Management of Massive Hemoptysis with Oren Friedman

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Alexandros Sfakianakis
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The Penetrance of Paraganglioma and Pheochromocytoma in SDHB germline mutation carriers

Abstract

Germline mutations in SDHB predispose to hereditary paraganglioma syndrome type 4. The risk of developing paraganglioma (PGL) or pheochromocytoma (PHEO) in SDHB mutation carriers is subject of recent debate.

In the present nationwide cohort study of SDHB mutation carriers identified by the clinical genetics centers of the Netherlands, we have calculated the penetrance of SDHB associated tumors using a novel maximum likelihood estimator. This estimator addresses ascertainment bias and missing data on pedigree size and structure. 195 SDHB mutation carriers were included, carrying 27 different SDHB mutations. The 2 most prevalent SDHB mutations were Dutch founder mutations: a deletion in exon 3 (31% of mutation carriers) and the c.423+1G>A mutation (24% of mutation carriers). One hundred twelve carriers (57.4%) displayed no physical, radiological or biochemical evidence of PGL or PHEO. Fifty-four patients had a head and neck PGL (27.7%), 4 patients had a PHEO (2.1%), 26 patients an extra-adrenal PGL (13.3%). The overall penetrance of SDHB mutations is estimated to be 21% at age 50 and 42% at age 70 when adequately corrected for ascertainment.

These estimates are lower than previously reported penetrance estimates of SDHB-linked cohorts. Similar disease risks are found for different SDHB germline mutations as well as for male and female SDHB mutation carriers.

Graphical abstract

The overall penetrance of SDHB mutations is estimated to be 21% at age 50 and 42% at age 70 when adequately corrected for ascertainment.Similar disease risks are found for different SDHB germline mutations as well as for male and female SDHB mutation carriers.The maximum likelihood estimate of the age-related penetrance of SDHB mutations for paraganglioma and/or pheochromocytoma (continuous line) and 95% confidence interval (dashed line).

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Mismatch repair cancer syndrome (MMRCS) : Multiple hyperpigmented and hypopigmented skin areas, brain malformations, pilomatricomas, a second childhood malignancy, a Lynch syndrome (LS)-associated tumour in a relative and parental consanguinity.

http://sfaki.blogspot.com/2017/05/mismatch-repair-cancer-syndrome-mmrcs.html

Haematologica. 2010 May; 95(5): 699–701.

doi:  10.3324/haematol.2009.021626

PMCID: PMC2864372

Constitutional mismatch repair-deficiency syndrome

Katharina Wimmer1 and Christian P. Kratz2

1 Division of Human Genetics, Medical University Innsbruck, Innsbruck, Austria

2 Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD 20852, USA. E-mail: ta.ca.dem-i@remmiw.anirahtak

Katharina Wimmer, PhD, is Associate Professor at the Department for Medical Genetics, Molecular and Clinical Pharmacology, Medical University Innsbruck. She is supervising the onco-genetic laboratory for the diagnostics of cancer predisposition syndromes which are also her main research interest. Christian P. Kratz, M.D. is an investigator in the Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics at the National Cancer Institute, National Institutes of Health. His research focuses on individuals with inherited cancer predispositions.

Author information ▼ Copyright and License information ►

See "Constitutional mismatch repair deficiency and childhood leukemia/lymphoma – report on a novel biallelic MSH6 mutation" on page 841.

This article has been cited by other articles in PMC.

The mismatch repair (MMR) machinery contributes to genome integrity and the MLH1, MSH2, MSH6 and PMS2 genes play a crucial role in this process. MMR corrects single base-pair mismatches and small insertion-deletion loops that arise during replication. Moreover, the MMR system is involved in the cellular response to a variety of agents that damage DNA1 and in immunoglobulin class switch recombination.2 Heterozygous germline mutations in MLH1, MSH2, MSH6 and PMS2 cause Lynch syndrome (LS), an autosomal dominant cancer syndrome associated with hereditary non-polyposis colorectal cancer (HNPCC), endometrium carcinoma and other malignancies, occurring on average in the fourth and fifth decade of life. Notably, LS associated tumors display somatic loss of the remaining wild type MLH1, MSH2, MSH6 or PMS2 allele and evidence of microsatellite instability (for review see 3).

