Impact of Delay in Diagnosis in Outcomes in MEN1: Results From the Dutch MEN1 Study Group

Abstract Objective: Identifying a germline mutation in the multiple endocrine neoplasia type 1 (MEN1) gene in an index case has consequences for a whole family. Eligible family members should be offered genetic counseling and MEN1 mutation testing. Subsequently, clinical screening of mutation carriers according to the guidelines should be initiated. We assessed whether there is a lag time from MEN1 diagnosis of the index case to MEN1 diagnosis of family members. In addition, we determined whether this lag time was associated with an increased morbidity and mortality risk. Design: A cohort study was performed using the Dutch MEN1 database, including >90% of the Dutch MEN1 population >16 years of age (n = 393). Results: Fifty-eight MEN1 families were identified, of whom 57 were index cases and 247 were non-index cases (n = 304). The median lag time in MEN1 diagnosis of family members was 3.5 (range, 0–30) years. At the time of MEN1 diagnosis, 30 (12.1%) non-index cases had a duodenopancreatic neuroendocrine tumor, of whom 20% had metastases with a mean lag time of 10.9 years, in comparison with 7.1 years without metastases. Twenty-five (10.1%) non-index cases had a pituitary tumor, of whom 80% had a microadenoma and 20% had a macroadenoma, with mean lag times of 7.2 and 10.6 years, respectively. Ninety-five (38.4%) non-index cases had a primary hyperparathyroidism with a mean lag time of 9.5 years in comparison with seven patients without a primary hyperparathyroidism with a mean lag time of 3 years (P = .005). Ten non-index cases died because of a MEN1-related cause that developed during or before the lag time. Conclusion: There is a clinically relevant delay in MEN1 diagnosis in families because of a lag time between the diagnosis of an index case and the rest of the family. More emphasis should be placed on the conduct of proper counseling and genetic testing in all eligible family members.

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A new mutation of the MEN1 gene in an italian kindred with multiple endocrine neoplasia type 1

Acta Endocrinologica ◽

10.1530/eje.0.1400429 ◽

1999 ◽

pp. 429-433 ◽

Cited By ~ 10

Author(s):

F Cetani ◽

E Pardi ◽

L Cianferotti ◽

E Vignali ◽

A Picone ◽

...

Keyword(s):

Primary Hyperparathyroidism ◽

Multiple Endocrine Neoplasia ◽

Restriction Site ◽

Multiple Endocrine Neoplasia Type ◽

Family Members ◽

New Mutation ◽

Men1 Gene ◽

Endocrine Neoplasia ◽

Exon 9

OBJECTIVE: To report a new mutation of the multiple endocrine neoplasia type 1 (MEN1) gene in an Italian kindred. DESIGN: The study included the female proband, aged 50 years, affected by primary hyperparathyroidism, insulinoma and prolactinoma, and ten relatives. Blood samples were obtained for biochemical and genetic analyses. Clinical screening tests included serum glucose, ionized calcium, intact parathyroid hormone, GH, insulin and prolactin. The coding sequence, including nine coding exons and 16 splice sites, was amplified by PCR and directly sequenced. RESULTS: Two additional cases of primary hyperparathyroidism were identified among the paternal family members. The sequence analysis showed a heterozygous T to C transition at codon 444 in exon 9, resulting in a leucine to proline substitution (L444P) in the patient and in the two paternal family members with primary hyperparathyroidism. The L444P amino acid change was absent in 50 normal subjects. The mutation determined the loss of a BlnI restriction site of the wild-type sequence and the creation of a new restriction EcoRII site. The patient, but not her paternal affected relatives, also had a common heterozygous polymorphism (D418D) in exon 9. CONCLUSIONS: A new MEN1 mutation (L444P) in exon 9 has been identified; this substitution caused the loss of a BlnI restriction site and the creation of a new EcoRII site.

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Familial isolated primary hyperparathyroidism--a multiple endocrine neoplasia type 1 variant?

