The Current Landscape of European Registries for Rare Endocrine ConditionsAli SR, Bryce J, Cools M, Korbonits M, Beun JG, Taruscio D, Danne T, DattaniM, Dekkers OM, Linglart A, Netchine I, Nordenstrom A, Patocs A, Persani L,Reisch N, Smyth A, Sumnik Z, Visser WE, Hiort O, Pereira AM, Ahmed SF, OnBehalf Of Endo-ERN

Salma.Ali@glasgow.ac.uk

1451 1882 1914 1971 2015

Background

Rare endocrine conditions pose a challenge Gaps in knowledge of long-term outcomes Lack of expert, evidence based multidisciplinary care Variation in care

Registries are of key importance for centres of expertise Pooling of data Surveillance Communication between HCPs and patients Multicentre collaboration- best practice guidelines, clinical benchmarks

International registration of patients with rare conditions is encouraged by EU European initiatives (Orphanet, RD-Connect) have attempted to identify

existing registries

Endo-ERN

71 Reference Centres (RC) 8 Thematic Groups

European Reference Networks (ERN) - clinical networks that aim to manage rare conditions requiring specialist input and a concentration of knowledge and resources

ERN for rare endocrine conditions (Endo-ERN) - largest ERN and includes 36 groups of conditions

The range of cross-border registries that exist for Endo-ERN conditions is unclear

The creation of Endo-ERN provided an opportunity to study the existence of registries in Europe

Objectives

1. Identify international registries (led from Europe) for rare endocrine conditions within Endo-ERN

2. Determine the extent of engagement with international registries within an expert network such as Endo-ERN

Methods

A Survey of 71 RC from 19 countries within Endo-ERN (Oct-Nov 2016)

Awareness and participation in registries at an international, national and local level for Endo-ERN conditions within main thematic groups (MTG)

Views on future priorities for new registries for conditions within each MTG

Database search for international registries using Orphanet and RD-Connect using Orphacodes for all rare endocrine conditions within Endo-ERN

An ‘international registry’ was defined as that used by >1 country with the coordinating centre based in Europe

Results- Survey Response Rate

RC response rates categorised according to the Main Thematic Groups (MTG)

2824 23 24 24

35

27 28

5

5 94 6

8

10 7

0

5

10

15

20

25

30

35

40

45

50

Adrenal Ca & PO EndoTumours

Gluc & Ins Growth Pituitary Sex Thyroid

Ref

eren

ce C

entr

es (n

)

Response No response

Response rate= 82% (58/71)Average response rate across themes= 80%

Awareness of Endo-ERN Members of Registries

Greatest awareness of international registries- MTG1 (Adrenal), MTG3 (Glucose & Insulin), MT7 (Sex Dev)

Lowest awareness of international registries- MTG2 (Ca & Phos), MTG4 (Endo Tumours), MTG5 (Growth), MTG6 (Pituitary), MTG8 Thyroid

High levels of awareness of national and local registries

0

5

10

15

20

Phaeo CA Adenomas Macro Micro AI CAH FH

0

5

10

15

20

Hypercalcemia Hypocalcaemia Phosphate

Calcium & Phosphate

0

5

10

15

20

HI Insulin resist Rare DM

0

5

10

15

20

MEN 1 MEN 2 Carney Phaeo PGL VHL

0

5

10

15

20

PWS SRS BWS Noonan GH resis

0

5

10

15

20

Adenoma Cong hypopit Acq hypopit

0

5

10

15

20

Sex chr DSD 46, XX DSD 46, XY DSD Hypog hypog

0

5

10

15

20

Genetic Cong hypo Cong hyper CA RI sens DTC Non‐met CA

Thyroid

Adrenal

Rare Endocrine Tumours

Glucose & Insulin

Pituitary

Growth

Sex Development

LocalNationalInternational

Greatest participation in international registries for conditions within MTG1 (Adrenal), MTG3 (Glucose & Insulin), MT7 (Sex Dev)

Despite awareness of registries, participation rates lower e.g. 70% ‘aware’ of an

international registry for DSD, yet, participation rate was 52%

No participation in international registries for some conditions e.g. MTG8 (Thyroid)

