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Objective This work aims to expand knowledge regarding the genetic spectrum of HSPB1‐related diseases. HSPB1 is a gene encoding heat shock protein 27, and mutations in HSPB1 have been identified as the cause of axonal Charcot–Marie–Tooth (CMT) disease type 2F and distal hereditary motor neuropathy (dHMN). Methods Two patients with axonal sensorimotor neuropathy underwent detailed clinical examinations, neurophysiological studies, and next‐generation sequencing with subsequent bioinformatic prioritization of genetic variants and in silico analysis of the likely causal mutation. Results The HSPB1 p.S135F and p.R136L mutations were identified in homozygosis in the two affected individuals. Both mutations affect the highly conserved alpha‐crystallin domain and have been previously described as the cause of severe CMT2F/dHMN, showing a strictly dominant inheritance pattern. Interpretation Thus, we report for the first time two cases of biallelic HSPB1 p.S135F and p.R136L mutations in two families.

Background Hereditary spherocytosis (HS), a commonly encountered hereditary hemolytic disease, is mostly inherited in an autosomal dominant manner. The clinical manifestations in patients with HS show obvious heterogeneity. Moreover, the sensitivity or specificity of some HS diagnostic tests are not ideal and may easily result in misdiagnosis or missed diagnosis in some patients. The objective of this study was to propose a simple and practical diagnostic protocol, which can contribute to the diagnosis of HS and its differential diagnosis with different types of hemolytic anemia such as thalassemia (THAL), autoimmune hemolytic anemia (AIHA), and glucose‐6‐phosphate dehydrogenase (G6PD) deficiency, thus, to provide an alternative simple and reliable method for better clinical diagnosis of HS. Methods Through combing our research with existing experimental technologies and studies, we propose a simple and practical protocol for HS diagnosis, which will help clinicians to improve HS diagnosis. Results Compared with the existing HS diagnostic protocols, the HS diagnostic protocol we proposed is simpler. In this new protocol, some experimental tests with ideal diagnostic efficiency are added, such as mean reticulocyte volume (MRV), mean sphered cell volume (MSCV), mean corpuscular volume (MCV), in combination with the observation of clinical manifestations, family investigation, routine tests for hemolytic anemia, genetic testing, and other screening tests. Conclusion The HS diagnostic protocol we proposed could improve the clinical practice and efficiency of HS diagnosis., Hereditary spherocytosis (HS), a commonly encountered hereditary hemolytic disease, is mostly inherited in an autosomal‐dominant manner. The clinical manifestations in patients with HS show obvious heterogeneity. Moreover, the sensitivity or specificity of some HS diagnostic tests is not ideal and may easily result in misdiagnosis or missed diagnosis in some patients. Therefore, we propose a simple and practical protocol for HS diagnosis, helping clinicians to improve HS diagnosis.

Purpose To describe a unique case of unilateral benign yellow dot maculopathy. Observations A 25-year-man was evaluated after incidental finding of yellow dots in the right macula. Optical coherence tomography and electrophysiologic testing were unremarkable. The findings were in keeping with a diagnosis of benign yellow dot maculopathy. Conclusions and importance Benign yellow dot maculopathy is a recently described entity with either a sporadic or dominant inheritance pattern. This is the first known report of the characteristic findings of this phenotype presenting unilaterally.

X-linked hypophosphataemia in children is characterised by elevated serum concentrations of fibroblast growth factor 23 (FGF23), hypophosphataemia, rickets, lower extremity bowing, and growth impairment. We compared the efficacy and safety of continuing conventional therapy, consisting of oral phosphate and active vitamin D, versus switching to burosumab, a fully human monoclonal antibody against FGF23, in paediatric X-linked hypophosphataemia.In this randomised, active-controlled, open-label, phase 3 trial at 16 clinical sites, we enrolled children with X-linked hypophosphataemia aged 1-12 years. Key eligibility criteria were a total Thacher rickets severity score of at least 2·0, fasting serum phosphorus lower than 0·97 mmol/L (3·0 mg/dL), confirmed PHEX (phosphate-regulating endopeptidase homolog, X-linked) mutation or variant of unknown significance in the patient or a family member with appropriate X-linked dominant inheritance, and receipt of conventional therapy for at least 6 consecutive months for children younger than 3 years or at least 12 consecutive months for children older than 3 years. Eligible patients were randomly assigned (1:1) to receive either subcutaneous burosumab starting at 0·8 mg/kg every 2 weeks (burosumab group) or conventional therapy prescribed by investigators (conventional therapy group). Both interventions lasted 64 weeks. The primary endpoint was change in rickets severity at week 40, assessed by the Radiographic Global Impression of Change global score. All patients who received at least one dose of treatment were included in the primary and safety analyses. The trial is registered with ClinicalTrials.gov, number NCT02915705.Recruitment took place between Aug 3, 2016, and May 8, 2017. Of 122 patients assessed, 61 were enrolled. Of these, 32 (18 girls, 14 boys) were randomly assigned to continue receiving conventional therapy and 29 (16 girls, 13 boys) to receive burosumab. For the primary endpoint at week 40, patients in the burosumab group had significantly greater improvement in Radiographic Global Impression of Change global score than did patients in the conventional therapy group (least squares mean +1·9 [SE 0·1] with burosumab vs +0·8 [0·1] with conventional therapy; difference 1·1, 95% CI 0·8-1·5; p0·0001). Treatment-emergent adverse events considered possibly, probably, or definitely related to treatment by the investigator occurred more frequently with burosumab (17 [59%] of 29 patients in the burosumab group vs seven [22%] of 32 patients in the conventional therapy group). Three serious adverse events occurred in each group, all considered unrelated to treatment and resolved.Significantly greater clinical improvements were shown in rickets severity, growth, and biochemistries among children with X-linked hypophosphataemia treated with burosumab compared with those continuing conventional therapy.Ultragenyx Pharmaceutical and Kyowa Kirin International.