In contrast to individuals with LS who harbor a heterozygous mutant MMR gene allele, rare cases with biallelic deleterious germline mutations in MMR genes leading to constitutional mismatch repair-deficiency (CMMR-D) have been recognized since 1999.4,5 This cancer syndrome is characterized by a broad spectrum of early-onset malignancies and a phenotype that resembles neurofibromatosis type 1. In this issue of Haematologica, Ripperger and colleagues report on a patient with CMMR-D caused by a novel MSH6 mutation leading to a T-cell lymphoma and colonic adenocarcinoma at six and 13 years of age, respectively. In addition, they review 26 leukemia and/or lymphoma cases reported previously.6

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The clinical presentation and tumor spectrum of CMMR-D

Our knowledge of the CMMR-D syndrome originates primarily from the medical literature; consequently, potential publication bias must be kept in mind as we interpret these reports. Table 1 summarizes the malignancies observed in 89 reported6–11 and 3 unreported cases of CMMR-D. Neoplasms can be divided into four groups: (1) hematologic malignancies (reviewed in 6); (2) brain tumors; (3) LS-associated tumors; and (4) other malignancies. Notably, 31 out of the known 92 CMMR-D patients developed more than one malignancy, and in 19 cases the second or third neoplasm was an LS-associated tumor.

Table 1.

List of malignancies in 92 CMMR-D patients.

In some cases of CMMR-D, areas of skin hypo-pigmentation have been reported.12–15 However, signs reminiscent of neurofibromatosis type 1 (NF1), in particular café-aulait macules (CALMs), are much more common and were observed in the majority of the reported cases (63/92). There are only 2 patients explicitly reported to lack CALMs or other signs of NF1.9,13 Interestingly, several reports stress that CALMs in patients with CMMR-D differ from typical NF1-associated CALMs in that they vary in their degree of pigmentation, have irregular borders, and may display a segmental distribution. Other features of NF1 found in CMMR-D patients include skinfold freckling, Lisch nodules, neurofibromas and tibial pseudarthrosis. Hence, it is not surprising that a number of CMMR-D cases were initially diagnosed as having NF1. It has been speculated that the NF1-like clinical features in CMMR-D result from germline mosaicism arising early during embryonic development. The identification of a truncating NF1 mutation in the blood of one patient16 and data supporting the notion that the NF1 gene is a mutational target of MMR deficiency17 are in line with this assumption. However, extensive mutation analysis in other CMMR-D patients has not confirmed this theory (see 8,12,18 and papers cited therein).

Péron et al.2 have shown in 3 CMMR-D patients that constitutional PMS2 deficiency leads to impaired immunoglobulin class switch recombination characterized by increased serum IgM concomitant with decrease or absence of IgG2, IgG4, and IgA. Of note, one CMMR-D patient initially presented with a primary immunodeficiency,2 and patients with biallelic MSH2 and MSH6 mutations also show IgG2 and/or IgA deficiency 15,19,20. It remains to be seen whether defective IgA and IgG production is a common feature of CMMR-D. Fortunately, severe bacterial infections have not been reported to occur at high frequencies in persons with CMMR-D.

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Genotype-phenotype correlation of CMMR-D

A review of the literature suggests that the clinical features in patients with biallelic germline mutations of MLH1 or MSH2 differ from those with biallelic germline mutations of MSH6 or PMS2 (Table 2). Hematologic malignancies appear to occur more frequently in patients with MLH1 or MSH2 mutations than in patients with mutations of MSH6 or PMS2. In contrast, the latter group appears to have a higher prevalence of brain tumors. Furthermore, tumors tend to develop earlier in MLH1 or MSH2 mutation carriers than in patients with a mutation of MSH6 or PMS2. Patients with biallelic mutations in MSH6 or PMS2 are more likely to survive their first tumors and develop a second malignancy. Overall, the prevalence of LS-associated tumors is higher in patients with biallelic MSH6 or PMS2 mutations than in biallelic MLH1 or MSH2 mutation-positive individuals (Table 2). These factors facilitate the clinical diagnosis of CMMR-D in patients with mutations of MSH6 or PMS2 and may at least partly explain the preponderance of PMS2 mutations in published cases.

Table 2.

