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Background Mucopolysaccharidosis type VII (Sly syndrome) is an ultra-rare neurometabolic disorder caused by inherited deficiency of the lysosomal enzyme β-glucuronidase. Precise data regarding its epidemiology are scarce, but birth prevalence is estimated to vary from 0.02 to 0.24 per 100,000 live births. The clinical course and disease progression are widely heterogeneous, but most patients have been reported to show signs such as skeletal deformities or cognitive delay. Additionally, detection criteria are not standardized, resulting in delayed diagnosis and treatment. Methods We present a cohort of 9 patients with mucopolysaccharidosis VII diagnosed in the Iberian Peninsula, either in Spain or Portugal. The diagnostic approach, genetic studies, clinical features, evolution and treatment interventions were reviewed. Results We found that skeletal deformities, hip dysplasia, hydrops fetalis, hepatosplenomegaly, hernias, coarse features, respiratory issues, and cognitive and growth delay were the most common features identified in the cohort. In general, patients with early diagnostic confirmation who received the appropriate treatment in a timely manner presented a more favorable clinical evolution. Conclusions This case series report helps to improve understanding of this ultra-rare disease and allows to establish criteria for clinical suspicion or diagnosis, recommendations, and future directions for better management of patients with Sly syndrome.

The fecal immunochemical test (FIT) is a common colorectal cancer screening modality in the USA but often is not followed by diagnostic colonoscopy. We investigated the efficacy of patient navigation to increase diagnostic colonoscopy after positive FIT results and determined persistent barriers to follow-up despite navigation in a large, academic healthcare system. The study cohort included all health system outpatients with an assigned primary care provider, a positive FIT result between 12/01/2016 and 06/01/2019, and no documentation of colonoscopy after positive FIT. Two non-clinical patient navigators engaged patients and providers to encourage follow-up, offer solutions to barriers, and assist with colonoscopy scheduling. The primary intervention endpoint was completion of colonoscopy within 6 months of navigation. We documented reasons for persistent barriers to colonoscopy despite navigation and determined predictors of successful follow-up after navigation. There were 119 patients who received intervention. Of these, 37 (31.1%) patients completed colonoscopy at 6 months. In 41/119 (34.5%) cases, the PCP did not recommend colonoscopy, most commonly due to a normal colonoscopy prior to the positive FIT (19, 46.3%). There were 41/119 patients (34.5%) that declined colonoscopy despite the patient navigator and the PCP order. Male sex and younger age were significant predictors of follow-up (aOR = 2.91, 95%CI, 1.18-7.13; aOR = 0.92, 95%CI, 0.87-0.99). After implementation of patient navigation, diagnostic colonoscopy was completed for 31.1% of patients with a positive FIT result. However, navigation also highlighted persistent multilevel barriers to follow-up. Future work will develop targeted solutions for these barriers to further increase FIT follow-up rates in our health system.

The purpose of this study was to examine the applicability of the use of samples in dried blood spot (DBS) for the definitive diagnosis of Fabry disease (FD) in males and females and to compare the diagnostic role of α-galactosidase A activity (α-Gal A), levels of lyso-Gb3 and sequencing of the GLA gene in screening patients with suspected FD. Measurement of α-Gal A activity in suspected FD patients in DBS was made followed by lyso-Gb3 determination and GLA gene sequencing. Of the 2381 subjects analyzed, FD was confirmed in 24 patients. Thirteen different variants were considered like pathogenic, five of which had not been previously described (c.143A > G; c.455A > C; c.487G > T; c.554delA; c.1045_1046insA). None of the patients with normal enzyme activity had FD confirmation. The DBS measurement of α-Gal A was more sensitive than lyso-Gb3 levels in both men and women. Definitive diagnosis of FD from a single DBS is possible, allowing samples to be easily sent from anywhere to the reference laboratory.

