Novel FLNB Variants in Seven Argentinian Cases with Spondylocarpotarsal Synostosis Syndrome.

Spondylocarpotarsal synostosis syndrome (SCT) is a very rare skeletal dysplasia characterized by vertebral, carpal, and tarsal fusion; growth retardation; and mild dysmorphic facial features. Variants in FLNB, MYH3, and RFLNA have been implicated in this dysplasia. We report the clinical and radiological follow-up of seven SCT pediatric cases associated with biallelic FLNB variants, from four Argentinian families. The seven cases share previously described facial characteristics: round facies, large eyes, and wide based nose; all of them had variable height deficit, in one case noted early in life. Other findings included clinodactyly, joint limitation without bone fusion, neurosensorial hearing loss, and ophthalmological compromise. All cases presented with spinal fusion with variable severity and location, carpal bones coalition, and also delay in carpal ossification. The heterozygous carrier parents had normal height values to -2.5 score standard deviation, without skeletal defects detected. Three different FLNB variants, one nonsense and two frameshift, were detected, all of which were predicted to result in a truncated protein or are degraded by nonsense mediated decay. All cases had at least one copy of the nonsense variant, c.1128C> G; p. (Tyr376*), suggesting the presence of a common ancestor.

Duplication dup(1)(q41q44) defined by fluorescence in situ hybridization: delineation of the 'trisomy 1q42-->qter syndrome'.

We report on a novel case of pure partial tandem duplication 1q42q43 confirmed by fluorescence in situ hybridization (FISH). We compare the manifestations of our patient with similar cases previously reported. We conclude that the most common clinical manifestations of trisomy 1q42qter are prenatal and postnatal growth retardation, relative macrocephaly, triangular face, prominent forehead, broad nasal bridge, abnormal philtrum, micro/retrognathia, cardiac defects and mental retardation. We would like to emphasize the importance of the FISH technique in the identification of the duplicated segment.

Cardiopatías congénitas asociadas a la microdeleción 22q11. 2, en un hospital pediátrico / Congenital heart defects associated with a 22q11. 2 microdeletion at a pediatric hospital

Introducción: El síndrome de deleción 22q11.2, también llamado síndrome Velo-Cardio-Facial (VCFS/del22q11.2) o síndrome de DiGeorge, es una entidad causada por una anomalía cromosómica, deleción en la región q11.2 (brazo largo) del cromosoma 22. Se trata de una enfermedad multisistémica de expresión variable que afecta el aparato cardiovascular, la inmunidad, las funciones endocrinológicas, la cavidad oral, el desarrollo neurocognitivo, con una expresión facial particular. La prevalencia estimada es de 1:2000/4000. Objetivos: Identificar y describir las cardiopatías congénitas más frecuentemente asociadas a pacientes con síndrome de microdeleción 22q11.2. Materiales y métodos: Estudio descriptivo, transversal y retrospectivo que analiza los pacientes con diagnóstico de microdeleción 22q11.2 atendidos en el Hospital Garrahan desde Octubre de 1998 hasta Febrero 2018. El criterio diagnóstico fueron signos clínicos compatibles y la presencia de la microdeleción 22q11.2 por técnica de FISH o MLPA. Resultados: Población: 321 pacientes, 151 Femeninos (47%) 170 Masculinos (53%). Rango etario: 0 a 197 meses (1 día a 16,4 años). Mediana de edad al diagnóstico clínico: 31 meses. El 74,4% (239/321) de los pacientes evaluados con microdeleción 22q11.2 tuvieron cardiopatías congénitas asociadas a facies peculiar. Las cardiopatías congénitas más frecuentemente asociadas fueron conotroncales. De los pacientes con cardiopatías congénitas el 68,6% requirió cirugía cardiovascular. Fallecieron 24 pacientes (10%) con cardiopatías congénitas asociadas y en el 93% la causa de muerte estuvo relacionada a la afección cardiológica. Conclusiones: Los pacientes con microdeleción 22q11.2 se asocian con un alto porcentaje de cardiopatías congénitas, la gran mayoría son complejas (conotroncales) y requieren resolución quirúrgica en los primeros años de vida. Es de vital importancia la evaluación multidisciplinaria de este grupo especial de pacientes con cardiopatía asociada a otras alteraciones extra cardíacas para el diagnóstico precoz y tratamiento oportuno (AU)

