High prevalence of variants in skeletal dysplasia associated genes in individuals with short stature and minor skeletal anomalies.

OBJECTIVE: Next generation sequencing (NGS) has expanded the diagnostic paradigm turning the focus to the growth plate. The aim of the study was to determine the prevalence of variants in genes implicated in skeletal dysplasias in probands with short stature and mild skeletal anomalies. DESIGN: Clinical and radiological data were collected from 108 probands with short stature and mild skeletal anomalies. METHODS: A customized skeletal dysplasia NGS panel was performed. Variants were classified using ACMG recommendations and Sherloc. Anthropometric measurements and skeletal anomalies were subsequently compared in those with or without an identified genetic defect. RESULTS: Heterozygous variants were identified in 21/108 probands (19.4%). Variants were most frequently identified in ACAN (n = 10) and IHH (n = 7) whilst one variant was detected in COL2A1, CREBBP, EXT1, and PTPN11. Statistically significant differences (P < 0.05) were observed for sitting height/height (SH/H) ratio, SH/H ratio standard deviation score (SDS), and the SH/H ratio SDS >1 in those with an identified variant compared to those without. CONCLUSIONS: A molecular defect was elucidated in a fifth of patients. Thus, the prevalence of mild forms of skeletal dysplasias is relatively high in individuals with short stature and mild skeletal anomalies, with variants in ACAN and IHH accounting for 81% of the cases. An elevated SH/H ratio appears to be associated with a greater probability in detecting a variant, but no other clinical or radiological feature has been found determinant to finding a genetic cause. Currently, we cannot perform extensive molecular studies in all short stature individuals so detailed clinical and radiological phenotyping may orientate which are the candidate patients to obtain worthwhile results. In addition, detailed phenotyping of probands and family members will often aid variant classification.

Octreotide-related exocrine pancreatic insufficiency (EPI) in congenital hyperinsulinism.

Background Congenital hyperinsulinism (CH) is the most frequent cause of persistent hypoglycemia in the newborn. Octreotide, a long-acting somatostatin receptor analog (SSRA), is a second line treatment for diazoxide unresponsive CH patients. Although it has been found to be a safe and effective treatment, long-term benefits and side effects, have not been thoroughly evaluated. Case presentation Some authors have indicated that exocrine pancreatic insufficiency (EPI) is a common but under-recognized adverse reaction in adults treated with octreotide. However, no pediatric patient with SSRA-induced EPI has been reported to date. Here we report a case of an infant with diazoxide unresponsive, diffuse CH, caused by a heterozygous pathogenic paternally inherited mutation in the ABCC8 gene (NM_000352.4:c.357del), that developed exocrine pancreatic insufficiency and secondary vitamin K deficiency associated to chronic octreotide therapy. Conclusions We point out the atypical clinical onset with a cutaneous hemorrhagic syndrome, emphasizing the clinical relevance of this potential side effect.

Clinical and Molecular Description of 16 Families With Heterozygous IHH Variants.

CONTEXT: Heterozygous variants in the Indian hedgehog gene (IHH) have been reported to cause brachydactyly type A1 and mild hand and feet skeletal anomalies with short stature. Genetic screening in individuals with short stature and mild skeletal anomalies has been increasing over recent years, allowing us to broaden the clinical spectrum of skeletal dysplasias. OBJECTIVE: The objective of this article is to describe the genotype and phenotype of 16 probands with heterozygous variants in IHH. PATIENTS AND METHODS: Targeted next-generation sequencing or Sanger sequencing was performed in patients with short stature and/or brachydactyly for which the genetic cause was unknown. RESULTS: Fifteen different heterozygous IHH variants were detected, one of which is the first reported complete deletion of IHH. None of the patients showed the classical phenotype of brachydactyly type A1. The most frequently observed clinical characteristics were mild to moderate short stature as well as shortening of the middle phalanx on the fifth finger. The identified IHH variants were demonstrated to cosegregate with the short stature and/or brachydactyly in the 13 probands whose family members were available. However, clinical heterogeneity was observed: Two short-statured probands showed no hand radiological anomalies, whereas another 5 were of normal height but had brachydactyly. CONCLUSIONS: Short stature and/or mild skeletal hand defects can be caused by IHH variants. Defects in this gene should be considered in individuals with these findings, especially when there is an autosomal dominant pattern of inheritance. Although no genotype-phenotype correlation was observed, cosegregation studies should be performed and where possible functional characterization before concluding that a variant is causative.

