wegener’s,’ ‘GPA,’ ‘eosinophilic granulomatosis with polyangiitis,’ ‘Churg-Strauss,’ ‘EGPA,’ ‘overlap syndrome,’ ‘Wegener’s with eosinophilia,’ and ‘GPA with eosinophilia’ in English only journals from 1986 to 2017. Relevant case reports and review articles of overlap syndromes of GPA and EGPA were identified. We aim to report a unique case of GPA and EGPA overlap syndrome and review the cases that have been previously described.Between 1986 and 2017, we identified 15 cases that represent an overlap syndrome with compelling features of both GPA and EGPA. Patients ranged in age between 21 and 78. Of those whose gender was identified, 80 % of the patients were female. All cases described involved the lungs, 60 % reported sinus involvement, and more than 50 % displayed renal involvement. An overwhelming majority of patients were positive for c-ANCA and demonstrated eosinophilia (peripheral blood or tissue eosinophilia). A preponderance of the cases described were treated with systemic corticosteroids combined with an immunosuppressive/cytotoxic agents.

Conclusion

To our knowledge, there have been very few cases reported of an overlap syndrome of GPA and EGPA. Identification of patients with a polyangiitis overlap syndrome of GPA and EGPA is imperative as prognosis, longitudinal management and treatment modalities may differ between these entities.

     

Immunochemical quantification of Cu/Zn superoxide dismutase in prenatal diagnosis of Down's syndrome

Summary Cu/Zn Superoxide dismutase (SOD) was quantified by enzyme immunoassay for prenatal diagnosis of Down's syndrome. Overall, 154 samples of amniotic fluid, 72 samples of amniotic cells and 31 samples of chorionic tissue were investigated. Due to the large biological variance of the SOD concentrations in normal pregnancies (range for amniotic fluid 10.5–154.9, for amniotic cells 40.0–338.8, and for chorionic tissue 132.2–649.5 g SOD/g protein) the cases of Down's syndrome detected by karyotype analysis were not reliably identified by Cu/Zn SOD quantification. As in erythrocytes obtained from patients with Down's syndrome, a trisomy 21 was easily and accurately detected in the erythrocytes from very small quantities (about 50 l) of umbilical blood. The SOD concentrations in normal cases (n = 40) varied between 11.4 and 17.3 and in the cases of trisomy 21, as confirmed by karyotyping (n = 4), between 22.5 and 23.2ng/one million cells. SOD quantification in fetal erythrocyte is a helpful additional method in prenatal Down syndrome diagnosis under certain conditions, which are discussed.     

L'ültrastructure du Foie Humain Lors D'ictères Idiopathiques Chroniques

Summary 15 liver biopsies from 13 patients suffering from non-hemolytic constitutional jaundice (6 cases of Gilbert's, 2 cases of Rotor's and 5 cases of Dubin-Johnson's disease) provided the basis of an ultrastructural study of pigment inclusions in liver cells following various techniques of preparation.The lipofuscin in Gilbert's syndrom and the pigment characteristic of Dubin-Johnson's syndrom contain two distinct components which are present in both types of inclusions but their proportions are different in these syndromes: a globular component, probably of lipidic nature, is the main constituent of the lipofuscin, a granulo-filamentous component the main constituent of the Dubin-Johnson's pigment. These two components react in both syndromes identically to various techniques of fixation, embedding and section-staining. In Rotor's syndrome other pigment inclusions are observed which are not detectable in ordinary histological preparations: they consist essentially of aggregates of dense, ferritin-like material. The presence, in the hepatocytes, of pigment inclusions which have some features in common in the 3 types of syndromes and other characteristics specific for each of them, confirms the close relation between these types of jaundice, but emphasizes also their differences; moreover, this ultrastructural study underlines the difficulty of an exact classification of these syndromes.

---

---

Travail subventionné par la Fondation Fritz Hoffmann-La Roche pour l'expansion en Suisse du travail scientifique exécuté par équipe et par le Fonds National Suisse de la Recherche Scientifique.