Metabolic skeletal dysplasias comprise an extensive group of diseases capable of causing changes, usually progressive, in the bone and are due to hereditary disorders in many cases. The diagnosis and treatment of these diseases are not without difficulty, both because of their rarity and their possible confusion with more common diseases. A paradigmatic case of these metabolic skeletal dysplasias is X-linked hypophosphataemic rickets, which causes phosphaturia, a condition that alters the phosphate-calcium metabolism balance consequently causing, among other conditions, skeletal deformities and short stature. The genetic advances in recent years allow a much more accurate diagnosis of this disease when suspected, making differential diagnosis easier with similar entities but whose real causes are different. A better understanding of the phosphate-calcium metabolism allows us to replace the symptomatic treatment currently available with one that involves rebalancing the excess of fibroblast growth factor 23 (FGF23) by using monoclonal antibodies. In November 2018, a symposium sponsored by Kyowa Kirin Pharmaceuticals took place in Madrid, in which national and international experts addressed several aspects of these rare kidney diseases. Some topics addressed were the present and future genetic diagnosis, the use of multi-gene panels in renal or skeletal diseases, the role of animal models to better understand underlying skeletal changes, and the role of conventional radiology and surgery in the diagnosis and final treatment of bone deformities; all these without forgetting the important role of FGF23 and Klotho imbalances that result in the genetic change causing this disease. The optimization and limitations of conventional treatments currently available was also a topic addressed extensively, as well as the implications that new treatments against FGF23 could have in the future. This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by the author.

The use of first and second generation antiepileptic drugs during pregnancy doubles the risk of major congenital malformations and other teratogenic defects. Lacosamide (LCM) is a third-generation antiepileptic drug that interacts with collapsing response mediator protein 2, a protein that has been associated with neurodevelopmental diseases like schizophrenia. The aim of this study was to test the potential teratogenic effects of LCM on developing embryos and its effects on behavioural/histological alterations in adult mice. We administered LCM to pregnant mice, assessing its presence, and that of related compounds, in the mothers’ serum and in embryonic tissues using liquid chromatography coupled to quadrupole/time of flight mass spectrometry detection. Embryo morphology was evaluated, and immunohistochemistry was performed on adult offspring. Behavioural studies were carried out during the first two postnatal weeks and on adult mice. We found a high incidence of embryonic lethality and malformations in mice exposed to LCM during embryonic development. Neonatal mice born to dams treated with LCM during gestation displayed clear psychomotor delay and behavioural and morphological alterations in the prefrontal cortex, hippocampus and amygdala that were associated with behaviours associated with schizophrenia spectrum disorders in adulthood. We conclude that LCM and its metabolites may have teratogenic effects on the developing embryos, reflected in embryonic lethality and malformations, as well as behavioural and histological alterations in adult mice that resemble those presented by patients with schizophrenia., This work was supported by the Andalusian Regional Ministry of Economy, Science and Innovation (P11-cts-7634); the Andalusian Regional Ministry of Health (PI-0438-2010) and the Instituto de Salúd Carlos III (PS09/00050, CP08/00111, CPII14/00033) co-financed by European Development Regional Fund “A way to achieve Europe” ERDF to PYG; Fundación Ramón Areces, DGICYT BFU2011-27207, and the Junta de Andalucía CTS-2257 to AMC; Funding FEDER Project UNSE10–1E-429 to RFT and MVN; Francisco José de Caldas fellowship by COLCIENCIAS to V.V-L.

Rare diseases are heterogeneous life-threatening or seriously debilitating conditions that affect < 1 in 2000 individuals, and most have a genetic component. The diagnostic process is usually based on classic clinical practices, such as physical examination, personal and family history (inheritance pattern), laboratory tests and image studies, but diagnosis can be delayed several years after the initiation of symptoms. The advances in molecular genetics that have taken place in recent years have led to an important shift in medical practice and in its approach to the diagnosis and treatment of many rare diseases. The objective of this review is to promote a better understanding of the mechanisms underlying genetic diseases in humans and the tools available for their diagnosis. A practical example of X-linked hypophosphataemic rickets is described.

