Long-term follow-up and treatment of congenital alveolar proteinosis.

BACKGROUND: Clinical presentation, diagnosis, management and outcome of molecularly defined congenital pulmonary alveolar proteinosis (PAP) due to mutations in the GM-CSF receptor are not well known. CASE PRESENTATION: A 2 1/2 years old girl was diagnosed as having alveolar proteinosis. Whole lung lavages were performed with a new catheter balloon technique, feasible in small sized airways. Because of some interstitial inflammation in the lung biopsy and to further improve the condition, empirical therapy with systemic steroids and azathioprin, and inhaled and subcutaneous GMCSF, were used. Based on clinical measures, total protein and lipid recovered by whole lung lavages, all these treatments were without benefit. Conversely, severe respiratory viral infections and an invasive aspergillosis with aspergilloma formation occurred. Recently the novel homozygous stop mutation p.Ser25X of the GMCSF receptor alpha chain was identified in the patient. This mutation leads to a lack of functional GMCSF receptor and a reduced response to GMCSF stimulation of CD11b expression of mononuclear cells of the patient. Subsequently a very intense treatment with monthly lavages was initiated, resulting for the first time in complete resolution of partial respiratory insufficiency and a significant improvement of the overall somato-psychosocial condition of the child. CONCLUSIONS: The long term management from early childhood into young adolescence of severe alveolar proteinosis due to GMCSF receptor deficiency requires a dedicated specialized team to perform technically demanding whole lung lavages and cope with complications.

Pseudodominant inheritance of the hyperimmunoglobulinemia D with periodic fever syndrome in a mother and her two monozygotic twins.

Hyperimmunoglobulinemia D with periodic fever syndrome (HIDS) is a recessively inherited recurrent fever syndrome. We describe a family of 2 monozygotic twins and their mother with characteristic symptoms of HIDS, but normal levels of IgD and IgA, and with a dominant inheritance pattern. Mevalonate kinase (MK) activity was deficient in both children, and analysis of the MVK gene revealed compound heterozygosity for 2 new mutations, G25G and R277H. Being positioned adjacent to a donor splice site, the G25G mutation was shown by reverse transcription-polymerase chain reaction analyses to cause aberrant splicing of the MVK messenger RNA, thus being disease-relevant. The mother, who was also symptomatic during her childhood and adolescence, was a compound heterozygote for I268T and R277H. Our findings expand the genetic and ethnic spectrum of HIDS and show that the possible presence of this disease cannot be excluded based solely on inheritance patterns. In each case in which HIDS is clinically suspected, analysis of MK activity and/or the MVK gene (especially exons 9 and 11) should be performed.

Molecular analysis of the MVK and TNFRSF1A genes in patients with a clinical presentation typical of the hyperimmunoglobulinemia D with periodic fever syndrome: a low-penetrance TNFRSF1A variant in a heterozygous MVK carrier possibly influences the phenotype of hyperimmunoglobulinemia D with periodic fever syndrome or vice versa.

OBJECTIVE: To describe biochemical findings and the spectrum of mevalonate kinase (MVK) gene mutations as well as an associated TNFRSF1A low-penetrance variant in a series of patients with clinical features of the hyperimmunoglobulinemia D with periodic fever syndrome (HIDS). METHODS: The MVK gene was sequenced in 8 children and 1 adult (including 2 siblings) fulfilling the clinical criteria for HIDS. In addition, sequencing of exons 2, 3, 4, and 6 of the TNFRSF1A gene was performed in patients with only one or no MVK mutation. Mevalonate kinase (MK) enzyme activity in leukocytes and renal excretion of mevalonic acid were also measured. RESULTS: Mutations in the coding region of the MVK gene were detected in 6 patients, and the most common mutation was V377I. Among these patients were 2 novel mutations, both of which were located in exon 6. These novel mutations resulted in the substitution of tryptophan (TGG) by a stop codon (TGA) at amino acid position 188 (W188X) and in the exchange of valine (GTG) for alanine (GCG) at amino acid position 203 (V203A). In 1 patient, a combination of one MVK (V377I) mutation and one TNFRSF1A (R92Q) mutation was present. The patient's clinical phenotype resembled a mixture of variant-type HIDS and tumor necrosis factor receptor-associated periodic syndrome (TRAPS). Her IgD values varied between normal and slightly increased, and the MK activity was in the low-normal range, while urinary mevalonate concentrations were always normal. CONCLUSION: The genotype findings indicate that a relatively small number of genes may be involved in the clinical manifestation of HIDS, with low-penetrance TNFRSF1A variants possibly influencing the HIDS phenotype or MVK mutations contributing to TRAPS.

Microsatellite instability, loss of heterozygosity, and loss of hMLH1 and hMSH2 protein expression in endometrial carcinoma.

Microsatellite instability (MSI) due to replication errors occurs frequently in hereditary tumors. Association with functional inactivation of the mismatch repair (MMR) genes and lack of protein expression has been described. In endometrial carcinoma (EC), the prevalence and clinical significance of these phenomena are not well known. Therefore, DNA samples from 89 EC and 5 metachronous tumors were analyzed with polymerase chain reaction, using 5 microsatellite markers and a DNA sequencer for amplicon detection. The results were correlated with immunohistochemistry of hMLH1 and hMSH2. MSI at >or=2 loci (MSI-H) was detected in 10/89 EC (11%); 1 of 10 showed loss of both hMLH1 and hMSH2, and 5 of 10 showed loss of hMLH1 (P < 0.0001). MSI-H was observed frequently in tumors with mucinous differentiation (P = 0.048), >10% of solid-cribriform pattern (P = 0.037), International Federation of Obstetrics and Gynecology (FIGO) stage III to IV (4 of 13; P = 0.016), and necrosis >5% (P = 0.07). Loss of heterozygosity (LOH) in >or=1 loci was found in 17 of 156 (11%). Survival (Kaplan-Meier) was longer for patients with endometrioid tumors with predominant glandular pattern, <5% necrosis, low FIGO stage and grade, superficial myometrial infiltration, no lymph-vascular invasion (LVI), and loss of hMLH1 expression (all P