---

Avec la collaboration technique de Mlle M.-M. Bertholet.     

Molecular detection of a translocation (Y;11)(q11.2;q24) in a 45,X male with signs of Jacobsen syndrome

Summary A 45,X karyotype was found in a boy with dysmorphic features, hypoglycaemia and pancytopenia. DNA analysis showed the presence of the Y-chromosomal DNA sequences SRY, ZFY, DYZ4, DYZ3 and DYS1. Using fluorescent in situ hybridization, we located DYZ4 and DYZ3 on chromosome llqter and concluded that a de novo translocation (Y;11)(q11.2;q24) with a deletion of 11q24qter and a deletion of Yq11.2Yqter were present; Jacobsen syndrome and azoospermia are associated with these deletions. Signs of Jacobsen syndrome were observed in the patient.     

Heterogeneity of Dyggve-Melchior-Clausen dwarfism

Summary Sibs with apparent Dyggve-Melchior-Clausen (DMC) dwarfism and normal intelligence are described. Three other familial and 3 sporadic cases with DMC dwarfism and normal intelligence are known. Twelve familial and 9 sporadic cases are known with the usual combination of DMC dwarfism and severe mental retardation. Since the two conditions appear to breed true they seem to be genetically different. We propose to name the former Smith-McCort dwarfism to clearly distinguish it from the DMC syndrome in which mental retardation is a constituent part. Both conditions are inherited as autosomal recessive traits. Spinal cord compression due to atlantoaxial instability is a serious and preventable complication of both disorders.     

Christ-Siemens-Touraine syndrome. Investigations on two large brazilian kindreds with a new estimate of the manifestation rate among carriers

Summary Two large Brazilian families with 34 males and 32 females presenting Christ-Siemens-Touraine syndrome are reported. As unusual features, one kindred presented two very severely affected girls, nine affected males with a normal nose, and a very heterogeneous trichodysplasia among both males and females; oligohydramnios was verified in the pregnancies of carriers from both kindreds. Carrier detection was possible in 0.73–0.04 of all the cases.     

Two unrelated children with partial trisomy 1q and monosomy 6p,presenting with the phenotype of the Larsen syndrome

Summary Two unrelated children presented with similar clinical features (facial dysmorphism and multiple joint dislocations) suggesting the diagnosis of Larsen syndrome. Both carried an inherited unbalanced translocation resulting in partial trisomy 1q and partial monosomy 6p. Analysis of skin collagen from one of the probands disclosed a decreased 1/2 chain ratio of collagen type I, increased thermal stability and increased hydroxylation of proline and lysine. The present findings suggest that, as a result of the chromosome rearrangements, both patients have a mutation on a gene involved in collagen production, located either on chromosome 1q or, more probably, on 6p. It is furthermore suggested that other cases of Larsen syndrome are the result of a similar mutation.     

The HLE hybrid dysgenesis syndrome in the midgeChironomus thummi: Differences in the dysgenic potential between strains

After crossing experiments between twoChironomus subspecies the HLE hybrid dysgenesis syndrome occurs non-reciprocally in the F1 hybrids if the males of each of the fourCh. th. thummi strains (HL, So, G, Kr) are crossed to females ofCh. th. piger, strain E. In hybrid egg masses, differences in the strength of the abnormal trait reduced egg hatch were found between the differentpiger E ×thummi interstrain crosses. From the results it is concluded that eachthummi strain has a specific hybrid dysgenesis potential which determines the severity of the HLE syndrome in the hybrids. The HLE syndrome occurs also in the hybrids of crosses of differentCh. th. thummi strains. In these hybrids the syndrome is only obtained if the male parent descends from a strain which has a higher HLE hybrid dysgenesis potential than that strain from which the female parent is derived. These results demonstrate that the HLE syndrome is not restricted to the hybrids of thethummi × piger subspecies cross. In theCh. th. thummi interstrain crosses the hybrids of that cross direction are normal, which is reciprocal to the cross direction affected by the HLE syndrome. This is in contrast to thethummi × piger subspecies crosses, where the hybrids of one cross direction always show the HLE syndrome and the hybrids of the reciprocal cross direction the Rud syndrome. Thus, the present study also demonstrates that the HLE and Rud hybrid dysgenesis syndrome inChironomus are independent from one another.     