Background: Hypophosphatasia (HPP) (OMIM 146300, 241510, 241500) is an inborn error of metabolism caused by pathogenic variants in the gene ALPL that codifies for the tissue non-specific alkaline phosphastase (1). The disease presents with different degrees of severity, from perinatal forms to mild adult phenotypes, including odontohypophosphatasia where only dental complications are described. Until now, more than 380 variants are described to cause HPP, and only 2,9% are large deletions or duplications (http://www.sesep.uvsq.fr/03_hypo_mutations.php). Objectives: Identify the genetic cause of the disease in the girl with an infantile HPP. Methods: The patient is a female child born by cesarean at week 37 of gestation. The child required reanimation. Weight, length and cranial perimeter were bellow percentile 10th (1735g, 42 cm, 31,5 cm respectively). She presented and obstetric femur fracture and normal to low alkaline phosphatase (AF) activity (158 UI/L (reference 142-335 UI/L). After fracture, a second determination of AF (127UI/L) and pyridoxal-5′-phosphate (PLP) concentration (240,41 mgc/L, reference 6,4-23) were measured. Skeletal interrogation revealed low bone mineralization, tongues of radiofluency in long bones and narrow ribs. A clinical diagnose of hypophospatasia was done. At the three year-old revision she still presents weight and length below percentile 15th, a mild cardiac problem but had no fractures since birth. She presents lung malformation, and cannot eat solid food. She still has low AF activity (154 U/L) and high PLP (69,13 μg/L; refences 150-350 U/L and 3,6-18 μg/L respectively). She is on school but has language delay. Genetic analysis: DNA was extracted from peripheral blood of patient and her mother. From patient’s sample we perfomed Sanger sequencing of exons 1 to 12, CGH analysis using a customized whole genome CGH 4x44k Agilent array enriched in probes for ALPL gene (130 probes) and qPCR of exons 2 to 12. Results: The study of copy number variants of ALPL gene by qPCR revealed a duplication in exon 5 in the patient and her mother. Conclusion: Although gross deletions and duplications are a rare phenomenon in HPP, here we present a case of a 3 year old child and her mother that present a single exon duplication as a probable cause of the disease. Actually, the mother is under clinical evaluation. Part of the active site is codified in exon 5, suggesting that a duplication might alter the correct structure and/or function of the protein. So, including the screening of copy number variants during the genetic screening is important to reach the correct diagnosis of HPP. References: [1] Whyte, M.P. (2017). Hypophosphatasia: An overview For 2017. Bone 102, 15–25. Disclosure of Interests: Eva Gonzalez-Roca Paid instructor for: Alexion, Manuela Munoz-Torres: None declared, Pilar Carrasco: None declared, Antonio Gonzalez-Meneses: None declared, Raquel Yahyaoui: None declared, Ricard Isanta: None declared, Etienne Mornet: None declared

[Rationale] Clinical and genetic management of patients with rare syndromes is often a difficult, confusing, and slow task., [Patient concerns] Male child patient with a multisystemic disease showing congenital heart defects, facial dysmorphism, skeletal malformations, and eye anomalies., [Diagnosis] The patient remained clinically undiagnosed until the genetic results were conclusive and allowed to associate its clinical features with the germline ABL1 mutations-associated syndrome., [Interventions] We performed whole-exome sequencing to uncover the underlying genetic defect in this patient. Subsequently, family segregation of identified mutations was performed by Sanger sequencing in all available family members., [Outcomes] The only detected variant compatible with the disease was a novel heterozygous nonframeshift de novo deletion in ABL1 (c.434_436del; p.Ser145del). The affected residue lays in a functional domain of the protein, it is highly conserved among distinct species, and its loss is predicted as pathogenic by in silico studies., [Lessons] Our results reinforce the involvement of ABL1 in clinically undiagnosed cases with developmental defects and expand the clinical and genetic spectrum of the recently reported ABL1-associated syndrome. In this sense, we described the third germline ABL1 causative mutation and linked, for the first time, ocular anterior chamber anomalies to this pathology. Thus, we suggest that this disorder may be more heterogeneous than is currently believed and may be overlapping with other multisystemic diseases, hence genetic and clinical reassessment of this type of cases should be considered to ensure proper diagnosis., This work was supported by Instituto de Salud Carlos III (ISCIII), Spanish Ministry of Economy and Competitiveness, and co-funded by European Union (ERDF/ESF, “Investing in your future”) [PI15-01648 and PI16-01422], CIBERER ACCI [ER16P1AC702/2017] and Regional Ministry of Economy, Innovation, Science and Employment of the Autonomous Government of Andalusia [CTS-1664]. The CIBERER is an initiative of the ISCIII, Spanish Ministry of Economy and Competitiveness.

