Síndrome de Sjögren-Larsson: Reporte de caso pediátrico / Sjögren-Larsson syndrome: Pediatric case report

El síndrome de Sjogren-Larsson se caracteriza por retardo mental, ictiosis congènita y diplejía o cuadriplejía espástica. El defecto primario en este síndrome es la mutación del gen ALDH3A2, que codifica la enzima aldehído deshidrogenasa grasa y causa una deficiencia enzimática que produce una acumulación de alcoholes y aldehídos grasos en los tejidos que comprometen la integridad de la membrana celular, cuyos efectos pueden observarse en la piel, los ojos y el sistema nervioso central. El diagnóstico se realiza por medio de la cuantificación de la actividad de la enzima. Se describe el caso de una paciente con signos clínicos patognomónicos del síndrome de Sjogren-Larsson, cuyo diagnóstico se realizó por medio de la cuantificación de la actividad enzimática en un cultivo de fibroblastos. Además, tomando en cuenta el árbol genealógico de la paciente, se realizó el estudio en los padres y un hermano con signos sugestivos del síndrome de Sjogren-Larsson.

Sjogren-Larsson syndrome is characterized by congenital ichthyosis, mental retardation and spastic diplegia or quadriplegia. The primary defect in this syndrome is mutation of ALDH3A2 gen that codes for the fatty aldehyde dehydrogenase. Deficiency of this enzyme causes an accumulation of fatty alcohols and fatty aldehydes, leading to altered cell-membrane integrity. Skin, eyes, and the central nervous system are affected latter. The diagnosis is carried out through the cuantification of the enzyme activity.

FGF9 mutation causes craniosynostosis along with multiple synostoses.

Craniosynostosis is commonly caused by mutations in fibroblast growth factor receptors (FGFRs), highlighting the essential role of FGF-mediated signaling in skeletal development. We set out to identify the molecular defect in a family referred for craniosynostosis and in whom no mutation was previously detected. Using next-generation sequencing, we identified a novel missense mutation in FGF9. Modeling based upon the crystal structure and functional studies confirmed its pathogenicity showing that it impaired homodimerization and FGFR3 binding. Only one FGF9 mutation has been previously reported in a multigeneration family with multiple synostoses (SYNS3) but no signs of craniosynostosis. In contrast, our family has a greater phenotypic resemblance to that observed in the Fgf9 spontaneous mouse mutant, elbow-knee-synostosis, Eks, with both multiple synostoses and craniosynostosis. We have demonstrated for the first time that mutations in FGF9 cause craniosynostosis in humans and confirm that FGF9 mutations cause multiple synostoses.

A novel SMARCAL1 missense mutation that affects splicing in a severely affected Schimke immunoosseous dysplasia patient.

Schimke immunoosseous dysplasia (SIOD) is an autosomal recessive disease characterized by skeletal dysplasia, focal segmental glomerulosclerosis, renal failure and immunodeficiency. In this work, we report the molecular studies undertaken in a severely affected SIOD patient that died at six years old due to nephropathy. The patient was screened for mutations using a targeted skeletal dysplasias panel. A homozygous novel missense mutation was identified, c.1615C > G (p.[Leu539Val]) that was predicted as mildly pathogenic by in silico pathogenicity prediction tools. However, splicing prediction software suggested that this variant may create a new splicing donor site in exon 9, which was subsequently confirmed using a minigene assay in HEK293 cells. Thus, the splicing alteration, c.1615C > G; r.1615c > g, 1615_1644del; (p.[Leu539_Ile548del]), results in the loss of 10 amino acids of the HARP-ATPase catalytic domain and the RPA-binding domain. Several studies have demonstrated a weak genotype-phenotype correlation among such patients. Thus, the molecular characterization has helped us to understand why a predicted weakly pathogenic missense mutation results in severe SIOD and should be considered in similar scenarios.

Early severe scoliosis in a patient with atypical progressive pseudorheumatoid dysplasia (PPD): Identification of two WISP3 mutations, one previously unreported.