Acta Endocrinologica ◽

10.1530/eje.0.1450155 ◽

2001 ◽

pp. 155-160 ◽

Cited By ~ 35

Author(s):

S Miedlich ◽

T Lohmann ◽

U Schneyer ◽

P Lamesch ◽

R Paschke

Keyword(s):

Parathyroid Hormone ◽

Primary Hyperparathyroidism ◽

Multiple Endocrine Neoplasia ◽

Multiple Endocrine Neoplasia Type ◽

Family Members ◽

Statistical Comparison ◽

Men1 Gene ◽

Men 1 ◽

Endocrine Neoplasia

OBJECTIVE: Familial isolated primary hyperparathyroidism (FIHP) is defined as hereditary primary hyperparathyroidism without the association of other diseases or tumors. Linkage analyses suggest that different genotypes can lead to the same phenotype of primary hyperparathyroidism. Hereditary syndromes associated with primary hyperparathyroidism are multiple endocrine neoplasia type 1 and type 2 (MEN 1 and MEN 2). In MEN 1, multiple parathyroid adenomas occur in more than 90% of the patients. Therefore, it has been suggested that FIHP could represent a variant or partial expression of MEN 1. DESIGN: We report on a large FIHP kindred with a MEN1 gene mutation. Nineteen family members (aged 10 to 87 years) were screened. Furthermore, statistical comparison by Fisher's exact tests of FIHP families with MEN1 gene mutations and MEN 1 families with two or more endocrinopathies was carried out to investigate genotype-phenotype correlations. METHODS: Mutational analysis of leucocyte DNA was carried out by direct sequencing of the complete coding region of the MEN1 gene. Screening of MEN 1 manifestations was carried out by determination of serum calcium, phosphate, parathyroid hormone, prolactin, ACTH, cortisol, IGF-I, gastrin, glucose, insulin, glucagon, serum potassium, aldosterone, plasma renin and urinary hydroxyindoleacetic acid. RESULTS: We detected an in-frame deletion mutation in exon 8 of the MEN1 gene resulting in the deletion of one glutamine acid residue at position 363. It was found in eight individuals. Two of these family members (aged 42 and 60 years) were operated for primary hyperparathyroidism, and three (aged 13 to 40 years) showed mild hypercalcemia and parathyroid hormone levels within the upper normal range or slightly elevated, without any clinical symptoms. Two individuals (aged 12 and 19 years) were normocalcemic. One could not be tested. None of them had clinical evidence of other MEN 1 manifestations. Statistical comparison of the mutation types in families with FIHP and families with two or more MEN 1-associated endocrinopathies reported in other studies reveals a significant difference. In families with FIHP, missense/in-frame mutations have been found in 87.5% of cases whereas in families with tumors in various endocrine glands these mutation types occur much less frequently (21-34%, P<0.05). CONCLUSIONS: These studies indicate that FIHP can represent a partial MEN 1 variant and is often caused by missense/in-frame mutations.

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Detection of a Novel Nonsense Mutation of the MEN1 Gene in a Familial Multiple Endocrine Neoplasia Type 1 Patient and its Screening in the Family Members.

Endocrine Journal ◽

10.1507/endocrj.45.653 ◽

1998 ◽

Vol 45 (5) ◽

pp. 653-657 ◽

Cited By ~ 2

Author(s):

SHUJI MATSUBARA ◽

MAKOTO SATO ◽

HIDEMI OHYE ◽

YOSHIYASHU IWATA ◽

HITOMI IMACHI ◽

...

