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case epo
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1 Se iço de Endoc inologia, Diabe es
e Me abolismo, Hospi al Egas
Moniz, Lisbon, Po ugal. Unidad de
Endoc inología Pediá ica y C ecimien o.
IDIS. Hospi al Clínico Uni e si a io
de San iago de Compos ela,
San iago de Compos ela, Spain
2 Se iço de Endoc inologia,
Ins i u o Po ugues de Oncologia
de Lisboa, Po ugal
3 Unidad de Endoc inología Pediá ica
y C ecimien o. Pedia ía, Hospi al
Clínico Uni e si a io y Uni e sidad
de San iago de Compos ela, IDIS,
San iago de Compos ela, Spain
4 Unidad de Endoc inología Pediá ica
y C ecimien o. Pedia ía Hospi al
Clínico Uni e si a io y Uni e sidad
de San iago de Compos ela, IDIS,
San iago de Compos ela, Spain
5 Pedia ía, Hospi al Clínico Uni e si a io
de San iago de Compos ela,
San iago de Compos ela, Spain
6 Unidad de Endoc inología Pediá ica
y C ecimien o, IDIS. Hospi al
Clínico Uni e si a io de San iago de
Compos ela Spain. Endoc inología.
Hospi al Cu y Cab al. Cen o Hospi ala
de Lisboa Cen al, Lisboa, Po ugal
7 Fundación Publica Galega de
Medicina Xenómica, Hospi al
Clínico Uni e si a io de San iago
de Compos ela, Uni e sidad
de San iago de Compos ela,
San iago de Compos ela, Spain
8 Unidad de Endoc inología Pediá ica
y C ecimien o, Pedia ía, Hospi al
Clínico Uni e si a io y Uni e sidad
de San iago de Compos ela, IDIS,
San iago de Compos ela, Spain
Co espondence o:
F ancisco Sousa San os
Rua José Lins do Rêgo, 26, 4º esque do
1700-264 Lisboa, Po ugal
[email p o ec ed]
Recei ed on May/20/2017
Accep ed on Ap /30/2018
DOI: 10.20945/2359-3997000000077
Congeni al hype insulinism in wo
siblings wi h
ABCC8
mu a ion:
same geno ype, di e en
pheno ypes
F ancisco Sousa-San os1, Helde Simões2, Lidia Cas o-Feijóo3,
Paloma Cabanas Rod íguez4, Ana Fe nández-Ma miesse5,
Rebeca Sabo ido Fiaño5, Te esa Rego6, Ángel Ca acedo7,
Jesús Ba ei o Conde8
SUMMARY
Congeni al hype insulinism (CHI) is a he e ogenous disease caused by insulin sec e ion egula o y
de ec s, being ABCC8/KCNJ11 he mos commonly a ec ed genes. The apeu ic op ions include
diazoxide, soma os a in analogues and su ge y, which is cu a i e in ocal CHI. We epo he case
o wo siblings (bo n wo yea s apa ) ha p esen ed hemsel es wi h hypoke o ic hype insulinemic
pe sis en hypoglycemias du ing neona al pe iod. The diagnosis o di use CHI due o an ABCC8
compound mu a ion (c.3576delG and c.742C>T) was concluded. They did no bene i om diazoxide
he apy (o panc ea ec omy pe o med in pa ien numbe 1) ye esponded o soma os a in
analogues. Pa ien numbe 1 de eloped a ious neu ological de ici s (including epilepsy), howe e
pa ien numbe 2 expe ienced an en i ely no mal neu ode elopmen . We belie e his case shows
how p e ious knowledge o he i s bo n sibling’s disease con ibu ed o a be e and imelie medical
ca e in pa ien numbe 2, which could po en ially explain he be e neu ological ou come despi e
hei same geno ype.
A ch Endoc inol Me ab. 2018;62(5):560-5
INTRODUCTION
Congeni al hype insulinism (CHI) is he mos
common cause o pe sis en hypoglycemia
in in ancy and i can po en ially lead o pe manen
neu ological damage (1,2). I is he esul o a g oup
o gene ic diso de s which can lead o se e e and
pe sis en hypoglycemia (3). Es ima ed incidence is
1/50,000 li e bi hs (4).
The disease is caused by mu a ions in a ious genes
ela ed o insulin sec e ion egula ion (5), such as:
ABCC8 (6), KCNJ11 (7), GCK (8), GLUD1 (9),
HADH (10), SLC16A1 (11), HNF4A (12), HNF1A
(13), UCP2 (14), HK1 (15) and PGM1 (16). The
mos common mu a ions a ec ABCC8 and KCNJ11
genes and lead o inac i a ion o he ATP-dependen
po assium channel (KATP) subuni s (SUR1 and Ki 6.2
espec i ely), esul ing in un egula ed insulin β-cell
sec e ion (2,4,7,17).