Complex chromosome rearrangements (CCRs) are unusual structural chromosome alterations found in humans, and to date only a few have been characterized molecularly. New mechanisms, such as chromothripsis, have been proposed to explain the presence of the CCRs in cancer cells and in patients with congenital disorders and/or mental retardation. The aim of the present study was the molecular characterization of a constitutional CCR in a girl with multiple congenital disorders and intellectual disability in order to determine the genotype-phenotype relation and to clarify whether the CCR could have been caused by chromosomal catastrophic events. The present CCR was characterized by G-banding, high-resolution CGH, multiplex ligation-dependent probe amplification and subtelomeric 2q-FISH analyses. Preliminary results indicate that the de novo CCR is unbalanced showing a 2q37.3 deletion and 2q34q37.2 partial trisomy. Our patient shows some of the typical traits and intellectual disability described in patients with 2q37 deletion and also in carriers of 2q34q37.2 partial trisomy; thus, the clinical disorders could be explained by additional effects of both chromosome alterations (deletions and duplications). A posterior, sequential FISH study using BAC probes revealed the unexpected presence of at least 17 different reorganizations affecting 2q34q37.2, suggesting the existence of chromosome instability in this region. The present CCR is the first case described in the literature of heterogeneity of unbalanced CCRs affecting a small region of 2q, indicating that the mechanisms involved in constitutional chromosome rearrangement may be more complex than previously thought.

Inverted duplication 8p associated with deletion of the short arms of chromosome 8 (invdupdel[8p]) is a relatively uncommon complex chromosomal rearrangement, with an estimated incidence of 1 in 10,000-30,000 live borns. The chromosomal rearrangement consists of a deletion of the telomeric region (8p23-pter) and an inverted duplication of the 8p11.2-p22 region. Clinical manifestations of this disorder include severe to moderate intellectual disability and characteristic facial features. In most cases, there are also CNS associated malformations and congenital heart defects. In this work, we present the cytogenetic and molecular characterization of seven children with invdupdel(8p) rearrangements. Subsequently, we have carried out genotype-phenotype correlations in these seven patients. The majority of our patients carry a similar deletion but different size of duplications; the latter probably explaining the phenotypic variability among them. We recommend that complete clinical evaluation and detailed chromosomal microarray studies should be undertaken, enabling appropriate genetic counseling.

Hunter syndrome or mucopolysaccharidosis type II (MPSII) is a progressive multisystem X-linked lysosomal storage disease caused by mutations in the IDS gene that shows a wide spectrum of clinical symptoms and severity. Idursulfase, a specific enzyme replacement therapy (ERT) for MPSII, has been available since 2007. ERT, along with symptomatic management of patients, is fundamental for improving patient prognosis and quality of life. The aims of this study were to investigate whether Spanish pediatricians who are experts in managing the disease agreed with current international guidelines regarding MPSII patient diagnosis and follow-up; and to reach a consensus regarding which items are essential for the diagnosis, follow-up, and treatment of these patients in Spain. An advisory panel of 5 experts from the Hunter Spanish Working Group reviewed key studies, developed a questionnaire based on a modified Delphi method, sent the questionnaire to selected experts, and reviewed the responses. The final questionnaire had 83 items in the following categories: diagnosis, ERT considerations after diagnosis, Periodic assessments, and ERT considerations during follow-up. A total of 85 experts were invited to participate; 28 (35%) responded and showed a strong consensus for most items. The advisory panel decided not to perform a second Delphi round. There was strong agreement (>3.1 median value; range, 1 to 4) for 43/56 items in Diagnosis, for 4/6 items in “ERT considerations after diagnosis,” for 6/16 items in “Periodic assessments,” and for 3/5 items in “ERT considerations during follow-up.” Most responses were in agreement with international guidelines, and controversial items were discussed by the advisory panel. Based on the results, on the key studies, and on clinical experience and opinions, the panel developed and scheduled recommendations for the diagnosis and follow-up of patients with MPSII. An expert 5-person panel oversaw a Delphi survey of 28 pediatricians and reached a consensus on recommendations for the diagnosis and follow-up of MPSII patients. This document will help guide clinicians involved in the diagnosis, management, and treatment of MPSII.

Resumen Objetivos Describir los hallazgos clinicos y moleculares de 11 pacientes espanoles con sindrome cardiofaciocutaneo (CFC), y compararlos con una serie de 130 pacientes con otros trastornos neurocardiofaciocutaneos (111 pacientes con sindrome de Noonan [SN] y 19 con sindrome LEOPARD). Pacientes y metodos Se obtuvieron datos clinicos de los pacientes remitidos para estudio genetico. Se estudiaron los genes PTPN11, SOS1, RAF1, BRAF y MAP2K1 mediante secuenciacion bidireccional de los exones donde se localizan las mutaciones mas recurrentes, y todos los exones del gen KRAS. Resultados Se identificaron 6 mutaciones en BRAF en 9 pacientes, y 2 mutaciones en MAP2K1. La talla baja, el retraso psicomotor, los trastornos del lenguaje y las anomalias ectodermicas fueron mas frecuentes en el CFC que en el resto de los sindromes (p Discusion Los pacientes con CFC muestran un fenotipo mas grave, si bien se describe un paciente sin retraso psicomotor, lo que ilustra la variabilidad del espectro fenotipico asociado a las mutaciones en BRAF. El estudio genetico es una herramienta util en el diagnostico diferencial del CFC y de los trastornos relacionados con el SN.

