GENETIC SYNDROMES: CLINICAL FEATURES

Gregory Kaltsas MD FRCPEKPA-LAIKO ENETS Center of Excellence

Endocrinology Unit

National University of Athens

Greece

DISCLOSURE OF INTEREST

Honorarium : IPSEN

Departmental Research Grants: IPSEN, NOVARTIS, PFIZER, SHIRE, SANOFI

GENETIC SYNDROMES AND NEUROENDOCRINE

NEOPLASMS

� Multiple Endocrine Neoplasia 1 (MEN 1)

� Von Hippel Lindau (VHL)

� Tuberous Sclerosis (TS)

� Neurofibromatosis type 1 (NF1)

� Carneys Complex

DISTINCTIVE FEATURES OF NEOPLASMS IN GENETIC

SYNDROMES

� Many organs involved

� Multiple tumors

� Precursor hyperplasia

� Different time of evolution

� Young age presentation

� Inherited

CLINICAL COMPONENTS OF MEN 1ENDOCRINE NON-ENDOCRINE

1. Parathyroid hyperplasia - adenomas (95%) Face angiofibromas (85%)

2. Enteropancreatic Tumors (multiple) (40-70%) Collagenomas (70%)

- Gastrinomas (20-35%) Lipomas (30%)

- Insulinomas (10%) Leiomyomas (5%)

- Non Functioning tumors and PPomas (>55%) Meningiomas (8%)

- VIPomas, Glucagonomas, Somatistatinomas (each <2%) Ependymomas (<1%)

3. Anterior Pituitary Tumors (30-40%)

- Prolactinomas (20-30%)

- GH-secreting adenomas (10-20%) - mixed PRL/GH (5%)

- Non functioning adenomas (50%), ACTH-secreting adenomas (<5%), TSH-

secreting adenomas (rare)

4. Adrenal Neoplasms (30-40%)

- Cortex: Non functioning adenomas (30%)

Functioning adenomas or Carcinomas (2%)

- Medulla: Pheochromocytomas (<1%)

5. Foregut Carcinoids

- Thymic (2%)

- Bronchial (4%)

- Gastric Type II (ECLomas) (10%)

M

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JCEM 2012, 97: 2990-3011

MEN1: Clinical phenotype

LipomaLipoma

Collagenoma

Angiofibroma

LESS COMMON CLINICAL PHENOTYPES

Meningioma

Ependymoma

EPIDEMIOLOGY

� Post-mortem 0.25%

� Incidence: 1/10,000 to 1/100,000

� High penetranceo Age range 5 to 81 yr

o Penetrance of MEN1 by the ages of

o 20 years: 43%

o 35 years: 85%

o 50 years: 94%

o 80% (clinical) - 98% (biochemical) by the 5th decade

� 1-18% of PHP patients will have MEN 1

� 16-38% of Gastrinomas are due to MEN 1

� <3% of pituitary tumors in the context of MEN 1

JCEM 2012, 97: 2990-3011

MEN 1 DIAGNOSIS

Basis for MEN 1 Diagnosis

Clinical Familial Genetic

A patient with ≥2

MEN-1 associated

tumors

A patient with 1

MEN-1 associated

tumor and a 1st

degree relative with

MEN 1

An individual who has a

MEN 1 mutation but

does not have clinical or

biochemical

manifestations of MEN 1

(a mutant gene carrier)

JCEM 2012, 97: 2990-3011

MEN 1 GENE (TUMOR SUPPRESSOR GENE)

Exon size 468bp 209bp 128bp 42bp 88bp 137bp 136bp 165bp 1297bp

Intron size 1564bp 210bp 331bp 80bp 639bp 461bp 437bp 217bp

1 2 3 4 5 6 7 8 9 1010

>1000 mutations identified but no hot spot mutations

� Genomic MEN1: point mutations/deletions.