0

5

10

15

20

Phaeo CA Adenomas Macro Micro AI CAH FH

Adrenal

0

5

10

15

20

Hypercalcemia Hypocalcaemia Phosphate

Calcium & Phosphate

0

5

10

15

20

HI Insulin resist Rare DM

Glucose & Insulin

0

5

10

15

20

MEN 1 MEN 2 Carney Phaeo PGL VHL

Rare Endocrine Tumours

0

5

10

15

20

PWS SRS BWS Noonan GH resis

Growth

0

5

10

15

20

Adenoma Cong hypopit Acq hypopit

0

5

10

15

20

Sex chr DSD 46, XX DSD 46, XY DSD Hypog hypog

0

5

10

15

20

Genetic Cong hypo Cong hyper CA RI sens DTC Non‐metCA

Thyroid

Pituitary

Sex Development

Participation of Endo-ERN Members In RegistriesLocalNationalInternational

Views On Future Priorities

0

1

2

3

4

5

6

Phaeo CA Adenomas Macro Micro AI CAH FH

Adrenal MEDIANPriority (median, 10th 90th)

0

1

2

3

4

5

6

MEN 1 MEN 2 Carney Phaeo PGL VHL

Rare Endocrine Tumours

0123456

HI Insulin-resist Rare DM

Glucose

0123456

PWS SRS BWS Noonan GH res

Growth & Obesity

0123456

Hypercalcemia Hypocalcaemia Phosphatedisturbances

Calcium & Phosphate

0123456

Pit adenoma Cong hypopit Acq hypopit

Pituitary

0123456

Sex chr DSD 46, XX DSD 46, XY DSD Hypog hypog

Sex Development

0

1

2

3

4

5

6

Genetic Cong hypo Conghyper

CA RI sensDTC

Non‐metCA

Thyroid

A score of 5 attributed to all conditions within:

- MTG4 (Rare Endocrine Tumours)

- MTG5 (Growth & Obesity)- MTG7 (Sex Development)

International Registries for Rare Endocrine ConditionsInternational Rare Disease Registry

(Co-ordinating Centre Within Europe)

International Pheochromocytoma and Paraganglioma Registry (Freiburg, Germany)

ENSAT: European Network for the Study of Adrenal Tumours (Brussels, Belgium)

EU-AIR: European Adrenal Insufficiency registry (Shire) (Zug, Switzerland)EURADRENAL: European Patient Registry on Autoimmune Adrenal Failure (Bergen, Norway)I-CAH: International Registry for Congenital Adrenal Hyperplasia (Glasgow,UK)ERCUSYN: European Registry on Cushing’s Syndrome (Barcelona, Spain)

ESPN/ERA-EDTA Registry: European Registry for Children on Renal Replacement Therapy (Amsterdam, Netherlands)

X-ALD: X-linked Adrenoleukodystrophy Database (Amsterdam, Netherlands)European LeukoDatabase (LeukoDB) (Paris, France)

European Parathyroid Tumour Registry (Leiden, Netherlands)

EUROGLYCANET- International Patient Registry and Cohort for Congenital Disorders of Glycosylation (Leuven, Belgium)

XLH Registry: (X-linked Hypophosphatemia) (Galashiels, UK)

UK10K_RARE_SIR- The Severe Insulin Resistance (SIR) Variant Database (HInxton, UK)EUROWABB: An EU Rare Diseases Registry for Wolfram Syndrome, Alstrom Syndrome, Bardet-Biedl Syndrome and Other Rare Diabetes Syndromes (Birmingham, UK)

SWEET: ‘Better control in Pediatric and Adolescent diabetes: Working to create centers of reference’ (Hannover, Germany)

EcLip: European Consortium of Lipodystrophies (Murcia, Spain)

ENETS: European Neuroendocrine Tumour Society (Athens, Greece)

Cooperative European Paediatric Renal Transplant Initiative registry (Heidelberg, Germany)MD-NET: Muscle Tissue Culture Collection (MTCC) (EuroBioBankpartner) (Munchen, Germany)

International Registries for Rare Endocrine ConditionsInternational Rare Disease Registry