Thyroid Volume Assessment in 3-14 Year-Old Spanish Children from an Iodine-Replete Area.

BACKGROUND/AIMS: Few data exist on reference thyroid volumes (Tvols) for Spanish children. The standard tables of the World Health Organization (WHO) are only for children older than 6 years. The present cross-sectional study reports the normal Tvols of 3-14 year-old girls and boys living in Madrid (Spain). METHODS: The study subjects were 217 children aged 3-14 years. Urinary iodine was determined, and, on the same day, cervical ultrasound examinations were performed by a single, experienced paediatric radiologist. The sex-specific, upper normal limits for Tvol were then determined, based on age and body surface area (BSA). RESULTS: The median urinary iodine concentration was 120 µg/L (interquartile range 80-184); the population was therefore deemed to fall within the optimum range for iodine nutritional status. Eight children with heterogeneous glandular parenchyma were detected, as were 6 with increased vascularity, and 22 with intrathyroid cysts. Tvol increased with age and BSA in both sexes from the age of 3 years. In girls aged 11-12 years, Tvol was significantly larger than that in boys of the same age. When comparing children 6 years old and above, the 97th percentile Tvols with respect to gender/BSA were similar to WHO reference values, but by gender/age they were 30% larger. CONCLUSIONS: This work proposes reference ultrasound-determined Tvols for 3-14-year-old children living in Madrid.

¿Es suficiente la nutrición de yodo en la población infantil española? Revisión histórica y situación actual / Is iodine nutrition in the Spanish pediatric population adequate? Historical review and current situation

El yodo es un componente esencial de las hormonas tiroideas y su déficit es la causa principal de retraso mental prevenible en el mundo. España ha sido considera yododeficiente hasta 2003. A pesar de que desde 2004, la yoduria está en rango óptimo, la OMS reconoce que no se cumplen los requisitos necesarios para garantizar que la población no pueda sufrir un trastorno por déficit de yodo. El objetivo de este artículo es realizar una revisión de la situación nacional de este micronutriente. Los datos obtenidos en diversos estudios destacan el bajo consumo domiciliario de sal yodada. A pesar de los avances conseguidos en las últimas décadas, los niños españoles no están exentos de sufrir un trastorno por déficit de yodo. Es necesario, por tanto, implementar políticas que permitan controlar la nutrición yódica así como impulsar el consumo de sal yodada de manera universal

Iodine is an essential component of thyroid hormones, and iodine deficit is the leading cause of preventable mental retardation worldwide. Spain was considered iodine-deficient until 2003. Although iodine urinary levels have been in the optimal range in Spain since 2004, the WHO recognizes that our country does not meet the necessary requirements to ensure that the whole population is not at risk of an iodine deficiency disorder. The aim of this article is to review the current iodine status in Spain. Data from several studies emphasize the low consumption of iodized salt at home. Despite the progress made in recent decades, Spanish children are not exempt from suffering an iodine deficiency disorder. Policies that allow for controlling iodine nutrition and promote universal consumption of iodized salt should therefore be implemented

Is iodine nutrition in the Spanish pediatric population adequate? Historical review and current situation. / ¿Es suficiente la nutrición de yodo en la población infantil española? Revisión histórica y situación actual.

Iodine is an essential component of thyroid hormones, and iodine deficit is the leading cause of preventable mental retardation worldwide. Spain was considered iodine-deficient until 2003. Although iodine urinary levels have been in the optimal range in Spain since 2004, the WHO recognizes that our country does not meet the necessary requirements to ensure that the whole population is not at risk of an iodine deficiency disorder. The aim of this article is to review the current iodine status in Spain. Data from several studies emphasize the low consumption of iodized salt at home. Despite the progress made in recent decades, Spanish children are not exempt from suffering an iodine deficiency disorder. Policies that allow for controlling iodine nutrition and promote universal consumption of iodized salt should therefore be implemented.