Differences in the overall tumor spectrum and age of malignancy onset between carriers of biallelic MLH1/MSH2 and MSH6/PMS2 mutations, respectively.

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Strategies for clinical and subsequent molecular diagnosis of CMMR-D

In view of the wide tumor spectrum that overlaps with Lynch and Turcot syndrome but also includes hematologic malignancies and embryonic tumors such as neuroblastoma, Wilms tumor and rhabdomyosarcoma (Table 1), CMMR-D should be considered in the differential diagnosis in all patients with malignancies (except clearly NF1-associated tumors) who show one or more of the following features: (1) CALMs and/or other signs of NF1 and/or hypo-pigmented skin lesions; (2) consanguineous parents; (3) family history of LS-associated tumors; (4) second malignancy; and (5) sibling with childhood cancer. It is important to note that especially in patients with PMS2 mutations, the family history will often not fulfill the Amsterdam or revised Bethesda criteria for LS.

Typically, confirmation of the diagnosis involves the analysis of microsatellite instability (MSI) and/or immunohistochemistry (IHC), followed by mutation analysis. MSI analysis follows current protocols used for LS-screening; however, this analysis may be unreliable in CMMR-D related brain tumors.7,11,21 IHC is a useful technique employed in patients with CMMR-D associated neoplasms including brain tumors and guides subsequent mutation analysis in the four MMR-genes. In general, a truncating mutation in PMS2 or MSH6 will result in isolated loss of these proteins, whereas a mutation in MLH1 or MSH2 will lead to concurrent loss of MLH1/PMS2 or MSH2/MSH6, respectively, since MLH1 and MSH2 are the obligatory partners in the formation of MLH1/PMS2 and MSH2/MSH6 heterodimers. Notably, in the case of an underlying missense mutation, IHC may show normal results. As CMMR-D patients constitutively lack the expression of one of the MMR genes, IHC detects loss in both neoplastic and non-neoplastic tissues. Conveniently, expression loss of one of the MMR genes can be demonstrated in blood lymphocytes (e.g. by Western blot 2). Similarly, it has been shown that MSI can be determined in normal non-neoplastic tissue of CMMR-D patients by analyzing DNA samples that are diluted to approximately 0–3 genome equivalents per PCR-reaction.22 Nonetheless, standardized procedures for the detection of MMR expression loss and MSI in non-neoplastic tissue from CMMR-D patients have not been developed to date. The diagnosis of CMMR-D should be confirmed by gene-specific mutation analysis. Reliable methods for all four MMR genes including PMS2 are now available.12 Mutation analysis will facilitate identification and surveillance of heterozygous and homozygous individuals in the wider family, and allow for informed decision-making about prenatal or pre-implantation genetic diagnosis.

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Treatment and surveillance of the patient and counseling of relatives

Genetic counseling should be offered to the parents prior to testing of the affected child, and should include information on the potential 25% recurrence risk and on the clinical consequences of a possible heterozygous mutation in both parents. Predictive testing following the established interdisciplinary counseling guidelines should be offered to all family members once a mutation has been identified. Heterozygous family members should be followed according to current LS-guidelines.23

Because of the wide spectrum of malignancies in CMMR-D patients, defining recommendations for surveillance of affected patients remains a challenge. Early diagnosis of CMMR-D and subsequent cancer screening at regular intervals may increase the likelihood of detecting associated cancers, such as colon cancer or brain tumors, at an operable stage. In theory, this screening could include regular exams such as: (1) clinical evaluation; (2) blood tests with full blood count and carcinoembryonic antigen (CEA); (3) magnetic resonance imaging of the brain; (4) endoscopic examination of the gastrointestinal tract; and (5) endometrial sampling and transvaginal ultrasound for endometrial and ovarian cancer. However, these recommendations rest only on clinical judgment and do not represent a standard of care. To date there is no available evidence to support any of these recommendations or to provide guidance on the optimal frequency of such tests. Likewise, there is currently no information available regarding the optimal treatment of CMMR-D patients. Several reports stress that careful attention should be given to the possibly increased cyto-toxicity and reduced efficacy of chemotherapeutic agents due to constitutionally impaired mutation repair, and the high risk of a second malignancy 6,8,14,15.