(Co-ordinating Centre Within Europe)Endo ERN MTGS (1-8)

International Pheochromocytoma and Paraganglioma Registry (Freiburg, Germany)

1, 4

ENSAT: European Network for the Study of Adrenal Tumours (Brussels, Belgium)

1, 4

EU-AIR: European Adrenal Insufficiency registry (Shire) (Zug, Switzerland)

1

EURADRENAL: European Patient Registry on Autoimmune Adrenal Failure (Bergen, Norway)

1

I-CAH: International Registry for Congenital Adrenal Hyperplasia (Glasgow,UK)

1

ERCUSYN: European Registry on Cushing’s Syndrome (Barcelona, Spain)

1, 4, 6

ESPN/ERA-EDTA Registry: European Registry for Children on Renal Replacement Therapy (Amsterdam, Netherlands)

1, 4, 8

X-ALD: X-linked Adrenoleukodystrophy Database (Amsterdam, Netherlands)

1

European LeukoDatabase (LeukoDB) (Paris, France) 1

European Parathyroid Tumour Registry (Leiden, Netherlands) 2

EUROGLYCANET- International Patient Registry and Cohort for Congenital Disorders of Glycosylation (Leuven, Belgium)

2

XLH Registry: (X-linked Hypophosphatemia) (Galashiels, UK) 2

UK10K_RARE_SIR- The Severe Insulin Resistance (SIR) Variant Database (HInxton, UK)

3, 5

EUROWABB: An EU Rare Diseases Registry for Wolfram Syndrome, Alstrom Syndrome, Bardet-Biedl Syndrome and Other Rare Diabetes Syndromes (Birmingham, UK)

3, 5

SWEET: ‘Better control in Pediatric and Adolescent diabetes: Working to create centers of reference’ (Hannover, Germany)

3

EcLip: European Consortium of Lipodystrophies (Murcia, Spain) 3

ENETS: European Neuroendocrine Tumour Society (Athens, Greece) 4

Cooperative European Paediatric Renal Transplant Initiative registry (Heidelberg, Germany)

4, 6

MD-NET: Muscle Tissue Culture Collection (MTCC) (EuroBioBank partner) (Munchen, Germany)

5

International Registries for Rare Endocrine ConditionsInternational Rare Disease Registry

(Co-ordinating Centre Within Europe)Endo ERN MTGS (1-8)

Endo-ERN Conditions (Orphacode)

International Pheochromocytoma and Paraganglioma Registry (Freiburg, Germany)

1, 4 Sporadic phaeochromocytoma-paraganglioma (PCC/PGL) (ORPHA276624); Hereditary PCC/PGL (ORPHA29072); Von Hippel Lindau Syndrome (ORPHA892)

ENSAT: European Network for the Study of Adrenal Tumours (Brussels, Belgium)

1, 4 Sporadic phaeochromocytoma-paraganglioma (PCC/PGL) (ORPHA276624); Adrenocortical carcinoma (ORPHA1501); MEN type 1 (ORPHA652); MEN type 2 (ORPHA653); Carney complex (ORPHA1359); Hereditary PCC/PGL (ORPHA29072); Von Hippel Lindau Syndrome (ORPHA892)

EU-AIR: European Adrenal Insufficiency registry (Shire) (Zug, Switzerland)

1 (Primary) Adrenal insufficiency (ORPHA101959)

EURADRENAL: European Patient Registry on Autoimmune Adrenal Failure (Bergen, Norway)

1 (Primary) Adrenal insufficiency (ORPHA101959)

I-CAH: International Registry for Congenital Adrenal Hyperplasia (Glasgow,UK)

1 Congenital adrenal hyperplasia (ORPHA418)

ERCUSYN: European Registry on Cushing’s Syndrome (Barcelona, Spain)

1, 4, 6 Adrenocortical carcinoma (ORPHA1501); Cortisol producing adenomas (ORPHA443287); MEN type 1 (ORPHA652); MEN type 2 (ORPHA653); Pituitary adenoma (ORPHA99408)

ESPN/ERA-EDTA Registry: European Registry for Children on Renal Replacement Therapy (Amsterdam, Netherlands)

