Neurological findings and genetic alterations in patients with Kostmann syndrome and HAX1 mutations.

OBJECTIVES: To describe the clinical profile and the prevalence of severe congenital neutropenia (SCN) and HAX1 mutations, so-called Kostmann syndrome, in France. STUDY DESIGN: Two pedigrees were identified from the French registry. RESULTS: The study included five subjects (three males), which represent 0.7% of the 759 SCN cases registered in France. The age at diagnosis was 0.3 years (range: 0.1-1.2 years) and the median age at the last follow-up was 7.3 years (range: 1.2-17.8 years). A novel large homozygous deletion of the HAX1 gene (exons 2-5) was found in one pedigree; while, a homozygous frameshift mutation was identified in exon 3 (c.430dupG, p.Val144fs) in the second pedigree. Severe bacterial infections were observed in four patients, including two cases of sepsis, one case of pancolitis, a lung abscess, and recurrent cellulitis and stomatitis. During routine follow-up, the median neutrophil value was 0.16 × 10(9)/L, associated with monocytosis (2 × 10(9)/L). Bone marrow (BM) smears revealed a decrease of the granulocytic lineage with no mature myeloid cells above the myelocytes. One patient died at age 2 from neurological complications, while two other patients, including one who underwent a hematopoietic stem cell transplantation (HSCT) at age 5, are living with very severe neurological retardation. CONCLUSIONS: SCN with HAX1 mutations, is a rare sub type of congenital neutropenia, mostly observed in population from Sweden and Asia minor, associating frequently neurological retardation, when the mutations involved the B isoform of the protein.

Classification of and risk factors for hematologic complications in a French national cohort of 102 patients with Shwachman-Diamond syndrome.

BACKGROUND: Patients with the Shwachman-Diamond syndrome often develop hematologic complications. No risk factors for these complications have so far been identified. The aim of this study was to classify the hematologic complications occurring in patients with Shwachman-Diamond syndrome and to investigate the risk factors for these complications. DESIGN AND METHODS: One hundred and two patients with Shwachman-Diamond syndrome, with a median follow-up of 11.6 years, were studied. Major hematologic complications were considered in the case of definitive severe cytopenia (i.e. anemia <7 g/dL or thrombocytopenia <20 × 10(9)/L), classified as malignant (myelodysplasia/leukemia) according to the 2008 World Health Organization classification or as non-malignant. RESULTS: Severe cytopenia was observed in 21 patients and classified as malignant severe cytopenia (n=9), non-malignant severe cytopenia (n=9) and malignant severe cytopenia preceded by non-malignant severe cytopenia (n=3). The 20-year cumulative risk of severe cytopenia was 24.3% (95% confidence interval: 15.3%-38.5%). Young age at first symptoms (<3 months) and low hematologic parameters both at diagnosis of the disease and during the follow-up were associated with severe hematologic complications (P<0.001). Fifteen novel SBDS mutations were identified. Genotype analysis showed no discernible prognostic value. CONCLUSIONS Patients with Shwachman-Diamond syndrome with very early symptoms or cytopenia at diagnosis (even mild anemia or thrombocytopenia) should be considered at a high risk of severe hematologic complications, malignant or non-malignant. Transient severe cytopenia or an indolent cytogenetic clone had no deleterious value.

Diagnosis, management, and prognosis of HNF1B nephropathy in adulthood.

Mutations in HNF1B are responsible for a dominantly inherited disease with renal and nonrenal consequences, including maturity-onset diabetes of the young (MODY) type 5. While HNF1B nephropathy is typically responsible for bilateral renal cystic hypodysplasia in childhood, the adult phenotype is poorly described. To help define this we evaluated the clinical presentation, imaging findings, genetic changes, and disease progression in 27 adults from 20 families with HNF1B nephropathy. Whole-gene deletion was found in 11 families, point mutations in 9, and de novo mutations in half of the kindred tested. Renal involvement was extremely heterogeneous, with a tubulointerstitial profile at presentation and slowly progressive renal decline throughout adulthood as hallmarks of the disease. In 24 patients tested, there were cysts (≤5 per kidney) in 15, a solitary kidney in 5, hypokalemia in 11, and hypomagnesemia in 10 of 16 tested, all as characteristics pointing to HNF1B disease. Two patients presented with renal Fanconi syndrome and, overall, 4 progressed to end-stage renal failure. Extrarenal phenotypes consisted of diabetes mellitus in 13 of the 27 patients, including 11 with MODY, abnormal liver tests in 8 of 21, diverse genital tract abnormalities in 5 of 13 females, and infertility in 2 of 14 males. Thus, our findings provide data that are useful for recognition and diagnosis of HNF1B disease in adulthood and might help in renal management and genetic counseling.

Anomalies of the TCF2 gene are the main cause of fetal bilateral hyperechogenic kidneys.

Prenatal discovery of fetal bilateral hyperechogenic kidneys is very stressful for pregnant women and their family, and accurate diagnosis of the cause of the moderate forms of this pathology is very difficult. Hepatocyte nuclear factor-1beta that is encoded by the TCF2 gene is involved in the embryonic development of the kidneys. Sixty-two pregnancies with fetal bilateral hyperechogenic kidneys including 25 fetuses with inaccurate diagnosis were studied. TCF2 gene anomalies were detected in 18 (29%) of these 62 patients, and 15 of these 18 patients presented a complete heterozygous deletion of the TCF2 gene. Family screening revealed de novo TCF2 anomalies in more than half of the patients. TCF2 anomalies were associated with normal amniotic fluid volume and normal-sized kidneys between -2 and +2 SD in all patients except for two sisters. Antenatal cysts were detected in 11 of 18 patients, unilaterally in eight of 11. After birth, cysts appeared during the first year (17 of 18), and in patients with antenatal cysts, the number increased and developed bilaterally with decreased renal growth. In these 18 patients, the GFR decreased with longer follow-up and was lower in patients with solitary functioning dysplastic kidney. Heterozygous deletion of the TCF2 gene is an important cause of fetal hyperechogenic kidneys in this study and showed to be linked with early disease expression. The renal phenotype and the postnatal evolution were extremely variable and need a prospective long-term follow-up. Extrarenal manifestations are frequent in TCF2-linked pathologies. Therefore, prenatal counseling and follow-up should be multidisciplinary.