WOS: 000377110800007, PubMed ID: 26908836, Background Mucopolysaccharidosis VII (MPS VII) is an ultra-rare disease characterised by the deficiency of beta-glucuronidase (GUS). Patients' phenotypes vary from severe forms with hydrops fetalis, skeletal dysplasia and mental retardation to milder forms with fewer manifestations and mild skeletal abnormalities. Accurate assessments on the frequency and clinical characteristics of the disease have been scarce. The aim of this study was to collect such data. Methods We have conducted a survey of physicians to document the medical history of patients with MPS VII. The survey included anonymous information on patient demographics, family history, mode of diagnosis, age of onset, signs and symptoms, severity, management, clinical features and natural progression of the disease. Results We collected information on 56 patients from 11 countries. Patients with MPS VII were classified based on their phenotype into three different groups: (1) neonatal non-immune hydrops fetalis (NIHF) (n=10), (2) Infantile or adolescent form with history of hydrops fetalis (n=13) and (3) Infantile or adolescent form without known hydrops fetalis (n=33). Thirteen patients with MPS VII who had the infantile form with history of hydrops fetalis and survived childhood, had a wide range of clinical manifestations from mild to severe. Five patients underwent bone marrow transplantation and one patient underwent enzyme replacement therapy with recombinant human GUS. Conclusions MPS VII is a pan-ethnic inherited lysosomal storage disease with considerable phenotypical heterogeneity. Most patients have short stature, skeletal dysplasia, hepatosplenomegaly, hernias, cardiac involvement, pulmonary insufficiency and cognitive impairment. In these respects it resembles MPS I and MPS II. In MPS VII, however, one unique and distinguishing clinical feature is the unexpectedly high proportion of patients (41%) that had a history of NIHF. Presence of NIHF does not, by itself, predict the eventual severity of the clinical course, if the patient survives infancy., Ultragenyx Pharmaceutical [16232], This work was supported in part by Ultragenyx Pharmaceutical grant number 16232.

Mucopolysaccharidosis type IVA (Morquio A) is an inherited metabolic disease with autosomal recessive inheritance. The pathology is due to a deficient activity of N-acetylgalactosamine-6-sulfate-sulfatase, which is involved in the degradation of keratan sulfate and chondroitin-6-sulfate. To date more than 150 mutations have been described in the GALNS gene in different populations. The aim of this study was to analyze the mutations and polymorphisms in Spain in order to know the epidemiology of our population and also to offer genetic counseling to affected families. We found 30 mutant alleles in the 15 families analyzed completing all the genotypes. Most of the mutations that we found were missense mutations, six of which were novel: p.S74F, p.E121D, p.Y254C, p.E260K, p.T394P and p.N495Y; we also found a small deletion (c.1142delC) and a probable deep intronic mutation that causes the loss of exon 5 (c.423_566del) found in cDNA. Both mutations are described in this study for the first time. We also identified 20 polymorphisms previously reported and 2 novel ones: (c.633+222T/C and c.898+25C>G). In conclusion, we have identified the mutations responsible for Mucopolysaccharidosis IV A in Spain. We found great allelic heterogeneity, as occurs in other populations, which hinders the establishment of genotype-phenotype correlations in Spain. This study has been very useful for genetic counseling to the affected families.

