familial glucocorticoid defceincy in pediatric

3. • 2year 6 month old boy case of HRAD
presented with 2nd
attack of hypoglycemia.
• On exam:
• Ht:>97th
. hyperpigmented.
• Lab:
• ACTH:440 . Cortisol:9
• U/E:WNL.

4. • 2year 6 month old girl case of HRAD
presented with S.O.B hypoglycemia and
Weakness .
• Her elder sister K/C of FGD1.
• On exam:
• Ht:97th
. hyperpigmented.
• Lab:
• ACTH:90 . Cortisol:6
• U/E:WNL.

5. • Definition:
• Familial Glucocorticoid deficiency (FGD) is
a disease in which the zona fasciculata in
the adrenal cortex fail to respond
appropriately to stimulation by ACTH to
produce cortisol.

7. history

8. introduction
• also known as hereditary unresponsiveness
to adrenocorticotropic hormone (ACTH) .
• Or ACTH resistance.
• The disease is characterized by isolated
glucocorticoid deficiency.
• is a rare, potentially lethal, autosomal
recessive disorder.

9. • The exact incidence of FGD is unknown.
• it is a rare disease.
• The incidence of FGD may be
underestimated.
• F=M.
• The most frequent cause of FGD death is
undiagnosed glucocorticoid insufficiency

10. • It manifests as deficient adrenal secretion
of cortisol and androgens
• typically with a well preserved renin-
angiotensin-aldosterone axis.
• Nevertheless, minor disturbances of the
renin-aldosterone axis at the time of
presentation and during illness not
requiring long-term mineralocorticoid
replacement, are well established.

12. • Mutations in the ACTH receptor .
• Commonest known type.
• known as FGD type 1
• accounted for approximately 25-40% of
FGD patients.
• over 40 pathogenetic MC2R mutations
have been reported throughout the world.

13. • mutations in MRAP are responsible for a
further 15-20% of FGD.
• known as FGD type 2
• MRAP is required for MC2R expression in
certain cell types, suggesting
that MRAP plays a role in processing,
trafficking, or function of the MC2R

15. • Such patients are considered to have non-
classical Lipoid CAH.
• partial loss of function mutations leading to
a ‘milder’ phenotype of non-classical
LCAH
• Similarly CYP11A1 mutations (partial)
usually give same phenotype.

16. • Such cases are more common than
previously recognized and account for up to
5% of FGD cases.
• The relative preservation of mineralocorticoid
production probably reflects the lower
production rate of aldosterone compared with
cortisol which allows the adrenal zona
glomerulosa to escape damage by lipid
deposition.

17. • Unlike other forms of FGD, cortisol
deficiency was not as pronounced and
onset was usually in childhood following a
period of normal adrenal function.
• patients had short stature,
• there is evidence of increased
chromosomal breakage.
• natural killer cell deficiency

18. • MCM4 is one part of a heterohexameric
complex responsible for normal DNA
replication and genome stability in all
eukaryotes.

19. • Account for 10% of cases of FGD.
• NNT is involved in the glutathione system
that protects cells against oxidative stress.
• NNT located in the inner mitochondrial
membrane, provides the high
concentrations of reduced nicotinamide
adenine dinucleotide phosphate (NADPH)
required by the thioredoxin and
glutathione systems to detoxify
mitochondrial H2O2.
Mutations in nicotinamide nucleotide
transhydrogenase (NNT)

20. • TXNRD2 also involved in the glutathione
system that protects cells against
oxidative stress.
• homozygous mutation in the mitochondrial
selenoprotein, thioredoxin reductase 2
(TXNRD2) associated with FGD in an
consanguineous Kashmiri kindred.
mutations in TXNRD2

21. • mutations in TXNRD2 were identified in 3
Patients with a diagnosis of dilated
cardiomyopathy.
• BecauseTXNRD2 falls on chromosome
22, this raises the possibility
thatTXNRD2contributes to the cardiac
phenotype of DGS.
mutations in TXNRD2

23. • Pathologic evaluation reveals that the
zona glomerulosa of the adrenal glands is
well preserved.
• The zona fasciculata and zona reticularis
are markedly atrophic.
Pathology

24. presentation
• hypoglycemic seizures.
• failure to thrive.
• recurrent infections.
• respiratory distress.
• Jaundice .
• learning difficulties.
• Hyper pigmentation.
• Tall stature.
Presentation