Prenatal diagnosis of genetically determined early manifestation of autosomal dominant polycystic kidney disease?

Summary A case of an unusually early manifestation of autosomal dominant polycystic kidney disease (ADPKD) is reported that was prenatally diagnosed by ultrasound. The ultrasonographic picture showed greatly enlarged kidneys and increased echogenicity that was indistinguishable from cases of autosomal recessive polycystic kidney disease or Meckel syndrome without further information. Because of two further cases of early manifestation of ADPKD within the family reported (brother and cousin), as well as several other familial cases reported in the literature, we postulate that genetic factors are involved (modifying alleles). When repeated observations of familial cases of early manifestations of ADPKD are made, genetic counseling should be considered.     

Epidemiology of childhood Guillan-Barre syndrome in the north west of Iran

Background and aims

This study was carried out to investigate the incidence, annual time trend and some epidemiological and clinical features of Guillain-Barre syndrome in children in the north west of Iran.

Materials and methods

In this population-based cross sectional research, epidemiological and clinical features of 143 cases with Guillain-Barre syndrome between 2001 and 2006 were studied. The setting of the study was Tabriz Children Medical Centre, the major University-Hospital located in Tabriz city of the East Azarbaijan province covering whole region. Data collected included age, gender, chronological information, preceding events, functional grade of motor deficit.

Results

The mean age (standard deviation) of subjects was 5.4 (3.6) years. The male/female ratio was 1.3. The average annual incidence rate was 2.27 per 100 000 population of 15 years children (CI95%: 1.9–2.6). The majority of cases occurred in March, July and November and the highest proportion of the syndrome was observed in winter (29 percent, P > 0.10).

Conclusion

The results indicated that an unexpected high incidence of Guillain-Barre syndrome has occurred in 2003 in the region. We concluded that a monitoring and surveillance system for Guillain-Barre syndrome is essential to set up in this region.

     

Predisposition for cysteine substitutions in the immunoglobulin-like chain of FGFR2 in Crouzon syndrome

Four cases of Crouzon syndrome, one familial and three sporadic, were investigated for mutations in exon B of the fibroblast growth factor receptor 2 (FGFR2) gene. In the familial case, a mutation was found at codon 340 that exchanged tyrosine for histidine. Mutations at codon 342, detected in the three sporadic cases, replaced a cysteine by another amino acid. While three of the mutations have been described before, the fourth mutation, a CG transversion at codon 342 in one of the sporadic cases, has not been recognized previously. Compilation of all exon B mutations in Crouzon syndrome described to date revealed that 6 of the 8 sporadic and 2 of the 9 familial cases have mutations in codon 342. These mutations caused the substitution of cysteine for another amino acid. Given that a mutation in codon 342 was found in 8 out of 17 cases and that in 9 cases the mutation occurred at five additional positions, codon 342 of exon B of the FGFR2 gene may be predisposed to mutations in Crouzon syndrome.     

SOD-A and chromosome 21

Summary A balanced maternal chromosome translocation (9p24;21q214) resulted in two offspring with unbalanced karyotypes. One of these, a girl trisomic for both segment 9pter9p24 and segment 21pter21q214, was found to have a SOD-A activity not significantly different from those found in a group of five cases with trisomy 21. However, clinical evaluation of this girl revealed no symptoms of the Down syndrome. These findings suggest that, providing the gene dosage theory is correct, the gene for SOD-A is probably localized on chromosome 21 proximal to, or in, band q21.     