Heterozygous aggrecan variants are associated with short stature and brachydactyly: Description of 16 probands and a review of the literature.

OBJECTIVE: Mutations in the aggrecan gene (ACAN) have been identified in two autosomal dominant skeletal dysplasias, spondyloepiphyseal dysplasia, Kimberley type (SEDK), and osteochondritis dissecans, as well as in a severe recessive dysplasia, spondyloepimetaphyseal dysplasia, aggrecan type. Next-generation sequencing (NGS) has aided the identification of heterozygous ACAN mutations in individuals with short stature, minor skeletal defects and mild facial dysmorphisms, some of whom have advanced bone age (BA), poor pubertal spurt and early growth cessation as well as precocious osteoarthritis. DESIGN AND METHODS: This study involves clinical and genetic characterization of 16 probands with heterozygous ACAN variants, 14 with short stature and mild skeletal defects (group 1) and two with SEDK (group 2). Subsequently, we reviewed the literature to determine the frequency of the different clinical characteristics in ACAN-positive individuals. RESULTS: A total of 16 ACAN variants were located throughout the gene, six pathogenic mutations and 10 variants of unknown significance (VUS). Interestingly, brachydactyly was observed in all probands. Probands from group 1 with a pathogenic mutation tended to be shorter, and 60% had an advanced BA compared to 0% in those with a VUS. A higher incidence of coxa valga was observed in individuals with a VUS (37% vs 0%). Nevertheless, other features were present at similar frequencies. CONCLUSIONS: ACAN should be considered as a candidate gene in patients with short stature and minor skeletal defects, particularly those with brachydactyly, and in patients with spondyloepiphyseal dysplasia. It is also important to note that advanced BA and osteoarticular complications are not obligatory conditions for aggrecanopathies/aggrecan-associated dysplasias.

Síndrome de Muenke / Muenke syndrome

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Achondroplasia with 47, XXY karyotype: a case report of the neonatal diagnosis of an extremely unusual association.

BACKGROUND: The association of achondroplasia and Klinefelter syndrome is extremely rare. To date, five cases have been previously reported, all of them diagnosed beyond the postnatal period, and only one was molecularly characterized. We describe the first case of this unusual association diagnosed in the neonatal period, the clinical findings and the molecular studies undertaken. CASE PRESENTATION: The boy was born at term with clinical and radiological features indicating the diagnosis of achondroplasia or hypochondroplasia combined with the prenatal karyotype of Klinefelter syndrome (47,XXY). Neonatal FGFR3 mutation screening showed that the newborn was heterozygous for the classic achondroplasia G340R mutation. Microsatellite marker analysis showed that the sex chromosome aneuploidy had arisen from a non-disjunction error in paternal meiosis I, with a recombination event in the pseudoautosomal region 1 (PAR1). CONCLUSION: Specific mutation analysis is appropriate to confirm the clinical diagnosis of achondroplasia for appropriate diagnosis, prognosis, and genetic counseling, especially when the karyotype does not explain the abnormal prenatal sonographic findings. In the present case, a recombination event was observed in the PAR1 region, although recombinational events in paternally derived Klinefelter syndrome cases are much rarer than expected.

Síndrome de agenesia valvular pulmonar con emergencia ductal de arteria pulmonar izquierda. Papel de la ecocardiografía Doppler Color / Absent Pulmonary Valve Syndrome with Ductal Origin of the Left Pulmonary Artery. Diagnosis only by 2-D echo Doppler Color Flow Mapping

Se describe el caso de un lactante de dos meses portador de una rara asociación: sindrome de agenesia valvular pulmonar, comunicación interventricular, estenosis 'anular' pulmonar y origen ductal de la arteria pulmonar izquierda. El diagnóstico, realizado con ecocardiografía bidimensional Doppler color sin el auxilio del cateterismo cardíaco, fue confirmado en la sala operatoria (AU)