Endocrine Sequelae in 157 Pediatric Survivors of Hematopoietic Stem Cell Transplantation (HSCT).

Context: Successful rates of hematopoietic stem cell transplantation (HSCT) face paralleled escalation of late endocrine and metabolic effects. Objective: This work aimed to characterize these sequelae distinguishing between the underlying pathologies and treatments received. Methods: A retrospective descriptive study was conducted in 157 children post-HSCT (hematopoietic pathology [N = 106], solid tumors [N = 40], and rare entities [N = 11]) followed at a single endocrine department between 2009 and 2019. Regression analysis was used to ascertain association. Results: Of all patients, 58.7% presented with at least one endocrine abnormality. Endocrinopathies post HSCT were most frequently developed in lymphoblastic leukemia (60.5% of them), whereas myeloid leukemias had the fewest. A total of 64% of patients presented with primary hypogonadism, 52% short stature, and 20% obesity. Endocrinopathy was associated with older age at HSCT (9.78 years [6.25-12.25] vs 6.78 years [4.06-9.75]) (P < .005), pubertal Tanner stage V (P < .001), chronic graft-vs-host disease (GVHD) (P = .022), and direct gonadal therapy (P = .026). The incidence of endocrinopathies was higher in girls (15% more common; P < .02) and in patients who received radiotherapy (18% higher), steroids (17.4% increase), allogenic HSCT (7% higher), thymoglobulin, or cyclophosphamide. Those on busulfan presented with a 27.5% higher rate of primary hypogonadism (P = .003). Conclusion: More than half of children surviving HSCT will develop endocrinopathies. Strikingly, obesity has risen to the third most frequent endocrine disruption, mainly due to steroids, and partly adhering to the general population tendency. Lymphoblastic leukemia was the condition with a higher rate of endocrine abnormalities. Female sex, older age at HSCT, pubertal stage, allogenic transplant, radiotherapy, alkylating drugs, and GVHD pose risk factors for endocrine disturbances.

Primary Dwarfism, Microcephaly, and Chorioretinopathy due to a PLK4 Mutation in Two Siblings.

INTRODUCTION: Primary autosomal recessive microcephalies (MCPHs) are characterized by primary dwarfism with MCPH and may present delayed psychomotor development and visual impairment. Biallelic loss of function variants in the PLK4 gene, which encodes the polo-like kinase 4 protein involved in centriole biogenesis, has been recently identified in several patients with MCPH and various ethnic backgrounds. CASE PRESENTATION: Here, we describe 2 siblings of different sex from Equatorial Guinea harboring a homozygous frameshift mutation in PLK4 (c.1299_1303del, p.Phe433Leufs*6). A Seckel syndrome spectrum phenotype was present in both siblings, with short stature, severe MCPH, reduced brain volume, and distinctive facial features. They also presented severe intellectual disability, lissencephaly/pachygyria, subependymal heterotopia, and ophthalmological impairment. One of them suffered from deafness, and scoliosis was observed in the other. DISCUSSION/CONCLUSION: Biallelic variants in PLK4 lead to a syndrome where severe short stature, MCPH, and cognitive impairment are constant features. However, ocular, skeletal, and other neurological manifestations can vary upon the same genetic basis.

LZTR1: Genotype Expansion in Noonan Syndrome.

BACKGROUND: LZTR1 participates in RAS protein degradation, hence limiting the RAS/MAPK cascade. Pathogenic mutations in LZTR1 (MIM:600574) have been described in a few patients with Noonan syndrome (NS). Three patients with LZTR1 mutations of different genetic transmission and NS phenotype are herein characterized. CLINICAL CASES: Case 1 is a 5-year-old boy with NS phenotype. Sanger sequencing of PTPN11 and SOS1 identified no mutations. Whole exome sequencing (WES) detected a heterozygous missense mutation in LZTR1:c.742G>A (p.Gly248Arg) (exon 8, Kelch 4 functional domain). Bioinformatic algorithms predict a deleterious effect of this variant, previously described to cause NS. Case 2 is a 4-year-old boy with NS phenotype. Direct sequencing of 8 genes associated with NS identified no mutations. WES localized a homozygous missense mutation in LZTR1:c.2074T>C (p.Phe692Leu, exon 18). This mutation has not been reported before and is predicted to have a deleterious effect on the protein. Case 3 is an 8-year-old boy who shares NS phenotype with his mother. A multigene panel for RASopathies showed a heterozygous missense variant in LZTR1:c.730T>C (p.Ser244Pro) (exon 8; Kelch 4 functional domain) that was maternally inherited. This variant has not been previously described; however, in silico predictors classify it as deleterious. Familial segregation suggests its pathogenicity. CONCLUSIONS: The molecular approach for syndromic phenotypes associated with various genes should involve complete/updated panels or WES rather than gene-by-gene sequencing. RASopathy genetic panels should incorporate LZTR1. Patients with pathogenic mutations in LZTR1 exhibit a characteristic NS gestalt but variable cardiac, height, and neurodevelopment expressions, with recessive inheritance possibly associating with a more severe phenotype.