Progressive pseudorheumatoid dysplasia (PPD) is a rare autosomal recessive disorder characterized by spondyloepiphyseal dysplasia associated with pain and stiffness of multiple joints, enlargement of the interphalangeal joints, normal inflammatory parameters, and absence of extra-skeletal manifestations. Homozygous or compound heterozygous WISP3 mutations cause PPD. We report two siblings from a non-consanguineous Ecuadorian family with a late-onset spondyloepiphyseal dysplasia. Mutation screening was undertaken in the two affected siblings using a customized skeletal dysplasia next generation sequencing (NGS) panel and confirmed by Sanger sequencing. Two compound heterozygous mutations were identified in WISP3 exon 2, c.[190G>A];[197G>A] (p.[(Gly64Arg)];[(Ser66Asn)]) in the two siblings, both of which had been inherited. The p. (Gly64Arg) mutation has not been previously described whilst the p. (Ser66Asn) mutation has been reported in two PPD families. The two siblings presented with atypical PPD, as they presented during late childhood, yet the severity was different between them. The progression was particularly aggressive in the male sibling who suffered severe scoliosis by the age of 13 years. This case reaffirms the clinical heterogeneity of this disorder and the clinical utility of NGS to genetically diagnose skeletal dysplasias, enabling adequate management, monitorization, and genetic counseling. © 2016 Wiley Periodicals, Inc.

Fenotipo grave en dos medio hermanas con síndrome de Adams Oliver / Severe phenotype in two half-sibs with Adams Oliver syndrome

El síndrome de Adams Oliver (AOS) es una entidad heterogénea con defecto transverso terminal de extremidades (TTLD) y aplasia cutis congénita (ACC) con un amplio espectro fenotípico. Se han descrito diferentes modos de herencia en esta enfermedad; los defectos más graves se han asociado a un patrón autosómico recesivo (AR). Objetivo. presentar a una familia con dos medio hermanas con un fenotipo grave de Adams Oliver, con una madre sana. Reporte del caso: una mujer de 27 años de edad fue referida al Departamento de Genética. Su hija anterior presentó acránea, anillos de constricción y defectos transversos terminales de extremidades. Su hija actual presentaba encefalocele occipital, defecto amplio en huesos del cráneo, aplasia cutis congénita, defecto terminal transverso de extremidades y labio y paladar hendido bilateral. Sugerimos que algunos casos con fenotipo grave del síndrome de Adams Oliver pueden deberse a herencia autosómico dominante con penetrancia incompleta o a la presencia de mosaicismo gonadal.

Adams Oliver syndrome (AOS) is a highly variable entity with terminal transverse limb defects (TTLD) and aplasia cutis congenita (ACC) with a wide phenotypic spectrum. Several inheritance models have been observed; the most severe phenotype has been related to an autosomal recessive (AR) pattern of inheritance. Objective. To present a family with two half siblings with a severe phenotype of Adams Oliver syndrome in which the mother was healthy. Case report: A 27 year-old woman was referred to the Genetics Department. Her previous girl presented acrania, constriction rings and terminal transverse limb defects. The present girl had occipital encephalocele, large scalp defects, aplasia cutis congenita, terminal transverse limb defects and bilateral cleft lip and palate. Autosomal dominant inheritance with reduced penetrance or gonadal mosaicism has to be considered in Adams Oliver syndrome with severe intracranial anomalies.

Severe phenotype in two half-sibs with Adams Oliver syndrome.

UNLABELLED: Adams Oliver syndrome (AOS) is a highly variable entity with terminal transverse limb defects (TTLD) and aplasia cutis congenita (ACC) with a wide phenotypic spectrum. Several inheritance models have been observed; the most severe phenotype has been related to an autosomal recessive (AR) pattern of inheritance. OBJECTIVE. To present a family with two half siblings with a severe phenotype of Adams Oliver syndrome in which the mother was healthy. CASE REPORT: A 27 year-old woman was referred to the Genetics Department. Her previous girl presented acrania, constriction rings and terminal transverse limb defects. The present girl had occipital encephalocele, large scalp defects, aplasia cutis congenita, terminal transverse limb defects and bilateral cleft lip and palate. Autosomal dominant inheritance with reduced penetrance or gonadal mosaicism has to be considered in Adams Oliver syndrome with severe intracranial anomalies.