Fragile X syndrome is an inherited disorder with an X-linked dominant inheritance pattern that is the most commonly inherited cause of intellectual developmental disorder and has a strong association with autism spectrum disorder. This report describes the case of an 18-year-old male with fragile X syndrome and multiple psychiatric comorbidities who presented with new onset psychosis and catatonia.

Recessive mutations in FRAS1-related extracellular matrix 1 (FREM1) are associated with two rare genetic disorders, Manitoba-oculo-tricho-anal (MOTA) and bifid nose with or without anorectal and renal anomalies (BNAR). Fraser syndrome is a more severe disorder that shows phenotypic overlap with both MOTA and anorectal and renal anomalies and results from mutations in FRAS1, FREM2 and GRIP1. Heterozygous missense mutations in FREM1 were reported in association with isolated trigonocephaly with dominant inheritance and incomplete penetrance. Moreover, large deletions encompassing FREM1 have been reported in association with a syndromic form of trigonocephaly and were designated as trigonocephaly type 2. Trigonocephaly results from premature closure of the metopic suture and typically manifests as a form of nonsyndromic craniosynostosis. We report on 20 patients evaluated for developmental delay and without abnormal metopic suture. Chromosomal microarray analysis revealed heterozygous FREM1 deletions in 18 patients and in 4 phenotypically normal parents. Two patients were diagnosed with MOTA and had homozygous FREM1 deletions. Therefore, although our results are consistent with the previous reports of homozygous deletions causing MOTA, we report no association between heterozygous FREM1 deletions and trigonocephaly in this cohort.

Objective To find out whether the diagnostic yield of prenatal array comparative genomic hybridization (aCGH) can be improved by targeting preselected high-risk pregnancies. Method All the in-house arrays ordered by the Fetomaternal Medical Center from February 2016 until December 2018 were retrospectively analyzed. The indications for array analysis included fetal structural abnormalities, increased nuchal translucency ≥3.5 mm and a chromosomal abnormality in a parent or a sibling. Common aneuploidies were excluded. Results Diagnostic yield was 15.1% in the entire patient cohort and as high as 20% in fetuses with multiple structural anomalies. The diagnostic yield was lowest in the group with isolated growth retardation. A total of 76 copy number variants (CNVs) were reported from a total of 65 samples, including 16 CNVs associated with a well-described microdeletion/microduplication syndrome, six autosomal trisomies in mosaic form, and three pathogenic single-gene deletions with dominant inheritance and 12 CNVs known to be risk factors for eg developmental delay. Conclusion The diagnostic yield of aCGH was higher than what has previously been reported in less defined patient cohorts. However, the number of CNVs with unclear correlation to the fetal ultrasound findings was still relatively high. The importance of adequate pre- and posttest counseling must therefore be emphasized.

We present here a Finnish nemaline myopathy family with a dominant mutation in the skeletal muscle alpha-actin gene, p.(Glu85Lys), segregating in three generations. The index patient, a 5-year-old boy, had the typical form of nemaline myopathy with congenital muscle weakness and motor milestones delayed but reached, while his mother never had sought medical attention for her very mild muscle weakness, and his maternal grandmother had been misdiagnosed as having myotonic dystrophy. This illustrates the clinical variability in nemaline myopathy. (C) 2017 Elsevier B.V. All rights reserved.

Epidermolysis bullosa pruriginosa, a rare variant of dominant inheritance pattern, characterized by itchy, papules and/or nodules coalescing to form plaque(s), studded by blisters, is describe in a young man an index case. In all 12 afflicted individuals of the 27 family members was interesting, the diagnosis of which was made by its morphology and inflammatory changes in the epidermis, comprising hyperkeratosis, moderate acanthosis, presence of inflammatory cells, and above all inflammatory cell containing sub-epidermal cleavage or cleft.

Key Clinical Message Clinical features are variable in patients with Cornelia de Lange syndrome (CdLS). Milder forms exist with structural maintenance of chromosomes 3 (SMC3) mutations. Inherited milder forms of CdLS are uncommon and may be missed if genetic testing is limited to Nipped‐B‐like protein (NIPBL) and SMC1A. Parental studies should be pursued if there is a history of learning disabilities and/or dysmorphic features.

We genetically characterized 22 Swiss patients who had been diagnosed with Stargardt disease after clinical examination. We identified in 11 patients (50%) pathogenic bi-allelic ABCA4 variants, c.1760+2T&gt, C and c.4496T&gt, C being novel. The dominantly inherited pathogenic ELOVL4 c.810C&gt, G p.(Tyr270*) and PRPH2-c.422A&gt, G p.(Tyr141Cys) variants were identified in eight (36%) and three patients (14%), respectively. All patients harboring the ELOVL4 c.810C&gt, G p.(Tyr270*) variant originated from the same small Swiss area, identifying a founder mutation. In the ABCA4 and ELOVL4 cohorts, the clinical phenotypes of “flecks”, “atrophy”, and “bull”s eye like” were observed by fundus examination. In the small number of patients harboring the pathogenic PRPH2 variant, we could observe both “flecks” and “atrophy” clinical phenotypes. The onset of disease, progression of visual acuity and clinical symptoms, inheritance patterns, fundus autofluorescence, and optical coherence tomography did not allow discrimination between the genetically heterogeneous Stargardt patients. The genetic heterogeneity observed in the relatively small Swiss population should prompt systematic genetic testing of clinically diagnosed Stargardt patients. The resulting molecular diagnostic is required to prevent potentially harmful vitamin A supplementation, to provide genetic counseling with respect to inheritance, and to schedule appropriate follow-up visits in the presence of increased risk of choroidal neovascularization.

Introduction: Oral-facial-digital syndrome (OFDS) is a rare type of ectodermal dysplasias characterized by malformations of the face, oral cavity, and digits. The OFDS type 1 is most common and has an X-linked dominant inheritance. Case report: We report a child with a single patch of scalp alopecia who was found to have typical oral malformations such as high arched palate, accessory frenulae, tongue hamartoma, and dentition abnormalities. . She had associated central nervous system malformations and was diagnosed with OFDS 1. Discussion: The case highlights importance of recognizing this syndrome to detect systemic abnormalities on time.