Keyword(s):

Nonsense Mutation ◽

Multiple Endocrine Neoplasia ◽

Multiple Endocrine Neoplasia Type ◽

Family Members ◽

Men1 Gene ◽

Endocrine Neoplasia ◽

Endocrine Neoplasia Type ◽

The Family

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Secondary attack rates of COVID-19 in Norwegian families: a nation-wide register-based study

European Journal of Epidemiology ◽

10.1007/s10654-021-00760-6 ◽

2021 ◽

Author(s):

Kjetil Telle ◽

Silje B. Jørgensen ◽

Rannveig Hart ◽

Margrethe Greve-Isdahl ◽

Oliver Kacelnik

Keyword(s):

Young Children ◽

Index Case ◽

Family Members ◽

Age Group ◽

Older Children ◽

Index Child ◽

Individual Level ◽

The Family ◽

Index Cases ◽

Index Family

AbstractTo characterize the family index case for detected SARS-CoV-2 and describe testing and secondary attack rates in the family, we used individual-level administrative data of all families and all PCR tests for SARS-CoV-2 in Norway in 2020. All families with at least one parent and one child below the age of 20 who lived at the same address (N = 662,582), where at least one member, i.e. the index case, tested positive for SARS-CoV-2 in 2020, were included. Secondary attack rates (SAR7) were defined as the share of non-index family members with a positive PCR test within 7 days after the date when the index case tested positive. SARs were calculated separately for parent- and child-index cases, and for parent- and child-secondary cases. We identified 7548 families with an index case, comprising 26,991 individuals (12,184 parents, 14,808 children). The index was a parent in 66% of the cases. Among index children, 42% were in the age group 17–20 and only 8% in the age group 0–6. When the index was a parent, SAR7 was 24% (95% CI 24–25), whilst SAR7 was 14% (95% CI 13–15) when the index was a child. However, SAR7 was 24% (95% CI 20–28) when the index was a child aged 0–6 years and declined with increasing age of the index child. SAR7 from index parent to other parent was 35% (95% CI 33–36), and from index child to other children 12% (95% CI 11–13). SAR7 from index child aged 0–6 to parents was 27% (95% CI 22–33). The percent of non-index family members tested within 7 days after the index case, increased from about 20% in April to 80% in December, however, SAR7 stabilized at about 20% from May. We conclude that parents and older children are most often index cases for SARS-CoV-2 in families in Norway, while parents and young children more often transmit the virus within the family. This study suggests that whilst the absolute infection numbers are low for young children because of their low introduction rate, when infected, young children and parents transmit the virus to the same extent within the family.

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Secondary Attack Rates of COVID-19 in Norwegian Families: A Nation-Wide Register-Based Study

10.21203/rs.3.rs-378113/v1 ◽

2021 ◽

Author(s):

Kjetil Telle ◽

Silje B. Jørgensen ◽

Rannveig Hart ◽

Margrethe Greve-Isdahl ◽

Oliver Kacelnik

Keyword(s):

Young Children ◽

Index Case ◽

Family Members ◽

Age Group ◽

Older Children ◽

Index Child ◽

Individual Level ◽

The Family ◽

Index Cases ◽

Index Family

Abstract To characterize the family index case for detected SARS-CoV-2 and describe testing and secondary attack rates in the family, we used individual-level administrative data of all families and all PCR tests for SARS-CoV-2 in Norway in 2020. All families with at least one parent and one child below the age of 20 who lived at the same address (N=662 582), where at least one member, i.e. the index case, tested positive for SARS-CoV-2 in 2020, were included. Secondary attack rates (SAR7) were defined as the share of non-index family members with a positive PCR test within seven days after the date when the index case tested positive. SARs were calculated separately for parent- and child-index cases, and for parent- and child-secondary cases. We identified 7548 families with an index case, comprising 26 991 individuals (12184 parents, 14808 children). The index was a parent in 66% of the cases. Among index children, 42% were in the age group 17-20 and only 8% in the age group 0-6. When the index was a parent, SAR7 was 24% (95%CI 24 to 25), whilst SAR7 was 14% (95%CI 13 to 15) when the index was a child. However, SAR7 was 24% (95%CI 20 to 28) when the index was a child aged 0-6 years and declined with increasing age of the index child. SAR7 from index parent to other parent was 35% (95%CI 33 to 36), and from index child to other children 12% (95%CI 11 to 13). SAR7 from index child aged 0-6 to parents was 27% (95%CI 22 to 33). The percent of non-index family members tested within 7 days after the index case, increased from about 20% in April to 80% in December, however, SAR7 stabilized at about 20% from May. We conclude that parents and older children are most often index cases for SARS-CoV-2 in families in Norway, while parents and young children more often transmit the virus within the family. This study suggests that whilst the absolute infection numbers are low for young children because of their low introduction rate, when infected, young children and parents transmit the virus to the same extent within the family.