� 75% inactivating consistent with tumor suppressor gene

� Sporadic MEN1: 90% LOH, 10% (point mutation, small deletion/insertion)

� MEN1

� 10% de novo mutations germline (missense/in-frame deletions)

� 5-25% no mutations coding regions (MLPA)

STEPS IN ONCOGENESIS IN CARRIERS OF MUTATED

MEN 1 GENE

Chromosome 11

Normal copy

Mutated copy

11q13 locusOR

DeletionPoint Mutation

(missense, nonsense)

Mutant menin gene is inherited by an

affected progenitor or arises de novo (10%)

and is present in all cells of the body. The

normal allele produces sufficient amounts of

the menin protein so that its tumor

suppressor effect is present in all apparent

‘’normal’’ cells

In some cells a somatic

deletion/mutation of the normal

allele causes total loss of function

of the menin gene (no functional

gene product or truncated protein)

+ Mutations of

other genes?

Carrying 1

mutated

(germline) and

1 normal allele

Carrying 2

mutated alleles (1

germline - 1

somatic)

MEN 1 VARIANTS

o Families MEN1 only some manifestations of the syndrome

� Familial isolated hyperparathyroidism (FIHP)

� 42 FIHP kindreds

� 38% missense & 31% nonsense vs. 65% nonsense & 23% missense

� MEN1 prolactinoma (Burin) variant (nonsense mutation)

� High occurrence prolactinomas

� Low occurrence of gastrinomas

� MEN1 kindred Tasmania (splice variant mutation)

MEN 1 MUTATIONS IN CLINICAL PRACTICE

� Aid in confirming the diagnosis

� Identify mutation carriers in a family for screening and tumor

development

� Facilitate early treatment

� Identify 50% of family members not MEN 1 mutation

� Test as early as possible (<5 year for asymptomatic patients)

WHO SHOULD BE TESTED ?

� In an index case� Meeting clinical criteria MEN1 (2 or more MEN1-associated tumors or familial MEN1)

� Suspicious

� Multiple parathyroid adenomas < 40 years

� Recurrent hyperparathyroidism

� Gastrinomas or multiple panNENs at any age

� Atypical MEN1 (2 non-classical MEN1 tumors)

� A first degree relative of family MEN1 mutation

� A first-degree relative of family member with known MEN1 mutation� Asymptomatic first degree relative

� First degree relative with familial MEN1 (one MEN1 associated tumor)

PARATHYROID GLAND INVOLVEMENT

� Most common pathology MEN1

� Usually first manifestation (90% by age 30 years)

� Asymptomatic or symptomatic (mild hyperCa or PU)

� Earlier age of onset (25 yr vs. 55 yr)

� Greater BMD reduction

� Equal male/female ratio (1/1 vs. 1/3)

� Involvement of all parathyroid glands

� Only 3 patients with germline MEN1 mutations parathyroid carcinoma (+2)

Int J Surg 2016, 31, 10-16Int J Surg 2016, 31, 10-16

DIAGNOSIS

� Preoperative studies may be of limited benefit due to involvement of all

glands

� Neck exploration irrespective of pre-operative localization studies

PITUITARY TUMORS

� Macroadenomas (>1cm)

� (F>M) : 85% vs. 42%

� 60% PRL

� 25% GH

� 5% ACTH

� 15-25% NFPA

� Plurihormonal

� Occasional hyperplasia

� 30% invasive features

Age of onset: 5 - 85 yr (38 ± 15.3)

n Sex

Type Microadenoma Macroadenoma NA

PRL 52 38 30 20 2

GH 8 6 2 6

ACTH 4 0 4

LH/FSH 2 2 1 1

Pluri 5 4 5

NFPA 52 28 39 13

JCEM 2015, 100: 3288-3296JCEM 2015, 100: 3288-3296

Long term natural course pituitary tumors

Ducth MEN1

Long term natural course pituitary tumors

Ducth MEN1

PANCREATIC NEUROENDOCRINE NEOPLASMS (PANNEN)

� Earlier age & multiple

� Non-functioning tumors (>55%)

� Functioning

� Gastrinomas

� Insulinomas

� VIPomas

� Glucagonomas

Age range (yr) panNEN NF panNEN

20 9% 3%

50 53% 34%

80 84% 54%

CHARACTERISTICS OF PATIENTS WITH NF-PANNEN

Characteristics (mean ±±±± SD, range) Value

Age at MEN1 diagnosis 36.2±±±±14 (13-73)

Sex ratio (M/F) 0.5 (38/70)

Time from MEN diagnosis to NF panNEN 5±6.9 (0-33)

NF panNEN leading to MEN diagnosis (%) 16 (15%)

No of tumors 2.9±±±±2.3 (1-10)