Mutations in KCNQ2 are associated with a range of electroclinical syndromes with dominant inheritance that are differentiated by the age at onset of the seizures and are associated with good prognosis. These are benign familial neonatal seizures (BFNS), benign familial neonatal-infantile seizures (BFNIS) and benign familial infantile seizures. Herein, we report the results of a systematic screening of KCNQ2 in 27 unrelated Bulgarian patients with compatible clinical diagnoses. Two pathogenic point mutations were identified: a novel splice-site c. 1526-2A > G variation causing BFNS and a missense c. 998G > A alteration in a patient with BFNIS, who subsequently developed benign epilepsy with centro-temporal spikes. Additionally, multiplex ligation-dependent probe amplification analysis and array comparative genomic hybridization assay detected a de novo deletion on 20q13.3 encompassing 0.41 Mb genomic region and covering 11 genes, including KCNQ2 and CHRNA4. This large-scale rearrangement was found in a patient with typical BFNS and no additional developmental abnormalities. Overall, KCNQ2 genetic defects were found in 11% of the patients in our cohort. These findings enrich the genetic epidemiology and mutation spectrum of KCNQ2 and allow adequate genetic counselling in the affected families.

Rett syndrome (RTT) is a neurodevelopmental disorder in which a period of normal development is followed by regression of previously acquired skills. RTT was originally thought to be present exclusively in females. However, advances in genetic testing and phenotypic identification revealed that it is not a female-only disorder as cases of males with similar phenotype were reported. RTT was considered lethal in males as it has an X-linked dominant inheritance. The purpose of this review is to report a case of RTT in young male and elaborate genetics and phenomenology of this disorder in males.

Familial hypercholesterolemia (FH) is an autosomal dominant genetic disease caused mainly by LDL receptor (Ldlr) gene mutations. Unlike FH patients, heterozygous Ldlr knockout (KO) mice do not show a dominant FH trait. Hamsters, like humans, have the cholesteryl ester transfer protein, intestine-only ApoB editing and low hepatic cholesterol synthesis. Here, we generated Ldlr-ablated hamsters using CRISPR/Cas9 technology. Homozygous Ldlr KO hamsters on a chow diet developed hypercholesterolemia with LDL as the dominant lipoprotein and spontaneous atherosclerosis. On a high-cholesterol/high-fat (HCHF) diet, these animals exhibited severe hyperlipidemia and atherosclerotic lesions in the aorta and coronary arteries. Moreover, the heterozygous Ldlr KO hamsters on a short-term HCHF diet also had overt hypercholesterolemia, which could be effectively ameliorated with several lipid-lowering drugs. Importantly, heterozygotes on 3-month HCHF diets developed accelerated lesions in the aortas and coronary arteries. Our findings demonstrate that the Ldlr KO hamster is an animal model of choice for human FH and has great potential in translational research of hyperlipidemia and coronary heart disease., Highlights • Ldlr knockout hamsters were successfully generated by using the CRISPR/Cas9 editing system. • Loss of one copy of the Ldlr gene predisposes hamsters to diet-induced hyperlipidemia and coronary atherosclerosis. • Heterozygous Ldlr KO hamsters differentially respond to different lipid-lowering drugs. • Homozygous Ldlr KO hamsters on a chow diet develop severe hypercholesterolemia and spontaneous atherosclerosis. Genetically engineered animal models, especially mouse models, have been widely used to study the pathogenesis of cardiovascular disease. However, distinct differences in the metabolic profiles of mice and humans limit further applications of mouse models toward understanding atherosclerosis in humans. In the present study, we use the CRISPR/Cas9 editing system to delete the Ldlr gene in hamsters, a species exhibiting similar metabolic features to those of humans. Diet-induced heterozygous Ldlr KO hamsters show hyperlipidemia with atherosclerotic lesions in both the aorta and coronary arteries, which has been observed in FH patients but not in mice. Moreover, aged homozygous Ldlr KO hamsters on a chow diet display severe hypercholesterolemia and spontaneous atherosclerosis. Our work explores a human-like animal model for basic and translational research of human atherosclerosis.

Focal dermal hypoplasia, also known as Goltz-Gorlin syndrome (GGS) or Goltz syndrome, arises from a rare genetic abnormality in the WNT/β-catenin signaling pathway first described by Goltz et al in 1962.1 Molecularly, Goltz syndrome is caused by a mutation or deletion in PORCN that occurs sporadically or through X-linked dominant inheritance. We report on a 17-year-old patient who presented to our clinic with extensive papillomas on her right foot and focal dermal hypoplasia. The papillomas were a source of significant pain and prevented our patient from wearing adequate footwear. She was referred to plastic surgery for excision and skin grafting because of persistent symptoms that were not adequately controlled by topical therapy. We report this case because of paucity in the literature for this cutaneous finding and lack of reports for management.

Sir, We thank Drs Saenz and Lopez de Munain for their interest in our recently published paper describing a dominant transmission of calpainopathy associated with a muscle disease, resembling limb girdle muscular dystrophy type 2A (LGMD2A) (Vissing et al. , 2016). The authors, however, challenge some of the conclusions of our paper and suggest alternative genetic explanations for our findings, which we will respond to in the following. First, the authors notice a great variability in the phenotype of our patients, and that dominant inheritance could only clearly be demonstrated in half of the 10 reported families. Variability of phenotype is to be expected if the dominant form of calpainopathy resembles the recessive type, which was what we found. Indeed, LGMD2A is one of the recessive limb girdle types (LGMDs) with the greatest clinical variability. It may present as a classical LGMD2 with symmetric limb weakness starting in the lower limbs and with elevated creatien kinase (CK), but unlike other LGMDs, is often asymmetric and can start with upper limb weakness first (Angelini et al. , 2010), and CK doesn’t have to be elevated (Luo et al. , 2012). Furthermore, it may even present with distal weakness (Burke et al. , 2010; Angelini et al. , 2010; Luo et al. , 2012). The age of onset of symptoms is also highly variable, and has been shown to be associated with the genotype (Angelini et al. , 2010; Luo et al. , 2012; Richard et al. …