Rare Case of Monozygotic Twins Diagnosed With Klinefelter Syndrome During Evaluation for Infertility

Although neither Klinefelter syndrome nor monozygotic twins are particularly rare (1/667 male births and 3–4/1000 live births, respectively), the occurrence of both in the same pregnancy (ie, identical twins with Klinefelter syndrome) is exceedingly rare and has only been reported three times previously in the literature. This report describes the fourth ever reported case of monozygotic twins with Klinefelter syndrome (who presented to our male fertility clinic with failure to conceive) and sheds interesting light on the reproductive concordance observed with this rare clinical entity. To our knowledge, this is the first reported case of monozygotic twins with Klinefelter syndrome that describes the infertility workup and outcomes of microsurgical testicular sperm extraction.Key words: Klinefelter syndrome, Microsurgical testicular sperm extraction, Azoospermia, Sertoli only syndrome, Germ cell aplasiaKlinefelter syndrome, the most common sex chromosome disorder in men, is the clinical result of an additional X chromosome in human males. This syndrome, which affects an estimated 1 in 667 live male births, most commonly manifests as 47,XXY, but may also take the form of 46,XY/47,XXY (Klinefelter mosaicism), 48,XXXY, or 49,XXXXY.¹ Typical clinical manifestations of the syndrome include primary infertility, atrophic testes, hypergonadotropic hypogonadism, gynecomastia, eunuchoidism, and decreased facial and body hair.¹ This condition often goes undiagnosed in prepubertal boys, and even in adult men, despite the physical hallmarks of the syndrome; many cases come to light only during the evaluation of primary male factor infertility. The andrologist, therefore, plays a central role in the diagnosis, work-up, and management of men with Klinefelter syndrome.With an incidence approximately twice that of Klinefelter (3–4 per 1000 live births worldwide),² monozygotic (identical) twinning occurs when one fertilized egg splits and divides into two embryos. Monozygotic twins have been observed with various karyotypic abnormalities, including trisomy 21,³ trisomy 18,⁴ and trisomy 13.⁵ However, the presentation of monozygotic twins with Klinefelter syndrome (a fertilized egg with a 47, XXY karyotype splitting to produce identical embryos with Klinefelter syndrome) is exceedingly rare. In this report, we discuss one case of identical twin brothers diagnosed with Klinefelter syndrome at our fertility clinic (Glickman Urological & Kidney Institute, Cleveland, OH) as part of a work-up for inability to conceive.     

Teaching cases: Heterochromia

Abstract: A patient was noted to have 2 different eye colours and miosis in her left eye. She ultimately received a diagnosis of congenital Horner syndrome. Determinants of eye colour and possible clinical significance are discussed.The case: A 35-year-old woman with a hypertensive emergency and confusion presented to the emergency department. Incidentally, we noted that she had 2 different coloured eyes (heterochomia) and miosis of her left eye (Figure 1). The patient reported that her eyes had been different colours since very early in her childhood.Open in a separate windowFigure 1: This 35-year-old woman had different coloured eyes since birth. The entire iris of her right eye is brown, and the iris of the left eye is greenish brown. Her left pupil is smaller than the right, which is consistent with the diagnosis of congenital Horner syndrome.Although some patients have pigment changes involving only 1 segment of the iris (segmental heterochromia or heterochromia iridium),¹ our patient''s entire iris was involved (complete heterochromia or heterochromia iridis). Heterochromia iridis is rare, affecting fewer than 200 000 people in the United States.² Although uncommon in humans, it is common in some breeds of cats, dogs and horses.Eye colour is determined by the concentration and distribution of melanin in the iris, with both genetic and physiologic factors affecting determination and maintenance of iris colour. Most human cases of heterochromia are sporadic and benign, and they occur without any detectable underlying abnormality. Congenital heterochromia occurs in a variety of syndromes, including Sturge–Weber syndrome, Waardenburg syndrome and Parry–Romberg syndrome (3Table 1Open in a separate windowDisruption of the sympathetic stimulation of the melanocytes in the superficial stroma of the iris (especially as a child) can lead to heterochromia. Horner syndrome from the unilateral impairment of sympathetic nerves leads to ptosis, miosis, a lag in pupil dilation, enopthalmos (the impression of a sunken eye) and facial anhidrosis (decreased sweating on 1 side of the face). Acquired heterochromia can occur in adults in rare cases as a result of acquired Horner syndrome. In contrast to patients with acquired Horner syndrome, patients with congenital Horner syndrome, such as our patient, often lack several features of the syndrome.In adults with acquired heterochromia and miosis, Fuchs heterochromic cyclitis and sympathetic heterochromia must be considered. Unilateral sympathetic nerve lesions such as paravertebral neurilemmoma and neuroblastoma should also be considered. Our patient''s clinical presentation was inconsistent with any of these causes. Sympathetic heterochromia was suspected but investigations, including urinary catecholamines and an MIBG (iodine-131-meta-iodobenzylguanidine) scan, did not reveal excess catecholamine secretion or a sympathetic tumour.The patient''s blood pressure was managed with appropriate medication, and she was ultimately discharged from our care with a reversal of her confusion. There was no further follow-up with regard to her eye colour.Habib Ur Rehman MBBS Department of Internal Medicine Regina General Hospital Qu''Appelle Health Region Regina, Sask.     