His ologically he disease is cha ac e ized by
Lange hans isle hype plasia and can p esen as di use
(18) o ocal o m (19), which is a leas pa ially
de e mined by he ype o gene ic de ec (3). The wo
o ms a e clinically indis inguishable and he bes way
o di e en ia e is by pe o ming a 18F- luo o-L-DOPA
posi on emission omog aphy (PET) (20).
Pha maco he apeu ic op ions (3,21) include
o al diazoxide as i s line ea men and glucagon,
soma os a in analogues and calcium channel blocke s.
In cases o ocal hype plasia, he ea men o choice is
su gical emo al o he a ec ed issue, which is usually
cu a i e (19). In di use o ms ha a e un esponsi e
o medical he apy, nea - o al panc ea ec omy can be
an al e na i e, al hough isking complica ions such as
diabe es (3).
We epo he case o wo siblings diagnosed
in neona al pe iod wi h CHI who we e ound o
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A ch Endoc inol Me ab. 2018;62/5
ha e he same gene ic de ec bu di e en long-
e m disease cou se. The p e ious knowledge o he
i s bo n sibling’s disease and how i esponds o
di e en he apeu ic op ions led o a mo e app op ia e
he apeu ic in e en ion in he second sibling, which we
belie e con ibu ed decisi ely o a be e neu ological
ou come, e en wi h he same disease geno ype. We
belie e his is a p ime example o how a imely diagnosis
and app op ia e he apeu ic s a egy a e de e minan o
a be e clinical ou come.
CASE REPORT – PATIENT 1
An ea ly e m la ge- o -ges a ional age – bi h weigh :
4,200 g (SDS +2.84) and APGAR 9/10 – male pa ien
bo n o nonconsanguineous pa en s p esen ed wi h
se e e and pe sis en hypoglycemia 36 hou s a e
bi h, wi h impai ed consciousness le el, hypo onia
and b adyca dia. This was his 28-yea -old mo he s i s
ges a ion and she de eloped ges a ional diabe es a he
20 h week (con olled wi h die ). The e was no amily
his o y o hypoglycemic diso de s. S a ing on he
ou h day o li e, he equi ed con inuous in usion o
concen a ion glucose (glucose in usion a e 8-10 mg/
kg/minu e) o main ain no mal blood glucose.
Abdominal ul asound and compu ed omog aphy
did no iden i y any panc ea ic abno mali ies.
Labo a o y s udies (Table 1) demons a ed e y low
le els o ke one bodies and ee a y acids in he
p esence o low glycemic alues and inapp op ia ely
high insulin le els. Glucagon s imula ion es yielded
posi i e esul s – blood glucose inc eased 46.8 mg/
dL 30 minu es a e glucagon adminis a ion. Gene ic
analyses, pe o med a 5 yea s o age, iden i ied biallelic
ABCC8 mu a ion – a ameshi mu a ion, c.3576delG,
inhe i ed om his mo he and a nonsense mu a ion,
c.742C>T, inhe i ed om an una ec ed a he .
He was ini ially s a ed on diazoxide ( i a ed o
25 mg/kg/day) and la e added hyd ochlo o hiazide.
When he was 3 mon hs old, he was submi ed
o explo a o y abdominal su ge y and nea - o al
panc ea ec omy (> 90%) due o pe sis en se e e
hypoglycemic episodes associa ed wi h seizu es.
His ology e ealed di use panc ea ic isle s hype plasia.
Pos ope a i ely, he e we e no imp o emen s, so, a he
age o wo, he began gas os omy con inuous en e al
eeding using complex ca bohyd a es and was swi ched
o subcu aneous oc eo ide (20 µg/kg/day).
Table 1. Labo a o y indings a he ime o hypoglycemia
Pa ien (Age) Pa ien 1
(1 mon h)
Pa ien 2
(< 1 mon h)
Blood glucose (70-110 mg/dL) 28 12
Insulin (9.7-97.2 pmol/L) 64.6 110.4
C Pep ide (0.30-1.42 nmol/L) 0.9 2.3
Hyd oxybu y a e (< 300 µmol/L) Unde ec able Unde ec able
F ee a y acids (0.4-0.7 nmol/L) 0.33 0.43
Co isol (137.9-689.7 nmol/L) 855.3 634.6
GH (< 20 µg/L) 5.4 11
Ca ni ines:
To al (38-68 nmol/mL)
F ee (27-49 nmol/mL)
Acilca ni ines (7-19 nmol/mL)
60
46
14
42
Lac a e (0.6-2.3 mmol/L) 0.9 13.4
Py u a e (80-160 µmoI/L) 67 54.5
Glu amic Acid (0.2-2.8 mg/dL) 0.77
Ammonia (10-65 µmol/L) 61 45
U ina y o ganic acids Nega i e Nega i e
Neu ologic e alua ion a 5 yea s o age demons a ed
psychomo o de elopmen e a da ion, hemipa esis,
dyses hesias and in olun a y mo emen s o he le a m.