Size of tumor 21±±±±18 (3-90)

Cystic component (%) 17 (16%)

Metastases (no %)

LMN alone

Liver

Lung

Other

Synchronous

Metachronous

21(19%)

3(14%)

14(67%)

2(10%)

2(10%)

16(5%)

5(4.6%)

Follow up after NF panNET diagnosis 4.3±3.3 (0.1-16)

Ann Surg, 2006;243:265-272

OTHER NEUROENDOCRINE NEOPLASMS

Adrenocortical tumors (20-73%)� Cortical adenomas, hyperplasia, cysts, carcinomas

� 10% hypersecretion (>1cm)

� Conn’s, Cushing’s

� 1% carcinoma (↑ 13% > 1cm)

Carcinoids� Lung carcinoids (M/F:1/4)

� Bronchi, GI, pancreas

� Gastric carcinoids type II

� 70% ZES

� Multiple & < 1.5cm

Thymic carcinoids

� M/F:2-10/1, smokers

� Aggressive clinical course

� Patients asymptomatic

� HR 4.29

� Median survival 9.5 yr

� CT scan & SRS

THYMIC CARCINOID IN MEN1

Ghazi et al 2011

BIOCHEMICAL & IMAGING SCREENING IN PATIENTS

WITH MEN 1

TumorAge

screening (yr)Biochemical test Imaging test

Parathyroid 8 Ca, PTH None

panNEN

Gastrinoma 20 Gastrin (±gastric pH) None

Insulinoma 5 Fasting glucose, insulin None

Other panNEN <10 CgA, PP, VIP, Glucagon MRI, CT or EUS (annually)

Anterior pituitary 5 PRL, IGF-I MRI (3 yearly)

Adrenal <10 If symptoms/signs functioning

lesion or size > 1cm

MRI or Ct (annually with

pancreatic imaging)

Thymic & bronchial

carcinoid

15 None CT or MRI (1-2 years)

SURVIVAL OF MEN1 PATIENTS: RISK OF DEATH ACCORDING

TO MEN1 LESION (GTE COHORT, USING A FRAILTY MODEL)

HR 95%CI P

Women vs. men 0.46 0.28-0.76 0.003

Familial history MEN1 0.46 0.27-0.79 0.005

Period diagnosis

1980-1989 vs. <1980

1990-1995 vs.<1980

≥1996 vs. <1980

0.33

0.18

0.17

0.18-0.6

0.09-0.35

0.08-0.4

<0.001

<0.001

<0.001

Thymic tumor 4.64 1.73-12.41 0.002

*CVS 4.29 1.54-11.93 0.005

**NF panNEN 3.43 1.71-6.88 0.001

Gastrinoma 1.89 1.09-3.25 0.022

Adrenal tumor 1.72 0.97-3.06 0.064

Bronchial tumor 1.55 0.64-3.77 0.332

Pituitary tumor 1.17 0.72-1.9 0.536

Insulinoma 0.85 0.39-1.86 0.679

World J Surg 2010, 34:249-255*Glucagonomas, Vipomas, SMSomas

**Mean age death 43 yrs (tumor size>3cm)

CVD: cardiovascular disease

SURVIVAL OF NF-PANNEN ACCORDING TUMOR SIZE

Proportion of pts surviving 4 & 8 ys after NF

panNEN diagnosis

4 yrs(%) 8yrs(%)

No metastasis 98 (95-100) 98(75-100)

Distant metastasis 73(51-95) 34(6-62)

Ann Surg, 2006;243:265-272

RISK OF METASTASES ACCORDING TO TUMOR SIZE IN NF-PANNEN

4% 10% 18%

Ann Surg, 2006;243:265-272

REAL TIME RESULTS FROM DUTCH MEN 1 STUDY GROUP

� 59 MEN 1 families (57 index & 247 non-index

cases)

� Median lag time diagnosis 3.5 years

� 30 (12.1%) non-index duododeno-pancreatic NEN

� 20% metastases (10.9 year lag)

� 80% non-metastases (7.1 year lag)

� 25 (10.1%) non-index pit. tumor

� 80% microadenoma (7.2 year)

� 20% macroadenoma (10.6 year)