1, 4, 8 Adrenocortical carcinoma (ORPHA1501); Hereditary PCC/PGL (ORPHA29072); Von Hippel Lindau Syndrome (ORPHA892); Congenital hyperthyroidism (ORPHA424)

X-ALD: X-linked Adrenoleukodystrophy Database (Amsterdam, Netherlands)

1 (Primary) Adrenal insufficiency (ORPHA101959)

European LeukoDatabase (LeukoDB) (Paris, France) 1 (Primary) Adrenal insufficiency (ORPHA101959)

European Parathyroid Tumour Registry (Leiden, Netherlands) 2 Rare forms of hyperparathyroidism including parathyroid cancer and FHH (ORPHA181408)

EUROGLYCANET- International Patient Registry and Cohort for Congenital Disorders of Glycosylation (Leuven, Belgium)

2 Hyperphosphatemia (ORPHA306661)

XLH Registry: (X-linked Hypophosphatemia) (Galashiels, UK) 2 Hypophosphatemia (ORPHA 89937)

UK10K_RARE_SIR- The Severe Insulin Resistance (SIR) Variant Database (HInxton, UK)

3, 5 Insulin-resistance syndrome (ORPHA181368); Rare diabetes mellitus (ORPHA101952); Rare genetic obesity (ORPHA77828)

EUROWABB: An EU Rare Diseases Registry for Wolfram Syndrome, Alstrom Syndrome, Bardet-Biedl Syndrome and Other Rare Diabetes Syndromes (Birmingham, UK)

3, 5 Rare diabetes mellitus (ORPHA101952); Rare genetic obesity (ORPHA77828)

SWEET: ‘Better control in Pediatric and Adolescent diabetes: Working to create centers of reference’ (Hannover, Germany)

3 Rare diabetes mellitus (ORPHA101952)

EcLip: European Consortium of Lipodystrophies (Murcia, Spain) 3 Rare diabetes mellitus (ORPHA101952)

ENETS: European Neuroendocrine Tumour Society (Athens, Greece) 4 Hereditary PCC/PGL (ORPHA29072)

Cooperative European Paediatric Renal Transplant Initiative registry (Heidelberg, Germany)

4, 6 Von Hippel Lindau Syndrome (ORPHA892); Congenital hyperthyroidism (ORPHA424)

MD-NET: Muscle Tissue Culture Collection (MTCC) (EuroBioBank partner) (Munchen, Germany)

5 Prader Willi and Prader Willi-like syndrome (ORPHA739); Rare genetic obesity (ORPHA77828)

International Registries for Rare Endocrine ConditionsInternational Rare Disease Registry

(Co-ordinating Centre Within Europe)Endo ERN MTGS (1-8)

Endo-ERN Conditions (Orphacode)

Orphanet RD-Connect

Endo-ERN

International Pheochromocytoma and Paraganglioma Registry (Freiburg, Germany)

1, 4 Sporadic phaeochromocytoma-paraganglioma (PCC/PGL) (ORPHA276624); Hereditary PCC/PGL (ORPHA29072); Von Hippel Lindau Syndrome (ORPHA892)

+ - +

ENSAT: European Network for the Study of Adrenal Tumours (Brussels, Belgium)

1, 4 Sporadic phaeochromocytoma-paraganglioma (PCC/PGL) (ORPHA276624); Adrenocortical carcinoma (ORPHA1501); MEN type 1 (ORPHA652); MEN type 2 (ORPHA653); Carney complex (ORPHA1359); Hereditary PCC/PGL (ORPHA29072); Von Hippel Lindau Syndrome (ORPHA892)

+ - +

EU-AIR: European Adrenal Insufficiency registry (Shire) (Zug, Switzerland)

1 (Primary) Adrenal insufficiency (ORPHA101959) - - +

EURADRENAL: European Patient Registry on Autoimmune Adrenal Failure (Bergen, Norway)

1 (Primary) Adrenal insufficiency (ORPHA101959) + - +

I-CAH: International Registry for Congenital Adrenal Hyperplasia (Glasgow,UK)