Synaptic Dysfunction in Neurodevelopmental Disorders Associated with Autism and Intellectual Disabilities

The discovery of the genetic causes of syndromic autism spectrum disorders and intellectual disabilities has greatly informed our understanding of the molecular pathways critical for normal synaptic function. The top-down approaches using human phenotypes and genetics helped identify causative genes and uncovered the broad spectrum of neuropsychiatric features that can result from various mutations in the same gene. Importantly, the human studies unveiled the exquisite sensitivity of cognitive function to precise levels of many diverse proteins. Bottom-up approaches applying molecular, biochemical, and neurophysiological studies to genetic models of these disorders revealed unsuspected pathogenic mechanisms and identified potential therapeutic targets. Moreover, studies in model organisms showed that symptoms of these devastating disorders can be reversed, which brings hope that affected individuals might benefit from interventions even after symptoms set in. Scientists predict that insights gained from studying these rare syndromic disorders will have an impact on the more common nonsyndromic autism and mild cognitive deficits.It is estimated that ∼1% of the human population has an autism spectrum disorder (ASD). ASD has widely varied behavioral manifestations, severity, and comorbid conditions (hence the term “spectrum”), but those diagnosed with autism are characterized by impaired communication and reciprocal social interactions, and restricted and repetitive patterns of activities and interests (Baird et al. 2006). Approximately 70% of those diagnosed with autism also have intellectual disability (ID), and 25% have a seizure disorder (Tuchman and Rapin 2002). There is a strong genetic basis for autism, but the risk architecture is highly heterogeneous, and a large number of genes have been implicated (Abrahams and Geschwind 2008). This daunting phenotypic and etiologic complexity, shared by other major psychiatric illnesses, has slowed progress toward developing new therapies.However, autism researchers are optimistic that the possibility of substantial progress may soon be realized (Krueger and Bear 2011). First, the genes have been discovered for numerous syndromic disorders that prominently feature ASD and ID. Second, these gene mutations have been reproduced in animal models that allow detailed examination of the underlying brain pathophysiology. Third, animal research has converged on altered synaptic function as a likely basis for impaired cognition and possibly ASD. Fourth, insights gained on how synapses function differently in the face of these mutations have suggested novel therapeutic interventions validated in preclinical models and that have shown promise in preliminary human clinical trials. Fifth, the fact that ASD and ID can be diagnosed in early childhood maximizes potential benefits of therapy because it can be started at a time when the brain is most plastic. Finally, animal studies using gene reactivation or pharmacological interventions suggest that substantial improvements can be seen even when treatments begin in adulthood (Ehninger et al. 2008b). Thus, a genetic diagnosis of a developmental brain disorder need not be a “life sentence” of permanent and inexorable mental disability.The path from gene discovery to novel treatment is outlined in Figure 1. This process often begins with astute clinical observations that some patients can be distinguished by a common set of phenotypic traits, thus defining a syndrome. Molecular genetic studies can then be undertaken to test the hypothesis that the syndrome has a genetic cause. In the event that disruption of a single gene or DNA segment causes the disease (i.e., a “highly penetrant” mutation), then it is possible to create an animal