� 95 non-index PHP

� 9.5 year time lag

� 10 non-index died

Case Gender Age Cause death Delay

years

1 M 63 panNEN 2

2 M 41 thymic 2.3

3 M 40 thymic 2.5

4 M 55 panNEN 6

5 M 75 panNEN 6.3

6 M 52 panNEN 10

7 F 59 ZES 15.5

8 M 46 thymic 19.3

9 M 61 panNEN 20.5

10 M 74 panNEN 2.3

JCEM 2016, 101:1159-1165JCEM 2016, 101:1159-1165

PHENOTYPIC FEATURES OF VON HIPPEL-LINDAU (VHL)

� Retinal and CNS hemangioblastomas

� Endolymphatic sac tumors

� Cystadenomas of the epididymis

� Pheochromocytomas

� Renal cysts/carcinomas

� Pancreatic cysts/carcinomas, PanNENs (10-17%)

� Hepatic, pulmonary hemangiomas

Bilateral Pheos and renal cystic RCCs

Pancreatic cysts

DIAGNOSTIC CRITERIA

� More than one hemangiomas in CNS (brain & spinal cord) and retinal angiomas

� Single CNS/retinal hemangioma & visceral lesions

� Multiple renal, pancreatic, hepatic cysts

� Pheochromocytomas and solid pancreatic lesions

� Renal Cell Carcinomas (RCC)

� Positive family history and one manifestation

� VHL relevant mutation

� Sequence analysis

� Gene targeted deletion, duplication

PANCREATIC LESIONS IN VHL

� VHL incidence 1/36,000 live births

� Germline mutation VHL tumor suppressor gene

� Morbidity & mortality� Hemangioblastoma: 60-80%

� RCC: 24-45%

� Pancreatic lesions variable course� Pancreatic cysts

� Pancreatic cystadenomas

� Pancreatic solid tumors (panNENs), 15%

� Metastases from hemangioblastomas, RCC

NATURAL HISTORY OF VHL PANNENS

� Median age development 33-35 years

� Youngest reported patient 13 years

� Variable clinical course over 4 years

� 60% non-linear growth

� 20% stable largest lesion

� 20% decrease size

� Malignancy ≈ 12.8%

� Mortality ≈ 1.9%

� Vast majority well differentiated

� Extremely rare functional

� 1 case ectopic ACTH secretion

� Elevated somatostatin levels

TUBEROUS SCLEROSIS

� Autosomal dominant condition, high

penetrance (80% new mutations)

� Prevalence 1/10,000

� EPILOIA

� Epilepsy, Low IQ, Angiofibromas

� Facial angiofibromas (adenoma

sebaceum), cortical tubers,

subependymal giant cell

astrocytomas, periungual

fibromas, cardiac rhabdomyomas

MOLECULAR PATHOGENESIS

Loss of tumour suppressor tuberin (TSC2) or hamartin

(TSC1), intermediaries on Akt-mTOR pathway

Occasional panNENs (functional vs. non-functional),

especially insulinomas in young patients (<1%)

May be confused with underlying epilepsy

NEUROFIBROMATOSIS TYPE 1 (NF 1)

� Autosomal dominant condition

� One of largest genes sequenced

� Part of Ras-MAPK signalling pathway

� Tumour suppressor gene

� Multiple neurofibromas

� Other tumours

� Pheochromocytomas in ~1%

� Duodenal somatostatinomas

NF 1

� Duodenal somatostatinomas (DS) in

NF-1

� ~40 cases reported

� Mean size 3.8cm

� Unusual to be syndromic

� 30% of DS are related to NF-1

CONCLUSIONS

NENs can be familial (MEN 1) and/or have a known genetic cause

NENs may also occur in the context of TS, VHL and NF-1, but the syndrome should be

obvious

Always consider MEN1 in patients with pancreatic and thymic NENs

Diagnosis and management should be in the context of a multidisciplinary team offering

genetic screening

Central registration essential

PATHOPHYSIOLOGY OF VHL

Molecular Genetic Testing

� 5-20% of MEN1 patients do not harbour mutations in the coding region of the MEN1 gene

� No mutation identified by sequencing – can then do MLPA

� Several gross deletions reported to date

� MLPA (P017)� probes for exons 1-3, 7-10

� MLPA on 100 patients who met criteria for testing

� long-range PCR across exons 3-7