Objective: To critically re-evaluate cases diagnosed as adult neuronal ceroid lipofuscinosis (ANCL) in order to aid clinicopathologic diagnosis as a route to further gene discovery.Methods: Through establishment of an international consortium we pooled 47 unsolved cases regarded by referring centers as ANCL. Clinical and neuropathologic experts within the Consortium established diagnostic criteria for ANCL based on the literature to assess each case. A panel of 3 neuropathologists independently reviewed source pathologic data. Cases were given a final clinicopathologic classification of definite ANCL, probable ANCL, possible ANCL, or not ANCL.Results: Of the 47 cases, only 16 fulfilled the Consortium's criteria of ANCL (5 definite, 2 probable, 9 possible). Definitive alternate diagnoses were made in 10, including Huntington disease, early-onset Alzheimer disease, Niemann-Pick disease, neuroserpinopathy, prion disease, and neurodegeneration with brain iron accumulation. Six cases had features suggesting an alternate diagnosis, but no specific condition was identified; in 15, the data were inadequate for classification. Misinterpretation of normal lipofuscin as abnormal storage material was the commonest cause of misdiagnosis.Conclusions: Diagnosis of ANCL remains challenging; expert pathologic analysis and recent molecular genetic advances revealed misdiagnoses in >1/3 of cases. We now have a refined group of cases that will facilitate identification of new causative genes.

Association between the XRCC1 Arg399Gln polymorphism and susceptibility to gastric cancer has been investigated; overall, the results have been inconclusive. We made a meta-analysis of 13 case-control studies, including 3278 cases and 6243 controls. Crude odds ratios (OR) with 95% confidence intervals (95%CI) were used to assess this possible association. We found no evidence of a significant association between the XRCC1 Arg399Gln polymorphism and gastric cancer risk (in the additive inheritance model, OR = 0.986, 95%CI = 0.831-1.156, in the dominant inheritance model, OR = 1.044, 95%CI = 0.890-1.224 and in the recessive inheritance model, OR = 0.975, 95%CI = 0.894-1.063). We conclude that the XRCC1 Arg399Gln polymorphism is not a risk factor for developing gastric cancer.

Background Migraine limb pain may be under-recognized in adults and children. There is little information about familial forms of this disorder. Objectives To describe the clinical and inheritance patterns of familial migraine limb pain over four generations and to review the evidence for limb pain as a manifestation of migraine. Methods Prospective clinical and pedigree analysis with an 8-year follow-up of 27 family members. Results Eight members of the family had benign recurrent limb pain associated with headache in a dominant inheritance pattern. Limb pain occurred before, during or after the headache, with probable or definite migraine with aura, migraine without aura and lower-half headache. The limb pain fulfilled the International Headache Society criteria for aura in six patients and also occurred without headache in three. Four members of the family had recurrent abdominal pain and/or motion sickness in childhood. Conclusions This is the first report of dominant familial limb pain temporally associated with migraine headache, starting in adulthood or starting in childhood and continuing into adulthood. A search for a genetic marker is indicated. Limb pain should be included as a childhood periodic syndrome linked to migraine and recognized as part of the migraine spectrum in adults.

Cancer predisposition syndromes affecting children are rare. One can estimate that only 10% of all childhood cancers are related to predisposition. The identification of these syndromes remains important for the care of an affected child and relatives. If most of the known cancer predisposition syndromes are linked to a dominant inheritance associated with a high risk of cancer, new syndromes associated with complex inheritance are being identified. Diagnosis of a childhood cancer associated with early-onset or multiple lesions, or a malformation syndrome, or a positive family history of cancer should raise an alarm of a cancer predisposition syndrome.

Lipedema is a condition characterized by swelling and enlargement of the lower limbs due to abnormal deposition of subcutaneous fat. Lipedema is an under-recognized condition, often misdiagnosed as lymphedema or dismissed as simple obesity. We present a series of pedigrees and propose that lipedema is a genetic condition with either X-linked dominant inheritance or more likely, autosomal dominant inheritance with sex limitation. Lipedema appears to be a condition almost exclusively affecting females, presumably estrogen-requiring as it usually manifests at puberty. Lipedema is an entity distinct from obesity, but may be wrongly diagnosed as primary obesity, due to clinical overlap. The phenotype suggests a condition distinct from obesity and associated with pain, tenderness, and easy bruising in affected areas.

140 patients from 8 countries with granular corneal dystrophy Groenouw type I are described, and 21 slit-lamp photographs demonstrate inter-familial differences and intra-familial similarities. The clinical appearance varied from mild, with only a few granules on the cornea, to a monstrous course with an almost opaque cornea. The following diagnostic criteria are suggested for the disease, as these signs are described in extensively quoted key references and meet the descriptions in most papers on this subject: Dominant inheritance, as well as 1) typical slit-lamp appearance and/or 2) granules that stain with Masson trichrome histologically, and/or 3) rod-shaped bodies seen electron microscopically.

A family, with three members affected by a central retinal angiopathy, is reported. The fundus changes consisted of tortuous arterioles, ectatic capillaries, microaneurysms, small retinal haemorrhages and tiny white dots. The changes were demonstrated by colour fluorescein angiography. The retinal changes simulate those described in hereditary haemorrhagic teleangiectasia (Rendu-Osler-Weber's disease) and in familial retinal arteriolar tortuosity, both showing dominant inheritance. Although none of the three patients had other stigmata of hereditary haemorrhagic teleangiectasia, it is proposed to consider the presently reported cases, as well as those reported under the diagnosis of familial arteriolar tortuosity, as a localized manifestation of a disorder which in other families may give the clinical picture of Rendu-Osler-Weber's disease.