Introduction: 22q11.2 deletion syndrome, also called velocardiofacial syndrome (VCFS/del22q11.2) or DiGeorge syndrome, is a condition caused by chromosomal abnormality, a deletion in the q11.2 region (long arm) of chromosome 22. VCFS is a multisystem disease of variable expression that affects the cardiovascular, immune, and endocrine systems, the oral cavity, neurocognitive development, and is associated with specific facial features. The estimated prevalence is 1:2000/4000. Objectives: To identify and describe the most common congenital heart defects associated with 22q11.2 micro-deletion syndrome. Materials and methods: Descriptive, cross-sectional, and retrospective study analyzing patients diagnosed with a 22q11.2 microdeletion seen at Garrahan Hospital from October 1998 to February 2018. Diagnostic criteria were compatible clinical signs and the presence of a 22q11.2 microdeletion identified by FISH or MLPA. Results: Population: 321 patients, 151 female (47%) and 170 Male (53%). Age range: 0 to 197 months (1 day to 16.4 years). Median age at clinical diagnosis: 31 months. Overall, 74.4% (239/321) of patients with a 22q11.2 microdeletion had congenital heart defects associated with a peculiar facies. The most commonly associated congenital heart defects were conotruncal. Of the patients with congenital heart defects, 68.6% required cardiovascular surgery. Of the patients with congenital heart defects 24 patients died (10%) and in 93% the cause of death was related to the heart disease (p 0.002). Conclusions: A high percentage of patients with a 22q11.2 microdeletion have congenital heart defects, which are complex (conotruncal) in the majority, requiring surgical treatment in the first years of life. Multidisciplinary evaluation of this special group of patients with heart defects associated with other extracardiac disorders is essential for an early diagnosis and timely treatment (AU)

[Tarsal-carpal coalition syndrome: a familial case]. / Síndrome de coalición tarso-carpiana: un caso familiar.

Tarsal-carpal coalition syndrome (TCC, OMIM #186570) is an autosomal dominant disorder characterised by fusion of the carpals, tarsals, and phalanges, with the short first metacarpals causing brachydactyly and humeroradial fusion. Mutations in the NOG gene have been reported in many families. We describe a family with carpal tarsal fusion seen at a Skeletal Dysplasia Clinic and look at the differential diagnoses.

[Osteogenesis imperfecta. Clinical, functional and multidisciplinary evaluation of 65 patients]. / Osteogénesis imperfecta. Evaluación clínica, funcional y multidisciplinaria de 65 pacientes.

INTRODUCTION: Osteogenesis Imperfecta (OI) is a genetic disease, in which the main clinical features are increased bone fragility, pathological fractures, blue sclera, dentinogenesis imperfecta and conductive or mixed hearing loss. Clinical variability is wide. Although there is no curative treatment, there are several therapeutic tools capable of improving the course of the condition and patient quality of life. PATIENTS AND METHODS: Sixty-five children seen in a Paediatric Hospital during six months in 2007 were evaluated. RESULTS: Thirty-five were type I OI, and thirty were types III-IV. Median age was 7.8 years (range 1.9-19.2); mean length of follow up was 4.7 years. The majority of children attended regular school for their corresponding age. Mean height was -1.4 sDS and -5.64 sDS in types I and III-IV respectively. Nineteen percent of patients were overweight and 11% were obese. Mean age at first orthopaedic surgery inserting telescopic rods was 6.5 years. Scoliosis was present in 44.6% of patients and was directly related to severity. Bleck's motor scale showed that 93% of patients with mild forms and 29% of severe forms had a sustainable walking ability. A wheelchair was used by 25% of patients. Family inheritance was confirmed in 65% of cases. CONCLUSIONS: Integral care using a multidisciplinary approach is required due to the complexity and clinical variability of the condition.

Unusually severe expression of craniofacial features in Aarskog-Scott syndrome due to a novel truncating mutation of the FGD1 gene.

Aarskog-Scott syndrome (AAS) is a rare, clinically and genetically heterogeneous condition characterized by facial dysmorphic features, short stature, brachydactyly, and genital anomalies. The X-linked form is caused by mutations of the FGD1 gene. Although clinical manifestations and diagnostic criteria are well established, diagnosis is not simple, as the spectrum of phenotypical features may be extremely variable. Here, we report on the clinical and genetic characterization of a family in which molecular analyses revealed the inheritance of a novel truncating mutation of the FDG1 gene (c.945insC) in two affected brothers, with one of them displaying unusually severe craniofacial abnormalities. This previously unreported combination of anomalies might be due to the occurrence of two distinct disorders (AAS and hemifacial microsomia) or may represent an extension of the AAS phenotypic spectrum. Our findings highlight the phenotypic heterogeneity of AAS, supporting the opinion that the FGD1 mutations result in a broad spectrum of severity and, in some cases, may express a clinical appearance very different than typically described.