magne ic essonance imaging (MRI) showed di use
ce eb al a ophy and a T2 hype in ensi y o he medial
empo al igh lobe, sugges i e o hypoglycemic sequelae
(22). He was diagnosed wi h pa ial epilepsy and s a ed
on oxca bazepine and, subsequen ly, alp oic acid.
The esul o a con inuous glucose moni o ing
pe o med a 13 yea s o age, while on medical he apy
wi h oc eo ide and ni edipine, is shown in Figu e 1A. By
he age o 16 he pa ien exhibi ed imp o emen o his
glycemic p o ile. Oc eo ide was swi ched o lan eo ide
(60 mg each 30 days) when he was 18 yea s old.
A he ime o w i ing, he pa ien is 20 yea s old
and emains wi hou any ecen hypoglycemic episodes
al hough occasionally pos p andially hype glycemic
(diabe es c i e ia no me ). His BMI (body mass
index) is 22.8 kg/m2, hus showing imp o emen since
in ancy (BMI > 97 h pe cen ile). He is 169 cm all (SDS
-1.15) (23) and a ge heigh was: 177.5 cm (SDS +
0.25). IGF-1 and IGFBP-3 emained no mal du ing
all ollow-up and pube al de elopmen was adequa e.
He emains wi h sligh neu opsychological de ici s,
wi hou ecen clinical epilep ic ac i i y. He is cu en ly
medically managed wi h lan eo ide 60 mg each 30
days, me hylphenida e (s a ed a 12 yea s o age due
o a en ion de ici diso de ) and ca bamazepine.
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Thu sday F iday Sa u day Sunday Monday Tuesday Wednesday A e age
400
300
200
100
40
0
140
70
Time o day
0:00 2:00 4:00 6:00 8:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 0:00
Glucose - mg/dL
400
300
200
100
0
Time o day
03:00 06:00 09:00 12:00 15:00 18:00 21:00
Glucose - mg/dL
Figu e 1. Resul s o bo h pa ien s’ subcu aneous glucose moni o ing: (A) Pa ien numbe 1’s 24-hou moni o ing. Va ious pe iods o low blood glucose
(40-60 mg/dL) we e obse ed. (B) Pa ien numbe 2’s 6-days moni o ing. Va ious pe iods o low blood glucose (40-60 mg/dL) we e also egis e ed in
his case.
A
B
CASE REPORT – PATIENT 2
An ea ly e m – bi h weigh : 3,660 g (SDS +1.64)
and APGAR 9/10 – emale pa ien , sis e o pa ien
numbe 1 (bo n 2 yea s a e him), p esen ed wi h
se e e hypoglycemia (20 mgl/dL) one hou a e bi h.
This was he mo he ’s second ges a ion and she, once
mo e, de eloped ges a ional diabe es a he 20 h week
(managed wi h die a y measu es). Du ing he i s days
o li e she equi ed con inuous in usion o glucose
(glucose in usion a e 12 mg/kg/minu e) o main ain
euglycemia.
Abdominal imaging and labo a o y s udies (Table 1),
including glucagon simula ion es , e ealed simila
esul s as pa ien numbe 1. Gene ic analyses ound he
same compound mu a ion.
A he age o one mon h, she was s a ed on
diazoxide (12 mg/kg/day) and hyd ochlo o hiazide
bu showed no bene i . One mon h la e diazoxide
was swi ched o oc eo ide (20 mg/kg/day) and she
was s a ed on con inuous gas os omy en e al eeding.
Du ing in ancy and adolescence, he hypoglycemic
episodes became less equen and less se e e and he e
we e no eco ded hype glycemic episodes – esul s o
con inuous glucose moni o ing pe o med when she
was 13 a e shown in Figu e 1B. She was swi ched o
lan eo ide (60 mg each 30 days) when she was 16.