1 Congenital adrenal hyperplasia (ORPHA418) + - +

ERCUSYN: European Registry on Cushing’s Syndrome (Barcelona, Spain)

1, 4, 6 Adrenocortical carcinoma (ORPHA1501); Cortisol producing adenomas (ORPHA443287); MEN type 1 (ORPHA652); MEN type 2 (ORPHA653); Pituitary adenoma (ORPHA99408)

+ + +

ESPN/ERA-EDTA Registry: European Registry for Children on Renal Replacement Therapy (Amsterdam, Netherlands)

1, 4, 8 Adrenocortical carcinoma (ORPHA1501); Hereditary PCC/PGL (ORPHA29072); Von Hippel Lindau Syndrome (ORPHA892); Congenital hyperthyroidism (ORPHA424)

+ - -

X-ALD: X-linked Adrenoleukodystrophy Database (Amsterdam, Netherlands)

1 (Primary) Adrenal insufficiency (ORPHA101959) + - -

European LeukoDatabase (LeukoDB) (Paris, France) 1 (Primary) Adrenal insufficiency (ORPHA101959) - + +European Parathyroid Tumour Registry (Leiden, Netherlands) 2 Rare forms of hyperparathyroidism including parathyroid cancer and FHH

(ORPHA181408)+ - +

EUROGLYCANET- International Patient Registry and Cohort for Congenital Disorders of Glycosylation (Leuven, Belgium)

2 Hyperphosphatemia (ORPHA306661) + - -

XLH Registry: (X-linked Hypophosphatemia) (Galashiels, UK) 2 Hypophosphatemia (ORPHA 89937) - - +UK10K_RARE_SIR- The Severe Insulin Resistance (SIR) Variant Database (HInxton, UK)

3, 5 Insulin-resistance syndrome (ORPHA181368); Rare diabetes mellitus (ORPHA101952); Rare genetic obesity (ORPHA77828)

+ - -

EUROWABB: An EU Rare Diseases Registry for Wolfram Syndrome, Alstrom Syndrome, Bardet-Biedl Syndrome and Other Rare Diabetes Syndromes (Birmingham, UK)

3, 5 Rare diabetes mellitus (ORPHA101952); Rare genetic obesity (ORPHA77828) + + +

SWEET: ‘Better control in Pediatric and Adolescent diabetes: Working to create centers of reference’ (Hannover, Germany)

3 Rare diabetes mellitus (ORPHA101952) - - +

EcLip: European Consortium of Lipodystrophies (Murcia, Spain) 3 Rare diabetes mellitus (ORPHA101952) - - +ENETS: European Neuroendocrine Tumour Society (Athens, Greece) 4 Hereditary PCC/PGL (ORPHA29072) - + +Cooperative European Paediatric Renal Transplant Initiative registry (Heidelberg, Germany)

4, 6 Von Hippel Lindau Syndrome (ORPHA892); Congenital hyperthyroidism (ORPHA424)

+ - -

MD-NET: Muscle Tissue Culture Collection (MTCC) (EuroBioBank partner) (Munchen, Germany)

5 Prader Willi and Prader Willi-like syndrome (ORPHA739); Rare genetic obesity (ORPHA77828)

+ - -

International Registries for Rare Endocrine Conditions

European Prader-Willi Syndrome Database (Cambridge, UK) 5 Prader Willi and Prader Willi-like syndrome (ORPHA739); Rare genetic obesity (ORPHA77828)

+ - -

RaDiCo-IDMet- French and European Cohort in Imprinting Disorders and Metabolism Future (Paris, France)

2, 3, 5 Hypoparathyroidism (ORPHA181405); Rare diabetes mellitus (ORPHA101952); Prader Willi and Prader Willi-like syndrome (ORPHA739); Silver Russell Syndrome (ORPHA813); Beckwith Wiedemann Syndrome (ORPHA116); Rare genetic obesity (ORPHA77828)

+ + -

IGFD Registry: The Increlex Growth Forum Database (Ipsen) (Paris, France)

5 GH resistance syndromes (ORPHA633) - - +

Liège Acromegaly Survey (LAS) Database (Lèige, Belgium) 5, 6 Overgrowth syndrome (ORPHA93460); Pituitary adenoma (ORPHA99408) - - +

