Growth retardation and growth hormone deficiency in patients with Ataxia telangiectasia.

BACKGROUND: Ataxia telangiectasia (A-T) is a devastating human recessive disorder characterised by progressive cerebellar ataxia, immunodeficiency, genetic instability, and cancer susceptibility. In addition, many patients suffer from growth failure. METHODS: We analyzed growth and IGF-1/BP3 levels of 24 A-T-patients compared with an age-matched group of healthy controls (n = 36). RESULTS: Ten (41.7%) A-T patients and none of healthy controls had an IGF-1 level below the 3rd percentile for age. The growth hormone (GH) stimulation tests revealed a severe GH deficiency with no increase of >5 ng/ml in six of the ten A-T patients. The IGF-1 generation tests revealed normal increases in IGF-1 values in all patients. CONCLUSION: Our results show that a disturbance in the GH/IGF-1 axis was present in 58.3% of A-T patients. Low levels of GH were the result of reduced central GH secretion. GH treatment may be a therapeutic option for A-T patients with severe growth failure.

Childhood-Onset Movement Disorders Can Mask a Primary Immunodeficiency: 6 Cases of Classical Ataxia-Telangiectasia and Variant Forms.

Ataxia-telangiectasia (A-T) is a neurodegenerative and primary immunodeficiency disorder (PID) characterized by cerebellar ataxia, oculocutaneous telangiectasia, immunodeficiency, progressive respiratory failure, and an increased risk of malignancies. It demands specialized care tailored to the individual patient's needs. Besides the classical ataxia-telangiectasia (classical A-T) phenotype, a variant phenotype (variant A-T) exists with partly overlapping but some distinctive disease characteristics. Here we present a case series of 6 patients with classical A-T and variant A-T, which illustrates the phenotypic variability of A-T that can present in childhood with prominent extrapyramidal features, with or without cerebellar ataxia. We report the clinical data, together with a detailed genotype description, immunological analyses, and related expression of the ATM protein. We show that the presence of some residual ATM kinase activity leads to the clinical phenotype variant A-T that differs from the classical A-T. Our data illustrate that the diagnosis of the variant form of A-T can be delayed and difficult, while early recognition of the variant form as well as the classical A-T is a prerequisite for providing a correct prognosis and appropriate rehabilitation and support, including the avoidance of diagnostic X-ray procedures, given the increased risk of malignancies and the higher risk for side effects of subsequent cancer treatment.

Dynamic changes in clonal cytogenetic architecture during progression of chronic lymphocytic leukemia in patients and patient-derived murine xenografts.

Subclonal heterogeneity and clonal selection influences disease progression in chronic lymphocytic leukemia (CLL). It is therefore important that therapeutic decisions are made based on an understanding of the CLL clonal architecture and its dynamics in individual patients. Identification of cytogenetic abnormalities by FISH remains the cornerstone of contemporary clinical practice and provides a simple means for prognostic stratification. Here, we demonstrate that multiplexed-FISH can enhance recognition of CLL subclonal repertoire and its dynamics during disease progression, both in patients and CLL patient-derived xenografts (PDX). We applied a combination of patient-specific FISH probes to 24 CLL cases before treatment and at relapse, and determined putative ancestral relationships between subpopulations with different cytogenetic features. We subsequently established 7 CLL PDX models in NOD/Shi-SCID/IL-2Rγctm1sug/Jic (NOG) mice. Application of multiplexed-FISH to these models demonstrated that all of the identified cytogenetic subpopulations had leukemia propagating activity and that changes in their representation during disease progression could be spontaneous, accelerated by treatment or treatment-induced. We conclude that multiplexed-FISH in combination with PDX models have the potential to distinguish between spontaneous and treatment-induced clonal selection, and therefore provide a valuable tool for the pre-clinical evaluation of novel therapies.