Reports such as the article by Ripperger and colleagues are valuable in increasing awareness and knowledge of the syndrome in the clinical community. Nevertheless, systematic studies are needed in order to better define the phenotype of MMR-D. Data related to cancer screening, treatment and outcome should be collected and evaluated systematically to provide a basis for recommendations on how to manage patients with CMMR-D.

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Footnotes

( Related Original Article on page 841)

We thank Drs. Anne Durandy and Johannes Zschocke for their helpful comments on the manuscript. Dr. Kratz's work was supported by the Intramural Research Program of the US National Cancer Institute.

No potential conflict of interest relevant to this article was reported.

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References

1. Jiricny J. The multifaceted mismatch-repair system. Nat Rev Mol Cell Biol. 2006;7(5):335–46. [PubMed]

2. Peron S, Metin A, Gardes P, Alyanakian MA, Sheridan E, Kratz CP, et al. Human PMS2 deficiency is associated with impaired immunoglobulin class switch recombination. J Exp Med. 2008;205(11):2465–72. [PMC free article] [PubMed]

3. Peltomaki P. Role of DNA mismatch repair defects in the pathogenesis of human cancer. J Clin Oncol. 2003;21(6):1174–9. [PubMed]

4. Ricciardone MD, Ozcelik T, Cevher B, Ozdag H, Tuncer M, Gurgey A, et al. Human MLH1 deficiency predisposes to hematological malignancy and neurofibromatosis type 1. Cancer Res. 1999;59(2):290–3. [PubMed]

5. Wang Q, Lasset C, Desseigne F, Frappaz D, Bergeron C, Navarro C, et al. Neurofibromatosis and early onset of cancers in hMLH1-deficient children. Cancer Res. 1999;59(2):294–7. [PubMed]

6. Ripperger T, Beger C, Rahner N, Sykora KW, Bockmeyer CL, Lehmann U, et al. Constitutional mismatch repair deficiency and childhood leukemia/lymphoma - report on a novel biallelic MSH6 mutation. Haematologica. 2009 Dec 16; [Epub ahead of print] [PMC free article] [PubMed]

7. Giunti L, Cetica V, Ricci U, Giglio S, Sardi I, Paglierani M, et al. Type A microsatellite instability in pediatric gliomas as an indicator of Turcot syndrome. Eur J Hum Genet. 2009;17(7):919–27. [PMC free article] [PubMed]

8. Peters A, Born H, Ettinger R, Levonian P, Jedele KB. Compound heterozygosity for MSH6 mutations in a pediatric lymphoma patient. J Pediatr Hematol Oncol. 2009;31(2):113–5. [PubMed]

9. Sjursen W, Bjornevoll I, Engebretsen LF, Fjelland K, Halvorsen T, Myrvold HE. A homozygote splice site PMS2 mutation as cause of Turcot syndrome gives rise to two different abnormal transcripts. Fam Cancer. 2009;8(3):179–86. [PubMed]

10. Toledano H, Goldberg Y, Kedar-Barnes I, Baris H, Porat RM, Shochat C, et al. Homozygosity of MSH2 c.1906G-->C germline mutation is associated with childhood colon cancer, astrocytoma and signs of Neurofibromatosis type I. Fam Cancer. 2009;8(3):187–94. [PubMed]

11. Wimmer K, Etzler J. Constitutional mismatch repair-deficiency syndrome: have we so far seen only the tip of an iceberg? Hum Genet. 2008;124(2):105–22. [PubMed]

12. Etzler J, Peyrl A, Zatkova A, Schildhaus HU, Ficek A, Merkelbach-Bruse S, et al. RNA-based mutation analysis identifies an unusual MSH6 splicing defect and circumvents PMS2 pseudogene interference. Human Mut. 2008;29(2):299–305. [PubMed]

13. Rahner N, Hoefler G, Hogenauer C, Lackner C, Steinke V, Sengteller M, et al. Compound heterozygosity for two MSH6 mutations in a patient with early onset colorectal cancer, vitiligo and systemic lupus erythematosus. Am J Med Genet A. 2008;146A(10):1314–9. [PubMed]

14. Scott RH, Homfray T, Huxter NL, Mitton SG, Nash R, Potter MN, et al. Familial T-cell non-Hodgkin lymphoma caused by biallelic MSH2 mutations. J Med Genet. 2007;44(7):e83. [PMC free article] [PubMed]