25. • hypothyroidism and growth hormone
deficiency (GHD) has been reported as an
associated feature in a few cases.
• A positive family history of consanguinity
or early unexplained infant deaths or other
affected family members supports a
diagnosis of FGD
Presentation

26. • Clinical symptoms are manifested in
infancy or early childhood.
• considerable variation in the clinical
phenotype exists even for patients with
identical MC2R mutations.
• tall stature is more common with MC2R
mutations.
Clinical Presentation

27. • FGD type 2 appears to present earlier.
• This may reflect the functional significance
of the underlying mutations in that all
MRAP mutations are nonsense or splice
site mutations that result in abolition of a
functional protein.
• whereas most of the MC2R mutations are
missense mutations and give rise to
proteins with some residual function.
Clinical Presentation

29. • Children with hypoglycemia can present with:
• pallor. sweating.
• palpitations.
• hunger, abdominal symptoms,
• vision changes, or
• changes in mental status such as confusion,
mood changes, lethargy, seizures, and coma.
hypoglycemia

30. • In newborns, symptoms of hypoglycemia
can be subtle; a high index of suspicion is
needed.
• Newborns can present with :
• irritability, jitteriness, respiratory distress,
cyanosis, apnea, hypotonia, or seizures.
hypoglycemia

31. • hyperpigmentation of the skin is the most
common initial presenting sign and is
almost always present at diagnosis.
• excess pigmentation of skin, areolae,
genitalia, and mucous membranes.
hyperpigmentatoion

34. hyperpigmentation
• Excessive plasma ACTH often results in
hyperpigmentation due to overstimulation
of melanocortin 1 receptors (MC1R).
• This hyperpigmentation can be present
from birth or may develop over time.
• The lack of pigmentation was explained by
the coexistence of a homozygous,
inactivating MC1R variant previously
associated with red hair and fair skin
hyperpigmentatoion

35. • case of FGD without hyperpigmentation
due to
coexistent MC1R/MC2R mutations.

36. • The underlying mechanisms are not clear
and do not seem to be related to over-activity
of the growth hormone–insulin-like growth
factor I (IGF-I) axis.
• glucocorticoid deficiency itself or excessively
high ACTH levels may have a causative role.
• hypothesis is that ACTH at high
concentrations activates melanocortin
receptors in bone and the cartilaginous
growth plate and stimulates growth.
TALL stature

37. • In vitro, ACTH increase in proliferation and
differentiation of chondrocyte precursors.
• the anabolic properties of growth hormone
unopposed by cortisol may result in this
increase in height.
TALL stature

38. • Bone growth is stimulated by IGFBP-5.
• glucocorticoid inhibits the synthesis of IGF
binding protein 5 (IGFBP-5) in the
osteoblast.
• and thus cortisol deficiency results in a
lack of negative inhibition and the
consequent growth spurt seen in FGD .
TALL stature

39. neuro
• Severe recurrent prolonged neonatal
hypoglycemia can cause :
• brain injury. Epilepsy, mental retardation,
cerebral palsy
Neurological sequele

40. puberty
• Patients with FGD have no adrenarche
and often have undetectable levels of
adrenal androgens.
• androstenedione and DHEA-S were very
low even at an adult age.
• Although he did not develop adrenarche,
his gonadarche occurred at a normal age.
Puberty

41. • Triple A.
• congenital adrenal hyperplasia.
• Adrenoleucodystrophy.
• Addison’s disease.
DDX

42. lab
• elevated ACTH.
• low serum cortisol.
• no response to ACTH stimulation.
• normal renin-aldosterone levels.
• high ferritin.
Lab

43. • ACTH remained elevated despite cortisol
substitution.
• This incomplete ACTH suppression may
be explained by the ineffective MC2R-
dependent short feedback loop of ACTH
on the pituitary or the hypothalamus
Lab

44. • Bone age : advanced
• Adrenal MRI or CT scans: reveal small
adrenal glands in FGD.
Imaging

45. Treatment
• CBA: Managing of Shock .
• Correction of Hypoglycemia.
• Glucocorticoids:
• replacement with hydrocortisone at a dose
of 10-12 mg/m2
/day in three divided doses.
• The suppression of plasma ACTH levels in
FGD can be very difficult and should not
be used as the goal of treatment.
Treatment