model (usually a mouse) that carries the same genetic disruption. Although the effects of the genetic lesion will likely manifest differently at the behavioral level in animals and humans because of differences in the complexity of the brains, it is reasonable to postulate that disruptions in elementary neuronal functions are likely to be shared. Understanding this neuronal pathophysiology is critical for identifying potential therapeutic targets. If these targets can be validated in the animal models, then chemistry ensues to generate molecules that can engage the target and satisfy the pharmacodynamic and pharmacokinetic drug requirements. If they are shown to be safe, drug candidates may then advance to human clinical trials. There are currently clinical trials ongoing in several single-gene syndromic disorders associated with ASD and ID. Most of these target alterations in synaptic signaling.Open in a separate windowFigure 1.The promise of molecular medicine in genetically defined disorders of brain development.The notion that some ASD and associated ID represent “synapsopathies” (or “synaptopathies”) is supported by the preponderance of penetrant mutations in genes associated with synaptic structure and function. The most common single-gene mutations in ASD with ID are associated with fragile X syndrome (FMR1), tuberous sclerosis (TSC1, TSC2), neurofibromatosis (NF1), Angelman syndrome (UBE3A), Rett syndrome (MECP2), the PTEN hamartoma tumor syndrome, and Phelan-McDermid syndrome (SHANK3) (for review, see Betancur 2011). Rare mutations in the neuroligin (NLGN3, NLGN2) and neurexin (NRXN1) genes also cause autism (Jamain et al. 2003). Although this is by no means an exhaustive list of genes implicated in autism (and many await discovery), it is notable nonetheless that these highly penetrant mutations occur in genes that are critical regulators of synaptic function, and further, illuminate biochemical pathways that might be pathogenic in ASD and ID (Fig. 2).Open in a separate windowFigure 2.(A) Schematic of a neuron and axonal-dendritic synapse that depict examples of cellular localization of the various types of defects in ASD/ID. (B) A signaling pathway at the excitatory synapses that couples activity as registered by the release of glutamate to local control of protein synthesis. Disruption of the gene products indicated in the colored boxes greatly increases the risk of ASD/ID. Syndromic disorders with increased prevalence of ASD include Phelan-McDermid Syndrome (SHANK3); Noonan syndrome (RAF1, MEK1); Neurofibromatosis type 1 (NF1); Costello syndrome (H-Ras, MEK1); Cowden syndrome (PTEN); Cardio-facio-cutaneous (CFC) syndrome (MEK1/2); Tuberous sclerosis complex (TSC1/2); Fragile X syndrome (FMRP); Angelman syndrome (AS UBE3a); Rett syndrome (RTT–MeCP2); and Rubinstein-Taybi syndrome (RTS–CREB binding protein, p300). Rare, nonsyndromic ASDs include NLGN3/4 and NRXN1; ID/ASD: SHANK2.In this article, we focus on a few syndromic disorders associated with ASD and ID that are characterized by penetrant mutations in genes that have been shown in animal models to disrupt synaptic function. Our goal is to highlight the similarities and differences in these syndromes and their underlying synaptic pathophysiology. Optimal synaptic function occurs within a narrow dynamic range along many dimensions, and it is not surprising that pathophysiology occurs at the edges of these spectra. What has come as a surprise, however, is that ASD and ID appear to be common consequences of disruptive mutations that cause synaptic pathophysiology at both ends of a spectrum. In other words, both “gain-of-function” and “loss-of-function” mutations can manifest in similar ways. Insights into the pathophysiology of ASD and ID have raised the possibility of therapeutic interventions to bring synapses into a normal operating range.     