Three Danish pedigrees have been studied with a view to reduced thyroxine-binding globulin (TBG). The study confirmed that this defect is transmitted by X-chromosome-linked dominant inheritance, there being no man-to-man transmission, but also that it may occur in two types: deficient TBG and low, non-zero TBG. Definite changes of TBG and thyroid function tests were found in the hemizygous men, whereas the heterozygous women showed a marked variation in the range between the values for hemizygous men and normal persons. Determination of total thyroxine appears to afford more guidance than the protein-bound iodine suggested by others. Two of four women on oral contraception exhibited such deviating TBG values that they are assumed to be TBG heterozygous. In all persons free thyroxine proved normal or slightly reduced but all the persons tested were euthyroid. However, the propositus of one family had previously been treated for Graves' disease.

SUMMARY This case report details the investigations and family history in a child with familial congenital cerebellar ataxia, aniridia and moderate mental retardation. The aniridia was not due to dominant inheritance and may represent a hitherto unrecognised recessively inherited condition. RESUME Syndrome d'ataxie cerebelleuse congenitale, aniridie et retard mental Ce cas relate en detail les examens et 1'histoire familiale d'un enfant avec ataxie cerebelleuse congenitale familiale, retard mental modere et aniridie. L'aniridie n'etait pas due a une heredite dominante et pourrait etre reliee a une condition hereditaire recessive non reconnue anterieurement. ZUSAMMENFASSUNG Das Syndrom congenitaler cerebellarer Ataxie, mit Aniridie und geistiger Verspatung Dieser Fall berichtet uber Einzelheiten und Familiengeschichte bei einem Kind mit congenitaler cerebellarer Ataxie, masiger geistiger Retardierung und Aniridie. Die Aniridie ging nicht auf eine dominante Vererbung zuruck und konnte eine vorher nicht erkannte rezessive Vererbung darstellen. RESUMEN Sindrome de ataxia cerebelosa congenita aniridia y retraso mental Se detallan las investigaciones y la historia familiar en un nino con los citados sintomas. La aniridia no se debia a una herencia dominante y puede representar una condicion heredada recesivamente no reconocida anteriormente.

SUMMARY In the two cases reported here, the progressive ataxia started later than the age of first walking, which is usual. One child walked at the average age but was not noted to be ataxic until the age of 4 1/2 years. There are, however, four comparable cases on record. The present patient excreted in the urine the substance previously reported by Pelc and Vis in the Louis-Bar syndrome. The second patient's symptoms began with pain in the back and thighs at 10 years, followed by weakness and gradually increasing ataxia. Telangiectasia were not noted in the conjunctivae until two years later. The patient's father and two of his siblings are similarly affected. The father's ataxia started at 24, and at 43 he can walk only with a stick, though he can still work as an engineer. The conjunctival changes in this case are more striking than in his daughter. This family lacks the other cutaneous changes which may accompany the ocular telangiectasia and has no history of unusual sinusitis or pulmonary infection. The father shows a defect in the perception of pain, temperature, passive movement and vibration in the lower legs and feet. This family does not show the biochemical abnormality characteristic of the classical type of the disease. It is suggested that the family of Case 2 represent a coincidental occurrence of ocular telangiectasia in a dominantly transmitted familial spinocerebellar degeneration, rather than the classical ‘ataxia telangiectasia’. The mechanism is obscure but further examples of this and other combinations will probably be found. RESUME Variantes atypiques du syndrome ‘ataxia telangiectasia’ Dans les deux cas rapportes l'ataxie progressive n'a commence, comme d'habitude, qu'apres l'âge des premiers pas. Un enfant a marchea l'âge moyen mais son ataxie n'a ete notee qu'a l'âge de 4 ans 1/2. On connait pourtant 4 cas comparables. Ce patient excretait dans l'urine la substance deja decrite par Pelc et Vis dans le syndrome de Louis Bar. Chez le second patient les premiers symptomes ont apparu a 10 ans, d'abord des douleurs dans le dos et les cuisses, suivies de faiblesse et d'ataxie progressive. La telangiectasie ne fut notee sur la conjonctive que deux ans plus tard. Le pere du patient et deux de ses freres et soeurs presentaient les memes symptomes. L'ataxie du pere a commencea 24 ans et a 43 ans il ne peut marcher qu'aide d'une cane, mais il peut encore travailler comme ingenieur. Les modifications de la conjonctive etaient dans son cas plas marquees que chez sa fille. Il manque a cette famille les autres modifications cutanees qui semblent accompagner la telangiectasie oculaire et il n'y a aucune histoire extra-ordinaire de sinusite ou d'infection pulmonaire. De plus, le pere presente un defaut de perception de la douleur, la temperature, les mouvements et les vibrations passifs dans le bas des jambes et les pieds. En outre cette famille n'a aucune des anomalies biochimiques caracteristiques du schema classique de la maladie. On pense que dans la famille du cas No. 2 la telangiectasie oculaire se surajoute par coincidence a une degenerescence spinocerebelleuse familliale transmise par gene dominant. ZUSAMMENFASSUNG Die atypischen Varianten des ‘Ataxia Telangiectasia’ Syndroms In den hierbeschriebenen zwei Fallen trat die progressive Ataxie spater auf als zu dem Zeitpunkt der ersten Gehversuche, wie sonst ublich. Das eine Kind erlernte das Gehen zum durchschnittlich normalen Zeitpunkt, es wurden jedoch die ataxischen Zeichen erst bemerkt, als es 4 1/2 Jahre alt war. Es sind jedoch 4 vergleichbare Falle in der Literatur vorhanden. Der obige Patient schied im Urin einen Stoff aus, der vormals von Pelc und Vis im Zusammenhang mit dem Louis-Bar Syndrom beschrieben wurde. Die Symptome eines zweiten Falles begannen mit Genick- und Oberschenkel-schmerzen im Alter von 10 Jahren, darauf folgenden Muskelschwacheerscheinungen, sowie allmahlich steigernder Ataxie. Gefasserweiterungen in der Bindehaut wurden erst nach zwei weiteren Jahren festgestellt. Der Vater des Patienten und eines der Geschwister hatten ahnliche Symptome. Die Ataxie des Vaters begann im Alter von 24 Jahren und mit 43 kann er nur mit Hilfe eines Stockes gehen, obwohl er seinen Beruf als Techniker weiter ausuber kann. Die Bindehautveranderungen sind in seinem Fall betonter als bei seiner Tochter. In dieser Familie fehlen jegliche andere Hautaffektionen, die sonst manchmal die Augen-Telangiektasie begleiten; auch kommt in der Anamnese keine ungewohnliche Sinusitis oder Lungeninfektion vor. Weiterhin kan man bei dem Vater einen Defekt in Schmerzempfindung, Temperatur, passiven Bewegungen und Vibration der unteren Beine und Fusse feststellen. Auch zeigen die Familienmitglieder keinerlei biochemische Anomalie, die als charakteristisch fur die klassische Art der Krankheit zu bezeichnen ist. Die Autoren sind der Meinung, dass die Familie im Falle No. 2 eine zufallig auftretende Augengefasserweiterung darstellt, die eher einer pradominanten, familiaren Ruckenmarks-und Kleinhirndegeneration entspncht, als einer klassischen ‘Ataxia telangiectasia’. Der Mechanismus dieses Zustands ist undeutlich, doch werden wohl andere Beispiele dieser und anderer Kombinationen gefunden werden.