46. • The adequacy of a treatment regimen may
be clinically judged by noting decreased
hyperpigmentation, absence of weakness,
and normalization of blood sugar values.
• Intercurrent illness or stress necessitates
a readjustment of glucocorticoid dosage.
Treatment

47. • Administer the lowest dosage of
glucocorticoid sufficient to control
symptoms of adrenal insufficiency to
permit normal growth in these patients.
• Alternatively, overtreatment with
glucocorticoids may result in growth failure
and features of Cushing syndrome.
Treatment

50. • Educating parents and patients on the
need to increase hydrocortisone
• dosages during illness and emergency
management with intramuscular
hydrocortisone is vital.
Treatment

51. • As long as a diagnosis of adrenal failure is
considered, treatment is relatively
straightforward and the long-term
prognosis is good.
Prognosis

52. MC2R MRAP MCM4 NNT TXNRD2
prevalence 25-40% 15-20% 5% 10% -
Age of
presentation
Infant to
childhood
infant Late
childhood
variable variable
stature Tall normal short variable
race - - Irish - kashmir
other Chromosom
al breakage
,NK defect
Associated
cardiac

53. • FGD is a rare, treatable disease that can
be easily missed due to its nonspecific
presentation.
• delayed diagnosis are associated with
high rates of morbidity and mortality.
• Clinical awareness of this condition is of
considerable prognostic and therapeutic
significance.
conclusion

54. • 1- Eirini Meimaridou,Familial
glucocorticoid deficiency: New genes and
mechanisms. Molecular and Cellular
Endocrinology 371 (2013) 195–200.
• 2- Adrian J.L. ,The genetics of familial
glucocorticoid deficiency. Best Practice &
Research Clinical Endocrinology &
Metabolism 23 (2009) 159–165
references

55. • 3- Hessa M. al Kandari, Familial Glucocorticoid
Deficiency in Five Arab Kindreds with
Homozygous Point Mutations of the ACTH
Receptor (MC2R) : Genotype and Phenotype
Correlations. Horm Res Paediatr 2011;76:165–
171
• 4- R P Dias, Isolated Addison’s disease is unlikely
to be caused by mutations in MC2R, MRAP or
STAR, three genes responsible for familial
glucocorticoid deficiency. European Journal of
Endocrinology (2010) 162 357–359
references

56. • 5- H Rumie, Clinical and biological phenotype
of a patient with familial glucocorticoid
deficiency type 2 caused by a mutation of
melanocortin 2 receptor accessory protein.
European Journal of Endocrinology (2007)
157 539–542
• 6-Kotb A Metwalley, Familial glucocorticoid
deficiency presenting with generalized
hyperpigmentation in an Egyptian child: a
case report. Journal of Medical Case Reports
2012, 6:110
references

57. • 5- Serap tauran. An Atypical Case of Familial
Glucocorticoid Deficiency without
Pigmentation Caused by Coexistent
Homozygous Mutations in MC2R (T152K)
and MC1R(R160W). J Clin Endocrinol Metab.
May 2012; 97.
• 6- Teng-Teng L. L. Phenotypic characteristics
of familial glucocorticoid deficiency (FGD)
type 1 and 2. Clinical Endocrinology (2010)
72, 589–594
references

58. • 7- K. S. shivaprasad, Familial glucocorticoid
deficiency presenting with generalized
hyperpigmentation in adolescence. Report of
three siblings. Indian J Endocrinol Metab.
Dec 2012; 16(Suppl 2): S382–S384.
• 8-Shwetha Ramachandrappa ,The
melanocortin receptors and their accessory
proteins,fortiner in endocrinology published:
08 February 2013
references

59. • 9- Rathi Prasad, Thioredoxin Reductase 2
(TXNRD2) Mutation Associated With Familial
Glucocorticoid Deficiency (FGD). (J Clin
Endocrinol Metab 99: E1556–E1563, 2014).
• 10- Tatiana V Novoselova, NNT Pseudoexon
Activation as a Novel Mechanism for Disease
in Two Siblings with Familial Glucocorticoid
Deficiency. J Clin Endocrinol Metab 2014
references

60. • 11-abdulrahman al-hussaini, Isolated
Cortisol Deficiency: A Rare Cause of
Neonatal Cholestasis. Saudi J
Gastroenterol. 2012 Sep-Oct; 18(5): 339–
341
references