Cu en ly he pa ien is 18 yea s old and emains
wi h occasional non-se e e hypoglycemic episodes
bu is o he wise euglycemic. He psychomo o and
in ellec ual de elopmen emains no mal. BMI alues
(BMI > 97 h pe cen ile) consis en wi h obesi y we e
obse ed un il she was 6 yea s old, howe e he p esen
BMI is 22.6 kg/m2. He inal heigh is 160 cm (SDS
-0.60) (23) and a ge heigh was: 165.4 cm (SDS+
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0.23). No GH/IGF axis abno mali ies we e ound
h oughou ollow-up. She is cu en ly medically
managed wi h lan eo ide 60 mg each 28 days and is on
a ac iona ed die .
DISCUSSION
We desc ibe he case o wo siblings diagnosed
wi h diazoxide-un esponsi e CHI due o he same
compound he e ozygous ABCC8 mu a ion, ye
di e en disease cou ses.
In he p esence o CHI, molecula biology plays
an impo an ole in p o iding a p ecise diagnosis and
po en ially guiding he pha maco he apy (24). ABCC8
gene mu a ion a e he mos commonly ound de ec s in
pa ien s wi h CHI (6). Monoallelic ABCC8 mu a ions
can cause bo h diazoxide- esponsi e and un esponsi e
CHI, howe e mos biallelic mu a ions esul in
diazoxide-un esponsi e o m (25).
Ou pa ien s p esen ed wi h biallelic ABCC8
mu a ions – c.3576delG and c.742C>T (al eady
e e ed o in a Spanish gene ic mu a ion da abase
(17)). The o me mu a ion, has only been desc ibed
in he e ozygosi y and associa ed wi h he ocal o m
o he disease (26,27). The la e has been associa ed
wi h CHI bo h in homozygosi y and he e ozygosi y
p esen ing as his ologically di use disease (28,29).
Bo h mu a ions esul in p ema u e e mina ion codons.
The e o e, he e we desc ibe wo cases o a no el ( o
he bes o ou knowledge) compound mu a ion ha
e ains he his ological ea u es (di use disease based
on panc ea ic his ology o pa ien numbe 1) o he
c.742C>T mu a ion. Func ional s udies could con i m
he esul an p o ein g ade o dys unc ion, as o he
au ho s ha e done in di e en compound mu a ions
(25).
The i s he apeu ic app oach usually consis s
o diazoxide. I inhibi s panc ea ic insulin sec e ion
h ough in e ac ion wi h he SUR1 subuni o he KATP
and he e o e in case o abno mali ies in hese p o eins
i migh no be e ec i e (3,21,30). Such is he case
in ABCC8 mu a ions, making mos o hese pa ien s
diazoxide-un esponsi e, as we e hese subjec s.
In pa ien s wi h diazoxide-un esponsi e CHI,
soma os a in analogues, usually adminis e ed as
subcu aneous injec ions, ha e shown some p omise
(3,21). They ac on soma os a in ecep o s (SSTR2
and SSTR5), inhibi ing he sec e ion o a ious
ho mones, namely insulin. They ha e been used o
o e 20 yea s in he long- e m con ol o diazoxide-
un esponsi e o ms o he disease (31), howe e hey
ha e ye o be o icially app o ed o his pu pose.
In addi ion o i s side-e ec p o ile (which includes
gas oin es inal symp oms, bilia y li hiasis and a e
cases o nec o izing en e ocoli is), he e is a isk o
wo sening hypoglycemia (due o supp ession o GH
and glucagon p oduc ion) and achyphylaxis (due o
down egula ion o soma os a in ecep o s), which can
limi i s long- e m use (3,21). Oc eo ide is he d ug
wi h he mos clinical expe ience, howe e in he las
yea s he e ha e been epo s o success ul lan eo ide
(long-ac ing soma os a in analogue) use (32). The
p esen ed cases ep esen how bo h oc eo ide
and lan eo ide can be e ec i e in a aining blood
glucose con ol bo h pos (pa ien numbe 1) and
p e-ope a i ely (pa ien numbe 2) in case o di use
diazoxide-un esponsi e CHI. These d ugs seemed
be e ole a ed han diazoxide.
Al e na i e pha maco he apy op ions include
ni edipine (a calcium channel blocke ha has had
mixed esul s (18)) and glucagon (used o sho - e m
con ol o hypoglycemias (31)). Die a y ea men (21)
can be su icien in some cases and in ol es equen
glucose en iched o al eedings and con inuous o
equen en e al eedings.