The syndrome of ectrodactyly, ectodermal dysplasia and cleft lip and palate (EEC syndrome) is described in a mother and 3 of her 4 children. Autosomal dominant inheritance was suggested in this family. However, genetic heterogeneity may exist in this syndrome. The significance of associated finClings, incluCling carcinoma of the cervix uteri, lacrimal duct stenosis and urinary tract strictures in patients with ectodermal dysplasia is considered.

Focal dermal hypoplasia in five sisters and their mother is presented. The lesions present in this family and in eight additional Mexican cases are reviewed. Fourteen out of 15 cases were females and two were males. All cases had cutaneous lesions, clinically typical of focal dermal hypoplasia; these were confirmed histologically. Osseous changes and syndactyly were the more frequently associated lesions. The resemblance of this syndrome to incontinentia pigmenti and to aplasia cutis congenita is stressed. The study of this family, together with five families reported in the literature, suggests X-linked dominant inheritance with lethality in males. The known male cases could represent occasional survival or genetic heterogeneity.

A family with four members with split foot/split hand malformations and congenital nystagmus is described. The clinical characteristics in this family correspond to those seen in two other families previously reported. Taken together, these three families suggest that a single, pleiotropic dominant gene is causal. Karsch-Neugebauer syndrome is suggested as an appropriate eponymic designation for this disorder.

Family distribution data on alcoholism in Iceland are suggestive of dominant inheritance with incomplete penetrance. First-degree relatives of alcoholics are found to be successful in areas demanding high energy level and social ability, including theology, jurisprudence, and statesmanship.

Objective The aim of this study was to explore whether the interferon ( IFN)-γ +874 T/A polymorphism plays a role in modifying the risk of autoimmune diseases. Methods A meta-analysis was conducted on the association between the IFN-γ +874 T/A polymorphism and autoimmune diseases. Results Eighteen studies with a total of 2952 patients and 3832 controls were included in the meta-analysis. The meta-analysis revealed no association between autoimmune diseases and the IFN-γ +874 T allele in all study subjects (odds ratio (OR)=1.023, 95% confidence interval (CI) = 0.894–1.171, p = 0.738), but stratification by ethnicity indicated an association between the IFN-γ +874 T allele and autoimmune diseases in Latin American subjects (OR = 0.780, 95% CI = 0.629–0.953, p = 0.015). Meta-analysis also revealed an association between autoimmune diseases and the IFN-γ +874 T/A polymorphism in Caucasian and Middle Eastern subjects under a dominant inheritance model (OR = 0.686, 95% CI = 0.489–0.964, p = 0.003; OR = 1.414, 95% CI = 1.102–1.813, p = 0.006). Meta-analysis by autoimmune disease type indicated an association between ITP and the IFN-γ +874 T allele (OR = 1.753, 95% CI = 1.228–2.503, p = 0.002), but not for vasculitis, vitiligo, and auto-immune thyroid disease. Meta-analysis also showed a significant association between the IFN-γ +874 T/A polymorphism and systemic lupus erythematosus (SLE) under the dominant model (OR = 1.668, 95% CI = 1.114–2.497, p = 0.013). Conclusions This meta-analysis indicates that the IFN-γ +874 T/A polymorphism may play a significant role in modifying the risk of autoimmune diseases in Caucasian, Latin American, and Middle Eastern subjects, and in particular shows that the IFN-γ +874 T/A polymorphism is associated with increased genetic susceptibility to idiopathic thrombocytopenic purpura and SLE.

KIF1A gene encodes the kinesin 1a protein, an axonal motor protein working in cargo transport along neurites. Variants in KIF1A were identified in different forms of neurodegenerative diseases with dominant and recessive inheritance. Homozygous recessive mutations were found in the hereditary sensory and autonomic neuropathy type 2, HSAN2 and in a recessive subtype of hereditary spastic paraparesis, SPG30. De novo heterozygous dominant variants were found both in a dominant form of SPG30 (AD-SPG30) with one single family reported and in patients with different forms of progressive neurodegenerative diseases. We report the results of a genetic screening of 192 HSP patients, with the identification of four heterozygous variants in KIF1A in four cases, two of whom with family history for the disease. Three of the four variants fall within the motor domain, a frequent target for variants related to the AD-SPG30 subtype. The fourth variant falls downstream the motor domain in a region lacking any functional domain. The KIF1A-related patients show clinical pictures overlapping the known AD-SPG30 phenotype including pure and complicated forms with few differences. Of note, one of the families, originating from the Sicily island, carries the same variant p.S69L detected in the first AD-SPG30 family of Finnish origin reported; differently from the first one, the latter family shows a wide intra-familial phenotype variability. Overall, these data reveal a very low frequency of the AD-SPG30 subtype while confirming the presence of amino acid residues in the motor domain representing preferential targets for mutations, thereby supporting their functional relevance in kinesin 1a activity.