Engrosamiento del tallo hipofisario en niños y adolescentes con diabetes insípida central: causas y consecuencias / Thickening of the pituitary stalk in children and adolescents with central diabetes insipidus: Causes and consequences

Introducción: La diabetes insípida central (DIC) es una entidad poco frecuente en la edad pediátrica, siendo su etiología heterogénea. El objetivo de nuestro trabajo es demostrar que el seguimiento clínico y neurorradiológico de la región hipotálamo-hipofisaria, puede ayudar a establecer el diagnóstico etiológico de DIC y la presencia de otros déficits hormonales. Métodos: Se revisaron de forma retrospectiva 15 pacientes diagnosticados de DIC en un hospital pediátrico. Se analizaron las características clínicas y auxológicas; así como la valoración de la función adenohipofisaria junto con RM craneal de manera periódica. Resultados: La mediana de edad al diagnóstico fue de 9,6 años (rango: 1,3-15,9). El diagnóstico etiológico pudo establecerse en 9 de los 15 pacientes (germinomas: 7 e histiocitosis: 2). Tras una mediana de seguimiento de 5,5 años (rango: 1,6-11,8), los casos idiopáticos se redujeron a la mitad. Finalmente, los diagnósticos etiológicos fueron: germinoma 9 (60%), histiocitosis 3 (20%) y DIC idiopática 3 (20%). Existe una asociación estadísticamente significativa entre el engrosamiento del tallo y la etiología tumoral. El 67% desarrolló, al menos, una deficiencia hormonal adenohipofisaria, la mayoría en los dos primeros años de seguimiento. El déficit más prevalente fue el de hormona de crecimiento (60%). Conclusiones: En todos los pacientes con DIC se deberá realizar un control auxológico y hormonal, con especial atención, por su frecuencia, a la deficiencia de GH, y en aquellos con DIC idiopática se debería incluir una RM semestral, al menos durante los 2-3 primeros años después del diagnóstico, pues en nuestro estudio el 50% fueron diagnosticados de germinomas o histiocitosis en este periodo

Background: Central diabetes insipidus (CDI) is a rare disorder in children. The aetiology of CDI in childhood is heterogeneous. The aim of this study is to illustrate the importance of a careful clinical and neuro-radiological follow-up of the pituitary and hypothalamus region in order to identify the aetiology and the development of associated hormonal deficiencies. Methods: Clinical and auxological variables of 15 children diagnosed with CDI were retrospectively analysed in a paediatric hospital. Evaluations of adenohypophyseal function and cranial MRI were performed periodically. Results: The mean age at diagnosis of CDI was 9.6 years (range: 1.32-15.9). The aetiological diagnosis could be established initially in 9 of the 15 patients, as 7 with a germinoma and 2 with a histiocytosis. After a mean follow-up of 5.5 years (range: 1.6-11.8), the number of idiopathic cases was reduced by half. At the end of the follow-up, the aetiological diagnoses were: 9 germinoma (60%), 3 histiocytosis (20%), and 3 idiopathic CDI (20%). There is a statistically significant association between stalk thickening and tumour aetiology. At least one adenohypophyseal hormonal deficiency was found in 67% of cases, with the majority developing in the first two years of follow-up. Growth hormone deficiency (60%) was the most prevalent. Conclusion: The follow-up of CDI should include hormone evaluation with special attention, due to its frequency, to GH deficiency. In addition, a biannual MRI in an idiopathic CDI should be performed, at least during the first 2-3 years after diagnosis, as 50% of them were diagnosed with a germinoma or histiocytosis during this period

[Thickening of the pituitary stalk in children and adolescents with central diabetes insipidus: Causes and consequences]. / Engrosamiento del tallo hipofisario en niños y adolescentes con diabetes insípida central: causas y consecuencias.

BACKGROUND: Central diabetes insipidus (CDI) is a rare disorder in children. The aetiology of CDI in childhood is heterogeneous. The aim of this study is to illustrate the importance of a careful clinical and neuro-radiological follow-up of the pituitary and hypothalamus region in order to identify the aetiology and the development of associated hormonal deficiencies. METHODS: Clinical and auxological variables of 15 children diagnosed with CDI were retrospectively analysed in a paediatric hospital. Evaluations of adenohypophyseal function and cranial MRI were performed periodically. RESULTS: The mean age at diagnosis of CDI was 9.6 years (range: 1.32-15.9). The aetiological diagnosis could be established initially in 9 of the 15 patients, as 7 with a germinoma and 2 with a histiocytosis. After a mean follow-up of 5.5 years (range: 1.6-11.8), the number of idiopathic cases was reduced by half. At the end of the follow-up, the aetiological diagnoses were: 9 germinoma (60%), 3 histiocytosis (20%), and 3 idiopathic CDI (20%). There is a statistically significant association between stalk thickening and tumour aetiology. At least one adenohypophyseal hormonal deficiency was found in 67% of cases, with the majority developing in the first two years of follow-up. Growth hormone deficiency (60%) was the most prevalent. CONCLUSION: The follow-up of CDI should include hormone evaluation with special attention, due to its frequency, to GH deficiency. In addition, a biannual MRI in an idiopathic CDI should be performed, at least during the first 2-3 years after diagnosis, as 50% of them were diagnosed with a germinoma or histiocytosis during this period.

Braquidactilia tipo C debida a mutación de parada en el gen GDF5 / Brachydactyly type C due to a nonsense mutation in the GDF5 gene

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Mutación en gen RET: tiroidectomía profiláctica y valoración postoperatoria / Mutation in RET gene: Prophylactic thyroidectomy and postoperative follow-up

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Lipodistrofia parcial adquirida (síndrome de Barraquer-Simons) y nefropatía IgA / Acquired partial lipodystrophy (Barraquer-Simons syndrome) and IgA nephropathy

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Feocromocitoma / No disponible

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