15. Scott RH, Mansour S, Pritchard-Jones K, Kumar D, MacSweeney F, Rahman N. Medulloblastoma, acute myelocytic leukemia and colonic carcinomas in a child with biallelic MSH6 mutations. Nat Clin Pract Oncol. 2007;4(2):130–4. [PubMed]

16. Alotaibi H, Ricciardone MD, Ozturk M. Homozygosity at variant MLH1 can lead to secondary mutation in NF1, neurofibromatosis type I and early onset leukemia. Mutat Res. 2008;637(1–2):209–14. [PubMed]

17. Wang Q, Montmain G, Ruano E, Upadhyaya M, Dudley S, Liskay RM, et al. Neurofibromatosis type 1 gene as a mutational target in a mismatch repair-deficient cell type. Hum Genet. 2003;112(2):117–23. [PubMed]

18. Auclair J, Leroux D, Desseigne F, Lasset C, Saurin JC, Joly MO, et al. Novel biallelic mutations in MSH6 and PMS2 genes: gene conversion as a likely cause of PMS2 gene inactivation. Hum Mutat. 2007;28(11):1084–90. [PubMed]

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23. Vasen HF, Moslein G, Alonso A, Bernstein I, Bertario L, Blanco I, et al. Guidelines for the clinical management of Lynch syndrome (hereditary non-polyposis cancer) J Med Genet. 2007;44(6):353–62. [PMC free article] [PubMed]

Articles from Haematologica are provided here courtesy of Ferrata Storti Foundation

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com

Technology: Nucleic acid detection — it's elementary with SHERLOCK!

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The evolutionary significance of polyploidy

Polyploidy occurs frequently but is usually detrimental to survival; thus, few polyploids survive in the long term. Here, evidence linking the short-term evolutionary success of polyploids to environmental upheaval is reviewed and possible longer-term evolutionary benefits of polyploidy are discussed.

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WDR45B-related intellectual disability, spastic quadriplegia, epilepsy, and cerebral hypoplasia: a consistent neurodevelopmental syndrome

Abstract

The advancement in genomic sequencing has greatly improved the diagnostic yield for neurodevelopmental disorders and led to the discovery of large number of novel genes associated with these disorders. WDR45B has been identified as a potential intellectual disability gene through genomic sequencing of two large cohorts of affected individuals. In this report we present six individuals from three unrelated families with homozygous pathogenic variants in WDR45B: c.799C>T (p.Q267*) in one family and c.673C>T (p.R225*) in two families. These individuals shared a similar phenotype including profound development delay, early-onset refractory epilepsy, progressive spastic quadriplegia and contractures, and brain malformations. Neuroimaging showed ventriculomegaly, reduced cerebral white matter volume, and thinning of cerebral gray matter. The consistency in the phenotype strongly supports that WDR45B is associated with this disease.

Graphical abstract

WDR45B-related intellectual disability, spastic quadriplegia, epilepsy, and cerebral hypoplasia syndrome

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Constitutional mismatch repair deficiency in a healthy child: on the spot diagnosis?

Abstract

Constitutional mismatch repair deficiency (CMMRD) is a rare, recessively inherited childhood cancer predisposition syndrome caused by bi-allelic germline mutations in one of the mismatch repair genes. The CMMRD phenotype overlaps with that of neurofibromatosis type 1 (NF1), since many patients have multiple café-au-lait macules (CALM) and other NF1 signs, but no germline NF1 mutations.

We report of a case of a healthy six-year-old girl who fulfilled the diagnostic criteria of NF1 with >6 CALM and freckling. Since molecular genetic testing was unable to confirm the diagnosis of NF1 or Legius syndrome and the patient was a child of consanguineous parents, we suspected CMMRD and found a homozygous PMS2 mutation that impairs MMR function.

Current guidelines advise testing for CMMRD only in cancer patients. However, this case illustrates that including CMMRD in the differential diagnosis in suspected sporadic NF1 without causative NF1 or SPRED1 mutations may facilitate identification of CMMRD prior to cancer development. We discuss the advantages and potential risks of this CMMRD testing scenario.

Graphical abstract

CMMRD diagnosis in a child with café-au-lait macules and axillary freckling, but without malignancies: raising the question of when to test a healthy child.

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