We present a second family with survival to adulthood and dominant transmission of the Torrance-Luton type of platyspondylic chondrodysplasia, and demonstrate the radiographs at different ages together with radiographs and further data of the first family which was published in the Journal of Pediatrics (J Pediatr 136:411-413). Two families are described with survival to adulthood and dominant transmission of the Torrance-Luton type of platyspondylic chondrodysplasia. Although lethality is increased in patients with this disorder, mild expressions of the genetic defect are compatible with survival into adulthood. The heterogeneous group of platyspondylic lethal skeletal dysplasias (PLSD) originally included thanatophoric dysplasias (TD1/2: MIM 187600, 187100) as the most common forms of this condition, as well as TD variants San Diego type (PLSD-SD: MIM 270230) and Torrance-Luton type (PLSD-TL: MIM 151210). Fibroblast growth factor receptor 3 ( FGFR3) gene mutations have been detected in TD1/2 and PLSD-SD. Molecular studies in one of our two families with the Torrance-Luton type did not disclose mutations in the FGFR3 coding region, suggesting that this type of platyspondylic chondrodysplasia is not a thanatophoric dysplasia variant. In contrast to TD1/2 and PLD-SD, the Torrance-Luton type platyspondylic dysplasia is compatible with survival to adulthood.

Colorectal cancer is the third leading cause of cancer and the second leading cause of cancer death in the United States. About 130,000 new cases are diagnosed each year in North America, and 56,600 persons die annually from this disease. Approximately 5% of patients with colorectal cancer have clearly defined inherited syndromes such as familial adenomatous polyposis and hereditary nonpolyposis colorectal cancer. These conditions are well described both genetically and phenotypically, and are characterized by auto-somal dominant inheritance, high penetrance, and high risk of colorectal cancer. We review the current recommendations for the diagnosis and management of these two hereditary forms of colorectal cancer.

Branchiooculofacial syndrome (BOFS) is a rare autosomal-dominant condition characterized by branchial cleft sinus and ophthalmologic and craniofacial abnormalities that can range from mild to severe forms. Ectopic thymus, an uncommon condition with just over 100 cases reported in the literature, is seen in BOFS. We report a family with BOFS affecting the mother and two daughters, showing the dominant inheritance and variable phenotypical expression of BOFS.

A neurofibromatose tipo 1 é uma das enfermidades genéticas mais comuns da espécie humana com padrão de herança autossômica dominante. As alterações radiológicas encontradas com maior freqüência são: escoliose, cifose, cifoescoliose, áreas de erosão óssea, crescimento anormal do osso, pseudo-artrose, meningocele, deformidade da parede posterior dos corpos vertebrais ("scalloping"), peito escavado, lesões osteolíticas nos ossos longos e alterações do sistema nervoso central. Os autores apresentam dados estatísticos dos achados radiográficos prevalentes em 82 pacientes com neurofibromatose tipo 1 acompanhados pelo Centro de Pesquisa e Atendimento em Neurofibromatose, de São José do Rio Preto, SP, um centro multidisciplinar de estudo e tratamento dos portadores da doença. Neurofibromatosis type 1 is one of the most common genetic diseases with autosomic dominant inheritance pattern in humans. The main radiological findings are: scoliosis, kyphoscoliosis, bone erosions, abnormal osseous growth, pseudarthrosis, meningeal cysts, deformity of the posterior wall of the vertebral bodies ("scalloping"), pectus excavatum, osteolytic lesions in the long bones and central nervous system abnormalities. The authors present the statistical data from the analysis of the radiological findings in 82 patients with neurofibromatosis type 1 attending the "Centro de Pesquisa e Atendimento em Neurofibromatose", in São José do Rio Preto, SP, Brazil, a multidisciplinary center for the study and treatment of neurofibromatosis.

Objective Hereditary spastic paraparesis or paraplegias (HSPs) are a group of neurogenetic conditions with prominent involvement of the pyramidal tracts. Aim of this study is the clinical and molecular characterization of a cohort of patients with HSP. Moreover, we aim to study the minimum prevalence of HSP in our area and to propose a schematic diagnostic approach to HSP patients based on the available data from the literature. Methods Retrospective/perspective study on the subjects with clinical signs and symptoms indicative of pure or complicated HSP, in whom other possible diagnosis were excluded by appropriate neuroradiological, neurophysiologic and laboratory studies, who have been evaluated by the Neurogenetic Service of our Clinic in last two years (2011-2012). Results 45 patients were identified. The minimum prevalence of HSP in our area was of about 2.17-3.43/100,000. The SF-36 (quality of life) and SPRS (disease progression) scores were inversely related; the time-saving, four-stage scale of motor disability could predict the SPRS scores with a high statistical significance, and we encourage its use in HSP. Our study confirms SPG4 as the major cause of HSP. All SPG4 patients had a pure HSP phenotype, and the dominant inheritance was evident in the great majority of these subjects. SPG7 was the second genetic cause. Other genotypes were rarer (SPG10, SPG11, SPG17). Conclusion Exact molecular diagnosis will allow a more accurate patient counseling and, hopefully, will lead to specific, targeted, therapeutic options for these chronic, still incurable diseases.