Delecion 22q11.2: características de un grupo de pacientes atendidos en el Hospital Juan P. Garrahan / 22q11.2 deletions: features of a group of patients seen at the Juan P. Garrahan Hospital

El síndrome de Deleción 22q11.2 afecta el aparato cardiovascular, la inmunidad, las funciones endocrinológicas, la cavidad oral, el desarrollo neurocognitivo, con un fenotipo particular debido a una anomalía cromosómica. Objetivo: evaluar las características clínicas y citogenéticas de pacientes atendidos en forma multidisciplinaria, a través de un estudio observacional, descriptivo, transversal e interdisciplinario de una cohorte en seguimiento. Se diagnosticaron 194 pacientes con microdeleción 22q11.2, M 95/ F 99, con un rango etario: 0 a 192m (4días-16 a) y una mediana: 23m, el signo más constante fue la facies característica que se observó en un 100%, el 72,5% presentó malformación cardiovascular, 74,7% mostró defectos en su cavidad oral y el 30,5% hipoacusias. La mayoría de los pacientes evidenciaron compromiso de su neurodesarrollo en forma global, con retraso y trastorno de lenguaje. Se detectaron alteraciones en la inmunidad en el 64,31% con disminución de los linfocitos T, hipocalcemia en 36,8% y defectos urológicos en un 14,7%. Entre los diagnósticos citogenéticos se observó además dos pacientes con traslocaciones cromosómicos de novo que involucraban la microdeleción y un paciente con la deleción en mosaico. Los estudios parentales evidenciaron un 10% de casos heredados. La población estudiada mostró una clínica y frecuencia de anomalías similar a la referida en la bibliografía a excepción de los trastornos auditivos y urológicos que se vieron con menor frecuencia mientras que la prevalencia de alteraciones neurocognitivas fue mayor. La complejidad y variabilidad del síndrome requiere un manejo multidisciplinario.

22q11.2 deletion syndrome may affect the cardiovascular and immune systems, endocrine functions, the oral cavity, and neurocognitive development with a peculiar phenotype due to the chromosomal anomaly. Objective: To evaluate the clinical and cytogenetic features of patients followed-up by a multidisciplinary team in an observational, descriptive, cross-sectional and interdisciplinary cohort study. We diagnosed 194 patients with a 22q11.2 microdeletion, M 95/ F 99, with an age range of 0 to 192 months (4 days-16 years) and a me-dian age of 23 months. Characteristic facies was observed in 100% of the patients, cardiovascular malformation in 72.5%, oral cavity abnormalities in 74.7%, and hearing loss in 30.5%. The majority of the patients showed global impairment of neurological development, such as developmental delay and language disorders. Alterations in the immune system with a low T-lymphocyte count were found in 64.31% of the patients, hypocalcemia in 36.8%, and urinary abnormalities in 14.7%. Among the cytogenetic diagnoses, two patients were found to have de novo chromosome translocations involving the microdeletion and one patient had a mosaic deletion. Stud-ies in parents showed that the disease was inherited in 10% of the cases. Clinical findings and rate of anomalies in the study population were similar to those reported in the litera-ture, except for hearing loss and urinary disorders that were less frequently found, while the prevalence of neurocognitive impairment was higher. The complexity and variability of the syndrome warrants a multidisciplinay approach.

Partial deletion 10p syndrome. Report of two patients.

Two patients with partial deletion of the short arm of chromosome 10 are described. They showed most of the features observed in twenty other known patients, including growth retardation, mental deficiency, abnormally shaped skull, distinct facial dysmorphisms, cardiac and genitourinary malformations, and limbs anomalies. One of our patients also had features of the DiGeorge sequence, which has been found in five other cases with this imbalance.

Deletion 11q23-->qter (Jacobsen syndrome). Report of three new patients.

Three unrelated patients with de novo del 11q23-->qter are reported. Clinical features included growth and mental retardation, hypotonia, trigonocephaly, facial dysmorphism with hypertelorism, epicanthal folds, abnormally shaped palpebral fissures, eye globe malformations, depressed nasal bridge, "carp-shaped" mouth, highly arched palate, low set and malformed ears. One patient had congenital heart defect, and reduced platelet count. This syndrome, originally reported by Jacobsen, is now corroborated by more than 35 patients and appears as the most common deletion involving 11q. Since deletion of subband 11q24.1 is critical for full expression of this syndrome, the JBS phenotype could be an example of contiguous gene syndrome.

Radiographic findings in Wiedemann-Rautenstrauch syndrome.

We describe a girl who presents the features of Wiedemann-Rautenstrauch syndrome. This autosomal recessive condition has characteristic radiographic findings which can be considered manifestations of the syndrome.