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A clinicoepidemiological study of familial leprosy

IP Indian Journal of Clinical and Experimental Dermatology ◽

10.18231/j.ijced.2021.049 ◽

2021 ◽

Vol 7 (3) ◽

pp. 260-264

Author(s):

Dilip Kumar N R ◽

Shashikiran A R ◽

Laxmi B Horatti

Keyword(s):

Index Case ◽

Family Members ◽

World Health ◽

The Family ◽

Study Population ◽

Health Organization ◽

Multibacillary Leprosy ◽

Very High ◽

Index Cases ◽

Close Contacts

: Hansen’s disease (also known as leprosy) is an infection caused by Mycobacterium leprae which can affect the skin, mucous membranes and nerves. It is known to spread among and infect family members. There are very few published studies pertaining to family leprosy conducted in India and worldwide. : To find the prevalence of familial leprosy and to know the clinicoepidemiological patterns of these cases.: Observational study.: This was a descriptive study conducted for a period of five years from 2013-2018. The study population included all new documented cases of leprosy visiting our out-patient department during the study period. All the patients were diagnosed as leprosy on histopathological confirmation or by the presence of cardinal signs of leprosy according to the world health organization (WHO) definition. The data collected was analysed by simple descriptive statistics. Permission to conduct the study was taken from institutional ethical committee. Consent was taken from index case and family members.: A total of 302 new leprosy cases with 18 index cases (n=18) whose family members were affected, accounting for the prevalence of 5.96 %. Total number of family members with documented leprosy (old or newly detected) was 26. So, the total number of leprosy cases were 44 (index cases + family members). Out of the 18 families, 4 families had more than one person who was affected. 8 cases (18.18%) of Childhood leprosy were noted. Among the index cases 4 cases (22%) of paucibacillary leprosy were seen and 14 cases (78%) of multibacillary leprosy was seen. Among the family members, 18 cases of paucibacillary leprosy were seen and 8 cases of multibacillary leprosy were seen. Conjugal leprosy was seen in 10 families accounting for the prevalence of 3.31%. : Our study intends to emphasize the importance of examining the close contacts of a case of leprosy, especially the family members in whom the incidence of leprosy could be very high. By way of identifying leprosy cases early in its course we may be able to prevent deformities to a great extent.

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Secondary attack rates of COVID-19 in Norwegian families: A nation-wide register-based study

10.1101/2021.03.06.21252832 ◽

2021 ◽

Author(s):

Kjetil Telle ◽

Silje B. Jørgensen ◽

Rannveig Hart ◽

Margrethe Greve-Isdahl ◽

Oliver Kacelnik

Keyword(s):