ResumenLas enfermedades raras (ER) constituyen un verdadero problema de salud pública tanto en atención primaria como en atención hospitalaria. Revisamos someramente los mecanismos generadores de hipótesis diagnósticas basándonos en metáforas como «el ruido de cascos no siempre significa que vengan caballos, a veces son cebras las que se acercan» o aquella otra del anticuario que reconoce una pieza de museo paseando por «El Rastro». Los «Blitzdiagnosen» (diagnósticos relámpago) de Skoda son un antecedente histórico importante. Es muy sensata la aspiración de la profesora Greenhalgh de unir la medicina basada en la evidencia y el diagnóstico intuitivo. Exponemos también unas reglas de epidemiología clínica que ayudarán al médico de familia/pediatra a afianzarse en este campo. La formación ha de ser específica en sus contenidos y diferenciada para profesionales de hospital y de centros de salud. Es necesario el conocimiento de los signos patognomónicos clásicos. Los mapas conceptuales son útiles para el diagnóstico de ER en atención primaria.AbstractRare diseases are a real public health problem for hospitals and also for primary care. We describe some metaphor-based diagnosis procedures, such as: “When you hear hoof beats don’t always think horses, sometimes they could be zebras”, or that one about the antiquarian who recognised a museum masterpiece while walking in the Rastro (Madrid). The “lightning diagnoses” by Skoda are an important historic record.T. Greenhalgh has tried to cover the gap between evidence based medicine and the intuitive diagnosis. We point out some clinical epidemiology rules in order to improve their early detection by family practitioners and paediatricians. In our opinion, the training in the diagnosis of rare diseases has to be different for primary care level and for hospital doctors. Concept maps are useful for diagnosis in primary care clinics.

The "Osteopetroses" are genetic diseases whose clinical picture is caused by a defect in bone resorption by osteoclasts. Three main forms can be distinguished on the basis of severity, age of onset and means of inheritance: the dominant benign, the intermediate and the recessive severe form. While several genes have been involved in the pathogenesis of the different types of osteopetroses, the CLCN7 gene has drawn the attention of many researchers, as mutations within this gene are associated with very different phenotypes. We report here the characterization of 25 unpublished patients which has resulted in the identification of 20 novel mutations, including 11 missense mutations, 6 causing premature termination, 1 small deletion and 2 putative splice site defects. Careful analysis of clinical and molecular data led us to several conclusions. First, intermediate osteopetrosis is not homogeneous, since it can comprise both severe dominant forms with an early onset and recessive ones without central nervous system involvement. Second, the appropriateness of haematopoietic stem cell transplantation in CLCN7-dependent ARO patients has to be carefully evaluated and exhaustive CNS examination is strongly suggested, as transplantation can almost completely cure the disease in situations where no primary neurological symptoms are present. Finally, the analysis of this largest cohort of CLCN7-dependent ARO patients together with some ADO II families allowed us to draw preliminary genotype-phenotype correlations suggesting that haploinsufficiency is not the mechanism causing ADO II. The availability of biochemical assays to characterize ClC-7 function will help to confirm this hypothesis.

Monosomy 10p is a rare chromosomal disorder with a prevalence

Combined methylmalonic acidemia and homocystinuria is an inborn error of metabolism of vitamin B12 or cobalamin. It's a rare autosomal recessive disease in which there are several variants depending on the pathogenesis of the metabolic disorder (cblC, cblD, cblF and cblJ). The more frequent and more severe is the cblC variant, which usually manifests in the first months of life, although some cases have been reported at the beginning of adulthood. A proper diagnosis and effective therapeutic approach is fundamental. We report the case of a patient of 18 years with a history of epilepsy who consults for acute renal failure requiring renal replacement therapy and diagnosed with combined methylmalonic acidemia and homocystinuria cblC variant.La combinación de homocistinuria con acidemia metilmalónica es un error congénito del metabolismo de la vitamina B12 o cobalamina. Es una patología poco frecuente de herencia autosómica recesiva en la que existen diversas variantes en función de la patogenia del trastorno metabólico (cblC, cblD, cblF y cblJ). La más frecuente y más grave es la variante cblC, que suele manifestarse en los primeros meses de vida, aunque se han reportado casos al inicio de la edad adulta. Se hace fundamental un correcto diagnóstico y un abordaje terapéutico eficaz. Presentamos el caso clínico de una paciente de 18 años con antecedentes personales de epilepsia que acude por fracaso renal agudo con necesidad de terapia renal sustitutiva diagnosticándose de homocistinuria con acidemia metilmalónica variante cblC.