Renal phenotypes related to hepatocyte nuclear factor-1beta (TCF2) mutations in a pediatric cohort.

The hepatocyte nuclear factor-1beta encoded by the TCF2 gene plays a role for the specific regulation of gene expression in various tissues such as liver, kidney, intestine, and pancreatic islets and is involved in the embryonic development of these organs. TCF2 mutations are known to be responsible for the maturity-onset diabetes of the young type 5 associated with renal manifestations. Several observations have suggested that TCF2 mutations may be involved in restricted renal phenotypes. Eighty children (median age at diagnosis 0.2 yr) with renal cysts, hyperechogenicity, hypoplasia, or single kidneys were studied. Quantitative multiplex PCR amplification of short fluorescence fragments for the search of large genomic rearrangements and sequencing for the detection of point mutations were performed. TCF2 anomalies were detected in one third of patients (25 of 80). The main alteration was the complete deletion of the TCF2 gene detected in 16 patients. Family screening revealed de novo TCF2 anomalies in nine of 17 probands with a high prevalence of deletions (seven of nine). TCF2 anomalies were associated with bilateral renal anomalies (P < 0.001) and bilateral cortical cysts (P < 0.001). However, abnormal renal function, detected in 40% of patients, was independent of the TCF2 genotype. No difference in renal function or severity of renal morphologic lesions was observed between patients with a TCF2 deletion and those with point mutations. In conclusion, TCF2 molecular anomalies are involved in restricted renal phenotype in childhood without alteration of glucose metabolism. These findings have important implications in the diagnosis of patients with renal dysplasia with cysts and their follow-up.

Clinical spectrum associated with hepatocyte nuclear factor-1beta mutations.

BACKGROUND: Maturity-onset diabetes of the young type 5 (MODY5), a type of dominantly inherited diabetes mellitus and nephropathy, has been associated with mutations of the hepatocyte nuclear factor-1beta (HNF-1beta) gene, mostly generating truncated protein. Various phenotypes, including urogenital malformations, are related to HNF-1beta mutations. OBJECTIVE: To describe clinical and genetic findings in 13 patients with 8 novel HNF-1beta mutations. DESIGN: Multicenter, descriptive study. SETTING: 2 departments of diabetes, 1 department of internal medicine, and 1 department of nephrology. PARTICIPANTS: 8 probands with diabetes diagnosed before 40 years of age and nondiabetic kidney disease who were selected independent of their family history of diabetes, and 5 offspring. MEASUREMENTS: Characteristics of diabetes, renal function and structure, genital tract abnormalities, pancreas structure, insulin secretion, exocrine pancreas function, and liver test results. RESULTS: All mutations, including 5 missense changes, were found in the DNA-binding domain. Cosegregation of the mutation and MODY5 phenotype was observed in 4 families. Occurrence of a de novo mutation was demonstrated in 2 families. Diabetes was present in 10 of 13 mutation carriers. It was clinically overt in 5 participants and found by screening at age 19 to 38 years in 5 participants. Pancreas atrophy was observed in 5 of 6 probands, and pancreas exocrine insufficiency was observed in 6 of 7 probands. Renal involvement, consisting of structural changes and slowly progressive renal failure, was recognized in 9 patients at 18 to 41 years of age. Dysplastic kidneys were found by ultrasonography in 3 fetuses who subsequently showed transient neonatal renal failure. Genital tract abnormalities were present in 5 probands and liver enzyme levels were abnormal in 11 of 13 patients. LIMITATIONS: Since the study was small and not population-based, it could not estimate the prevalence of MODY5. Other phenotypes might be associated with HNF-1beta mutations. CONCLUSIONS: Maturity-onset diabetes of the young type 5 encompasses a wide clinical spectrum. Analysis for mutations of HNF-1beta is warranted, even without a family history of diabetes, in nonobese patients with diabetes and slowly progressive nondiabetic nephropathy, particularly when pancreatic atrophy or genital abnormalities are present.

Mutations in the ELA2 gene correlate with more severe expression of neutropenia: a study of 81 patients from the French Neutropenia Register.

Heterozygous mutations of the gene encoding neutrophil elastase (ELA2) have been associated with cyclic neutropenia (CN) and severe congenital neutropenia (SCN). To date, 30 different mutations have been reported, but no correlation has been found with the degree of neutropenia. To address this issue, we analyzed the clinical, hematologic, and molecular characteristics of 81 unrelated patients with SCN (n = 54) or CN (n = 27). We identified mutations in 31 patients, two thirds of whom had sporadic forms. Familial cases were consistent with dominant inheritance. Seventeen novel mutations were identified, showing that the mutational spectrum encompasses not only the region encoding the mature enzyme but also the prodomains and promoter region. Genotype-phenotype analysis strongly suggested that ELA2 mutations correlate with more severe expression of neutropenia, specifically in patients diagnosed with SCN. This study underlines the importance of ELA2 molecular screening to identify patients who may be at particular risk of severe bacterial infections and/or acute myeloid leukemia/myelodysplasia. By phenotypic analysis of affected relatives and carriers of the same ELA2 mutations, we showed that the expression of neutropenia in CN and SCN may be either homogeneous or variable according to the type of mutations, suggesting different pathogenetic mechanisms.