In order to recognize and control effectively dynamic information, the paper proposes the concept of F-recursive genetic information by introducing the concept of heredity in biology and using P-sets, including the concepts of F-recursive dominant inheritance information and -F-recursive recessive inheritance information. Meanwhile, the structure and characteristics about the F-recursive genetic information are provided. The paper gives the identification theorem and identification criterion as well as the reduction method for the F-recursive genetic information. Finally, the application of computer vision recognition of F-recursive genetic information is provided. The research indicates that the generated F-recursive genetic information is identifiable and the proposed recursive reduction method is more reliable than the non-recursive reduction method. The-recursive genetic information is a new tool to discover information, to forecast information and to control information.

Weaver syndrome is an autosomal dominant disorder comprising accelerated growth rate and rapidly advancing skeletal maturation. Previous reports suggest that the phenotype in adults may be sufficiently subtle to make diagnosis difficult. Half brothers with classical childhood findings of Weaver syndrome and their father with minimal clinical findings showed cervical spine anomalies that likely represent a consistent radiographic finding in this disorder. One of the children represents the third occurrence of neoplasia in Weaver syndrome.

Currarino syndrome is a disorder that has been first reported by Currarino and his coworkers in 1981 as a syndorome having three characteristics, namely, malfomation of the rectum, defect of the sacrum, and presacral tumor. Autosomal gene dominant inheritance is considered in the disorder and it has been reported that about the patients with the disease have family members with some malformation relating to the Currarino syndrome in family history. This paper deals with Currarino syndrome occurred in a father and his child. As to malformation of the rectum, stricture of the rectum is most common like in this father-and-child case. We must perform close examination by keeping the disease in mind as a probable diagnosis in the case of stricture of the rectum.

Cone electroretinograms (ERGs) elicited by different chromatic stimuli were recorded from patients with typical retinitis pigmentosa (RP) younger than 50 years of age. Ganzfeld color flashes on a bright white background illumination were used to elicit short-wavelength-sensitive (S-), and mixed long- (L-) and middle- (M-) wavelength-sensitive cone ERGs. Three patients with dominant inheritance, 22 patients with non-dominant inheritance, and 27 age-similar normal subjects were compared. Although the b-wave amplitudes of both the S- and L,M-cone ERGs were reduced in the RP patients, the S-cones were reduced to a greater degree than the L,M-cones. No significant difference in the S-cone reduction was observed between patients with dominant inheritance and those with non-dominant inheritance. The selective reduction of the S-cone system, reported previously in psychophysical studies, may be attributable not only to the macular region but also to the entire retina.

The proposita was operated on in this hospital in 1980 for pyloric stenosis, at the age of 13 days, after vomiting had started 5 days previously, and the diagnosis had been confirmed on radiological investigation. Her older sister and two male cousins of the father had the same operation in Israel in infancy. The other nine affected individuals in the family were known to have had projectile vomiting for several months in infancy, and two of them died in infancy. They were all born in the Jewish community in Georgia, U.S.S.R. The male:female sex ratio was 2:2 for the operated cases, and 4:5 for those with projectile vomiting history. There was no skipping of a generation. This family indicates that pyloric stenosis can exceptionally be inherited as a simple autosomal dominant trait.

We report two brothers, their mother and a maternal cousin who had a distinctive facial phenotype, mild brachydactyly and prominence of the interphalangeal joints. One brother and the mother also had multiple ventricular extrasystoles. Six other relatives in four generations were probably affected on the basis of history and family photographs. We also report a further individual from a different family with a similar facial phenotype, Pierre-Robin sequence, tapering fingers and multiple ventricular extrasystoles. These families have some similarities to those reported by Stoll et al. in a single family, showing dominant inheritance. Our patients would seem to have the same or a related condition.

UNLABELLED A 6-y-old boy presented with a mild, and apparently non-progressive, congenital myopathy, primarily affecting explosive movements such as running and jumping. Five other cases, spanning four generations, were identified in his family. A dominant inheritance pattern was suggested. Quadriceps muscle histology showed a selective type II fibre atrophy, which is otherwise considered a non-specific change associated with a number of conditions. CONCLUSION A Norwegian boy with an inherited muscle weakness is presented. Based on clinical and laboratory investigations, and in light of the inheritance pattern, a previously undescribed congenital myopathy is suggested.

A mild form of diabetes in young people was recognized in the pre-insulin era but was forgotten, probably because of Joslin’s dictum that all young people with diabetes should have insulin as a safeguard against complications. After the introduction of sulphonylureas in the 1950s it was found, most notably by Fajans and Conn at the University of Michigan, that tolbutamide could improve or normalize carbohydrate tolerance in some young non-obese mildly diabetic patients. These experiments were not primarily of genetic interest because diabetes was regarded as homogeneous with young and old patients forming part of the same continuum. The question was whether treatment could prevent young subjects with mild diabetes progressing to a total loss of insulin reserve. By 1973, Fajans had shown that the carbohydrate intolerance of 45 patients diagnosed under age 25 had not progressed after up to 16 years on sulphonylureas. Nearly all (43 out of 45) these subjects had a first degree relative with diabetes. In 1974, under the title ‘Mild familial diabetes with dominant inheritance’ Tattersall described three families in which diabetes, although diagnosed in adolescence, could be treated with sulphonylureas over 40 years later and was dominantly inherited. Collaboration between Fajans and Tattersall established that ‘chemical’ diabetes in Michigan was also predominantly inherited and distinct from classical ‘juvenile-onset’ diabetes. In Paris in 1973 Lestradet also described a non-insulin-dependent form of childhood diabetes and later established that it was dominantly inherited. In 1974, Tattersall and Fajans coined the acronym MODY which was defined as ‘fasting hyperglycaemia diagnosed under age 25 which could be treated without insulin for more than two years’. © 1998 John Wiley & Sons, Ltd.

We report on a total of 4 individuals in 2 families with Kabuki make-up syndrome. In family 1, the proposita, a 2 4/12-year-old girl and her mother had typical Kabuki make-up syndrome. The proposita also had early breast development. In family 2, the proposita, a 6-month-old girl and her mother had typical Kabuki make-up syndrome. The proposita died at age 6 months. Analysis of 2 families indicates that the condition is an autosomal dominant inheritance with variable expressivity.