Su gical emo al emains he bes op ion in cases
o an iden i iable ocal lesion associa ed wi h CHI
– 94% can be ende ed euglycemic a he ime o
discha ge (33). In cases o medically e ac o y di use
CHI, nea - o al panc ea ec omy (95-98%) may be he
only he apeu ic op ion o cu e o a leas acili a e
he medical managemen . The su gical ou come
in case o di use CHI is highly a iable: pe sis en
hypoglycemia in abou 50% o pa ien s and diabe es
in 20%, howe e mos imp o e hei glycemic con ol
(3). This op ion mus be ca e ully weigh ed also due
o i s po en ial complica ions (namely diabe es and
exoc ine panc ea ic insu iciency (34)) and he ac ha
spon aneous emission can be obse ed in some cases
(31). Rega ding ou cases, nea - o al panc ea ec omy
was pe o med in pa ien numbe 1 due o he se e i y
and neu ological epe cussions o his hypoglycemic
e en s and he lack o al e na i e pha maco he apeu ic
op ions, e en hough by ha ime he e was no a
molecula diagnosis no any o he da a o es ima e he
panc ea ic ex en o he disease (PET was no a ailable
and he e we e no mac oscopic panc ea ic lesions on
su gical explo a ion). The e was no clinical bene i
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pos -ope a i ely and his con ibu ed o he decision o
wi hhold su ge y in pa ien numbe 2 – also gi en he
new- ound knowledge o he ex en o CHI (di use
in ol emen based on pa ien numbe 1 panc ea ic
his ology) associa ed wi h his mu a ion.
The e ha e been epo s o pa ien s wi h CHI due
o HNF4A (35) and HNF1A mu a ions (36) who
p esen ini ially wi h hype insulinemic hypoglycemia
and de elop ma u i y-onse diabe es o he young
ype (MODY) la e in li e. ABCC8 mu a ions ha e
been implied in cases o neona al diabe es ( equen ly
ansien ), MODY (37) and he e a e epo s o
hype insulinemic hypoglycemic diso de in ea ly li e
p og essing o insulinopenic diabe es la e on (38).
Rega ding ou cases, pa ien numbe 1 con inues
o eco d pe iods o pos p andial hype glycemia,
al hough diabe es has been excluded using o al glucose
ole ance es and glyca ed hemoglobin measu emen .
This phenomenon is mos likely a complica ion o nea -
o al panc ea ec omy a he han ano he ea u e o he
disease/geno ype. Addi ional suppo o his hypo hesis
is p esen ed by he ac ha he e we e no hype glycemic
episodes eco ded o da e in he case o pa ien numbe
2, wi h he same disease geno ype. Ne e heless, gi en
hese cases conce n a new compound mu a ion, he
isk o p og ession o diabe es in adul hood is la gely
unknown and should no be dis ega ded.
An in e es ing inding is he ac ha he mo he
de eloped ges a ional diabe es in bo h p egnancies,
al hough hype glycemia did no pe sis a e deli e ies.
I has al eady been es ablished ha ma e nal
hype glycemia can induce e al hype insulinemia and be
esponsible o mac osomia and neona al hypoglycemia
(39). Ne e heless, no link has e e been implied
be ween ma e nal hype glycemia and he p esence
o insulin egula o y gene mu a ions ( he mo he
was ound o be ca ie o he ABCC8 c3576delG
mu a ion).
P olonged and se e e hypoglycemias expose pa ien s
o a poo neu ological ou come and, indeed, some
se ies epo neu ode elopmen delay issues in as much
as 30% o CHI pa ien s (18). This isk may be highe
in cases o neona al onse and diazoxide-un esponsi e
CHI (3). Some MRI b ain inju y pa e ns ha e been
iden i ied (22), such as ce eb al co ex T2 hype in ense
lesions while spa ing ce ebellum, b ains em, and
halamus – his was he case o pa ien numbe 1.
Taking his in o accoun , he be e neu ode elopmen
obse ed in pa ien numbe 2 can p obably be linked
o a mo e apid and app op ia e ea men app oach
due o he p e ious knowledge o he sibling’s disease.
In pa icula , oc eo ide was ini ia ed when she was 2
mon hs old while he b o he only s a ed a 2 yea s
o age, which p obably led o a lesse equency and
se e i y o hypoglycemic episodes du ing he in ancy
and could explain he be e neu ological ou come.
In conclusion, we epo he case o wo siblings wi h
diazoxide- esis an CHI caused by he same compound
ABCC8 mu a ion. Thei he apeu ic managemen
had some di e ences and his could o e a po en ial
explana ion o he dis inc neu ological ou come,
despi e he same gene ic basis o he disease. This case
highligh s he impo ance o he i s siblings index case
clinical and molecula diagnosis and how i seemed o
con ibu e o a be e disease knowledge and medical
ca e in pa ien numbe 2, ul ima ely esul ing in a
be e ou come in spi e o he same disease geno ype.
Disclosu e: no po en ial con lic o in e es ele an o his a icle
was epo ed.
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