KIMS database- Adults with GH Deficiency (Pfizer International Metabolic Database) (Stockholm, Sweden)

5 GH resistance syndromes (ORPHA633) - - +

KIGS (Pfizer International Growth Database) (Stockholm, Sweden) 5, 6, 7 Prader Willi and Prader Willi-like syndrome (ORPHA739); Silver Russell syndrome (ORPHA813); Congenital hypopituitarism (ORPHA95494); Acquired hypopituitarism (ORPHA95502); Sex chromosome DSD (ORPHA325546)

- - +

ACROSTUDY (Pfizer International Somavert Database) (Stockholm, Sweden)

5, 6 Overgrowth syndrome (ORPHA93460); Pituitary adenoma (ORPHA99408) - - +

Nordinet International Outcome Study (Novo Nordisk) (Bagsvaerd, Denmark)

5,7 Prader Willi and Prader Willi-like syndrome (ORPHA739); Noonan syndrome (ORPHA648); GH resistance syndromes (ORPHA633); Sex chromosome DSD (ORPHA325546)

- - +

DYSCERNE’s Dysmorphology Diagnostic System (DDS) (Manchester, UK)

5 Silver Russell Syndrome (ORPHA813) + - -

Global Familial Isolated Pituitary Adenoma (FIPA) consortium (London, UK)

6 Pituitary adenoma (ORPHA99408) + - +

COST Action BM1105 Patient Registry- GnRH Network (Lausanne, Switzerland)

6 , 7 Congenital hypopituitarism (ORPHA95494); Isolated congenital anosmic hypogonadotrophic hypogonadism (ORPHA478); Isolated congenital normosmic hypogonadotrophic hypogonadism (ORPHA432)

+ + -

I-DSD: International Registry for Disorders of Sex Development (Glasgow, UK)

7 Sex chromosome DSD (ORPHA325546); 46, XX DSD (ORPHA2982); 46, XY DSD (ORPHA98085)

+ + +

UK10K_RARE_THYROID- Congenital Hypothyroidism Variant Database (Cambridge, UK)

8 Thyroid signalling disorders (ORPHA183631); Congenital hypothyroidism (ORPHA442)

+ - -

MCT8 Registry. International registry of rare thyroid disorders (Rotterdam, the Netherlands)

8 Thyroid signalling disorders (ORPHA183631) - - +

International Rare Disease Registry (Co-ordinating Centre Within Europe)

Endo ERN MTGS (1-8)

Endo-ERN Conditions (Orphacode)

Orphanet RD-Connect

Endo-ERN

International Registries For Rare Endocrine Conditions

Registries exist for 76% (32/42) of Endo-ERN conditions 33 registries identified via Endo-ERN members, Orphanet, RD-Connect Of 27 registries identified via Orphanet and RD-Connect, Endo-ERN aware of 11 (41%)

Several commercial registries identified: EU-AIR (Shire), KIMS, KIGS, Acrostudy (Pfizer) Orphanet & RD-Connect not aware of commercial registries

Endo-ERN 21

RD-Connect7

Orphanet20 2

6 23

RaDiCo-IDMet (France)GnRH Network (Switzerland)

LeukoDatabase (France)ENETS (Greece)

International pheochromocytoma and paraganglioma registry (Germany)ENSAT (Belgium)EURADRENAL (Norway)I-CAH (UK)European parathyroid registry (Netherlands)FIPA Consortium (UK) ERCUSYN (Spain)

EUROWABB (UK)I-DSD (UK)

Summary

Several international registries exist for a wide range of rare endocrine conditions

There are gaps in the coverage of conditions that need addressing

Bigger gaps in the levels of awareness and use of existing registries

Conditions for which establishment of a registry was considered top priority were often those for which international registries already exist

‘Registry libraries’ such as Orphanet and RD-Connect do not have a record of several international registries led from Europe

Future Directions

A need to develop new registries for rare endocrine conditions

A more immediate need to improve the awareness and participation in existing registries

Development of a core registry which directs users to high quality detailed registries

www.eurreca.net