Infantile systemic hyalinosis (ISH) is a presumed autosomal recessive connective tissue condition. Symptoms usually begin at birth or shortly thereafter, and are characterized by pain when handled, painful and swollen joints and, later on, dermal anomalies, diarrhea, failure to thrive and recurrent infections, which usually lead to death around the age of 2. The skin has generally diminished elasticity with small pearly papules appearing on neck, ears, coccygeal region, and face. We present two unrelated patients with ISH, with specific focus on clinical and pathologic studies. In the first patient the diagnosis was made several years after she died, in a retrospective study of her clinical file. On ultrastructural examination both patients showed an accumulation of fibrillogranular material in the extracellular matrix with long-spacing collagen of 90 nm. The first child died at the age of 1(1/2) years and the second at 3 years.

Angelman syndrome (AS, OMIM 105830) is a neurogenetic disorder with firm clinical diagnostic guidelines, characterized by severe developmental delay and speech impairment, balanced and behavioral disturbance as well as microcephaly, seizures, and a characteristic electroencephalogram (EEG). The majority of AS cases (70%) are caused by a 15q11.2-q13 deletion on the maternally derived chromosome.The frequency of AS has been estimated to be between 1/10000 and 1/20000. Klinefelter syndrome (KS) occurs due to the presence of an extra X chromosome (karyotype 47,XXY). The main features in KS are small testes, hypergonadotropic hypogonadism, gynecomastia, learning difficulties, and infertility. We present what is, to our knowledge, the first case of a patient with both KS and AS due to a 15q11.2-q13 deletion on the maternally derived chromosome and an extra X chromosome of paternal origin. He showed dysmorphic features, axial hypotonia, and delayed acquisition of motor skills. Early diagnosis is essential for optimal treatment of AS children; this is one of the earliest diagnosed cases of AS probably due to the presence of two syndromes. Clinical findings in this patient here described may be helpful to identify any other cases and to evaluate recurrence risks in these families.

Objectives To describe 11 patients with cardiofaciocutaneous syndrome (CFC) and compare them with 130 patients with other RAS-MAPK syndromes (111 Noonan syndrome patients [NS] and 19 patients with LEOPARD syndrome). Patients and methods Clinical data from patients submitted for genetic analysis were collected. Bidirectional sequencing analysis of PTPN11, SOS1, RAF1, BRAF, and MAP2K1 focused on exons carrying recurrent mutations, and of all KRAS exons were performed. Results Six different mutations in BRAF were identified in 9 patients, as well as 2 MAP2K1 mutations. Short stature, developmental delay, language difficulties and ectodermal anomalies were more frequent in CFC patients when compared with other neuro-cardio-faciocutaneous syndromes (p Discussion CFC patients showed a rather severe phenotype but at least one patient with BRAF mutation showed no developmental delay, which illustrates the variability of the phenotypic spectrum caused by BRAF mutations. Molecular genetic testing is a valuable tool for differential diagnosis of CFC and NS related disorders.

[Objective] To study the molecular genetic and clinical features of cerebral cavernous malformations (CCM) in a cohort of Spanish patients., [Methods] We analyzed the CCM1, CCM2, and CCM3 genes by MLPA and direct sequencing of exons and intronic boundaries in 94 familial forms and 41 sporadic cases of CCM patients of Spanish extraction. When available, RNA studies were performed seeking for alternative or cryptic splicing., [Results] A total of 26 pathogenic mutations, 22 of which predict truncated proteins, were identified in 29 familial forms and in three sporadic cases. The repertoire includes six novel non-sense and frameshift mutations in CCM1 and CCM3. We also found four missense mutations, one of them located at the third NPXY motif of CCM1 and another one that leads to cryptic splicing of CCM1 exon 6. We found four genomic deletions with the loss of the whole CCM2 gene in one patient and a partial loss of CCM1and CCM2 genes in three other patients. Four families had mutations in CCM3. The results include a high frequency of intronic variants, although most of them localize out of consensus splicing sequences. The main symptoms associated to clinical debut consisted of cerebral haemorrhage, migraines and epileptic seizures. The rare co-occurrence of CCM with Noonan and Chiari syndromes and delayed menarche is reported., [Conclusions] Analysis of CCM genes by sequencing and MLPA has detected mutations in almost 35% of a Spanish cohort (36% of familial cases and 10% of sporadic patients). The results include 13 new mutations of CCM genes and the main clinical symptoms that deserves consideration in molecular diagnosis and genetic counselling of cerebral cavernous malformations., This work has been supported by grants CP10/00526 (Instituto de Salud Carlos III, Spain) and P07-CVI-02790 (Junta de Andalucía, Spain). RM received a fellowship of José Luis Castaño Foundation.