Marfan syndrome: exclusion of genetic linkage to five genes coding for connective tissue components in the long arm of chromosome 2

Summary Marfan syndrome represents a heterogeneous connective tissue disease, the symptoms arising in several tissues and organs. The defective gene(s) behind this autosomal dominant condition has not been found despite considerable research. The main targets of the research have been the genes coding for connective tissue components. Several of the candidate genes suspected to be defective in Marfan syndrome are located on the long arm of chromosome 2. These genes include a cluster of two genes coding for fibrillar collagens COL3A1 and COL5A2, and a third member of the collagen gene family: COL6A3. Furthermore, genes for elastin (ELN) and fibronectin (FN) are also located in this area of chromosome 2. We studied this chromosomal area using restriction fragment length polymorphism (RFLP) linkage analysis in five Finnish Marfan families with affected members in three generations. In two point linkage analyses, Lod scores of –3.192 ( = 0.1) to COL3A1, –1.683 ( = 0) to COL6A3 and –2.664 ( = 0.01) to FN were obtained, whereas the linkage analysis between elastin and the disease was non-informative (Lod score 0.444, = 0). With the multipoint linkage analysis that permits simultaneous examination of several loci and more efficient use of family data, we obtained an exclusion of all these loci as the site of the mutation leading to Marfan syndrome in these families.     

Testicule et sperme dans le Syndrome de Klinefelter chez l'adulte

Klinefelter's syndrome is characterised by azoospermia, gynecomastia and hypogonadotropic hypogonadism. The testes are reduced in volume. Microscopically, seminiferous tubules show a reduced diameter and a thickening of peritubular sheath. The seminiferous epithelium contains Sertoli cells with a clear typical nucleus and a heterogeneous nucleolus. Usually there are no germ cells. When present they degenerate at the spermatocyte stage. Very few achieve a complete maturation until the spermatozoon form. The interstitial gland appears relatively hypertrophied, due to the decrease in volume in the other components of the testis. Sometimes Leydig cells display an adenomatous morphology. Therefore the steroidogenic function is impaired. Azoospermia is a major event in Klinefelter's syndrome but sometimes restricted to severe oligozoospermia. In that cases, fertility may be somewhat preserved, and the caryotype usually reveals a mosaicism, 47,XY/47,XXY with a better prognosis than in pure syndrome.     

Rare causes of scoliosis and spine deformity: experience and particular features

Background

Spine deformity can be idiopathic (more than 80% of cases), neuromuscular, congenital or neurofibromatosis-related. However, there are many disorders that may also be involved. We present our experience treating patients with scoliosis or other spine deformities related to rare clinical entities.

Methods

A retrospective study of the records of a school-screening study in North-West Greece was performed, covering a 10-year period (1992–2002). The records were searched for patients with deformities related to rare disorders. These patients were reviewed as regards to characteristics of underlying disorder and spine deformity, treatment and results, complications, intraoperative and anaesthesiologic difficulties particular to each case.

Results

In 13 cases, the spine deformity presented in relation to rare disorders. The underlying disorder was rare neurological disease in 2 cases (Rett syndrome, progressive hemidystonia), muscular disorders (facioscapulohumeral muscular dystrophy, arthrogryposis) in 2 patients, osteogenesis imperfecta in 2 cases, Marfan syndrome, osteopetrosis tarda, spondyloepiphyseal dysplasia congenita, cleidocranial dysplasia and Noonan syndrome in 1 case each. In 2 cases scoliosis was related to other congenital anomalies (phocomelia, blindness). Nine of these patients were surgically treated. Surgery was avoided in 3 patients.

Conclusion

This study illustrates the fact that different disorders are related with curves with different characteristics, different accompanying problems and possible complications. Investigation and understanding of the underlying pathology is an essential part of the clinical evaluation and preoperative work-up, as clinical experience at any specific center is limited.