Young Children ◽

Index Case ◽

Family Members ◽

Control Measures ◽

Older Children ◽

Index Child ◽

Individual Level ◽

The Family ◽

Index Cases ◽

Index Family

Background Reported transmission rates of SARS-CoV-2 within families vary widely, and there are few reports on transmission from children to other family members. More knowledge is needed to guide infection control measures. Objective To characterize the family index case for detected SARS-CoV-2 and describe testing and secondary attack rates in the family. Design Register-based cohort study. Setting Individual-level administrative data of all families and all PCR tests for SARS-CoV-2 in Norway in 2020. Participants All families with at least one parent and one child below the age of 20, who lived at the same address (N=662 582), where at least one member tested positive for SARS-CoV-2 in 2020. Main outcome measures Secondary attack rates (SAR7) were defined as the share of non-index family members with a positive PCR test within seven days of the index case. SARs were calculated separately for parent- and child-index cases, and for parent- and child-secondary cases. Results We identified 7548 index cases, comprising 26 991 individuals, of which 12184 were parents and 14808 children. The index was a parent in 66% of the cases. Among the children, 42% of the index cases were in the age group 17-20 and only 8% 0-6 years. When the index was a parent, SAR7 was 24% (95%CI 24 to 25), whilst SAR7 was 14% (95%CI 13 to 15) when the index was a child. However, SAR7 was 24% (95%CI 20 to 28) when the index was a child aged 0-6 years and declined steeply with increasing age of the index child. SAR7 from index parent to other parents was 35% (95%CI 33 to 36), and from index child to other children 12% (95%CI 11 to 13). SAR7 from index child aged 0-6 to parents was 27% (95%CI 22 to 33). The percent of non-index family members tested within 7 days after the index case, increased from about 20% in April to 80% in December, however, SAR7 stabilized at about 20% from May. Conclusion Parents and older children are most often index cases for SARS-CoV-2 in families in Norway, while parents and young children more often transmit the virus within the families. This study suggests that whilst the absolute infection numbers are low for young children because of their low introduction rate, when infected, young children and parents transmit the virus to the same extent within the family.

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Prevalence of multiple endocrine neoplasia type 1 syndrome in primary hyperparathyroidism

Endocrine Abstracts ◽

10.1530/endoabs.31.p162 ◽

2013 ◽

pp. 1-1

Author(s):

Sunil Kumar Kota ◽

Lalit Kumar Meher ◽

Sruti Jammula ◽

Kirtikumar D Modi

Keyword(s):

Primary Hyperparathyroidism ◽

Multiple Endocrine Neoplasia ◽

Multiple Endocrine Neoplasia Type ◽

Endocrine Neoplasia ◽

Endocrine Neoplasia Type

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Germline MEN1 mutations in sixteen Japanese families with multiple endocrine neoplasia type 1 (MEN1)

Acta Endocrinologica ◽

10.1530/eje.0.1410475 ◽

1999 ◽

pp. 475-480 ◽

Cited By ~ 28

Author(s):

N Hai ◽

N Aoki ◽

A Matsuda ◽

T Mori ◽

S Kosugi

Keyword(s):

Multiple Endocrine Neoplasia ◽

Multiple Endocrine Neoplasia Type ◽

Family Members ◽

Premature Stop Codon ◽

Germline Mutations ◽

Endocrine Tumors ◽

Men1 Gene ◽

Endocrine Neoplasia ◽

Endocrine Neoplasia Type

OBJECTIVE: Multiple endocrine neoplasia type 1 (MEN1) is a syndrome of endocrine tumors involving the parathyroids, anterior pituitary and enteropancreatic neuroendocrine tissues, and is inherited in an autosomal dominant manner. Recently, the gene responsible for this syndrome, MEN1, was positionally cloned in 11q13. We aimed to assess the significance of MEN1 gene diagnostics in families with MEN1. DESIGN: Sixteen probands of familial MEN1 and their 40 family members were subjected to the study. METHODS: Full-length sequencing of the open reading frame and exon-intron boundaries in the MEN1 gene was performed with probands of familial MEN1. Family members were examined for the identified mutation in the proband. RESULTS: We identified heterozygous germline mutations of the MEN1 gene in all of 16 Japanese MEN1 families examined, achieving the highest detectability of MEN1 mutations in familial MEN1 among studies that examined more than 10 families. Eleven kinds of the identified MEN1 germline mutations were novel. More than half were nonsense or frameshift mutations resulting in a premature stop codon (9/15; 60%), and no mutation hot spots or no apparent genotype-phenotype relationships were observed, in support of the results of other studies. We identified 40 mutant MEN1 gene carriers and 16 non-carriers in the course of the present study in those families. CONCLUSIONS: Analysis of the germline mutations in the MEN1 gene, providing significantly useful clinical information to probands and family members of MEN1, should be considered as a standard procedure and categorized as belonging to Group 1 cancer predisposition testing by the American Society of Clinical Oncology.

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