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• 2year 6 month old boy case of HRAD
presented with 2nd
attack of hypoglycemia.
• On exam:
• Ht:>97th
. hyperpigmented.
• ...
• 2year 6 month old girl case of HRAD
presented with S.O.B hypoglycemia and
Weakness .
• Her elder sister K/C of FGD1.
• O...
• Definition:
• Familial Glucocorticoid deficiency (FGD) is
a disease in which the zona fasciculata in
the adrenal cortex ...
history
introduction
• also known as hereditary unresponsiveness
to adrenocorticotropic hormone (ACTH) .
• Or ACTH resistance.
• T...
• The exact incidence of FGD is unknown.
• it is a rare disease.
• The incidence of FGD may be
underestimated.
• F=M.
• Th...
• It manifests as deficient adrenal secretion
of cortisol and androgens
• typically with a well preserved renin-
angiotens...
• Mutations in the ACTH receptor .
• Commonest known type.
• known as FGD type 1
• accounted for approximately 25-40% of
F...
• mutations in MRAP are responsible for a
further 15-20% of FGD.
• known as FGD type 2
• MRAP is required for MC2R express...
• Such patients are considered to have non-
classical Lipoid CAH.
• partial loss of function mutations leading to
a ‘milde...
• Such cases are more common than
previously recognized and account for up to
5% of FGD cases.
• The relative preservation...
• Unlike other forms of FGD, cortisol
deficiency was not as pronounced and
onset was usually in childhood following a
peri...
• MCM4 is one part of a heterohexameric
complex responsible for normal DNA
replication and genome stability in all
eukaryo...
• Account for 10% of cases of FGD.
• NNT is involved in the glutathione system
that protects cells against oxidative stres...
• TXNRD2 also involved in the glutathione
system that protects cells against
oxidative stress.
• homozygous mutation in th...
• mutations in TXNRD2 were identified in 3
Patients with a diagnosis of dilated
cardiomyopathy.
• BecauseTXNRD2 falls on c...
• Pathologic evaluation reveals that the
zona glomerulosa of the adrenal glands is
well preserved.
• The zona fasciculata ...
presentation
• hypoglycemic seizures.
• failure to thrive.
• recurrent infections.
• respiratory distress.
• Jaundice .
• ...
• hypothyroidism and growth hormone
deficiency (GHD) has been reported as an
associated feature in a few cases.
• A positi...
• Clinical symptoms are manifested in
infancy or early childhood.
• considerable variation in the clinical
phenotype exist...
• FGD type 2 appears to present earlier.
• This may reflect the functional significance
of the underlying mutations in tha...
• Children with hypoglycemia can present with:
• pallor. sweating.
• palpitations.
• hunger, abdominal symptoms,
• vision ...
• In newborns, symptoms of hypoglycemia
can be subtle; a high index of suspicion is
needed.
• Newborns can present with :
...
• hyperpigmentation of the skin is the most
common initial presenting sign and is
almost always present at diagnosis.
• ex...
hyperpigmentation
• Excessive plasma ACTH often results in
hyperpigmentation due to overstimulation
of melanocortin 1 rece...
• case of FGD without hyperpigmentation
due to
coexistent MC1R/MC2R mutations.
• The underlying mechanisms are not clear
and do not seem to be related to over-activity
of the growth hormone–insulin-lik...
• In vitro, ACTH increase in proliferation and
differentiation of chondrocyte precursors.
• the anabolic properties of gro...
• Bone growth is stimulated by IGFBP-5.
• glucocorticoid inhibits the synthesis of IGF
binding protein 5 (IGFBP-5) in the
...
neuro
• Severe recurrent prolonged neonatal
hypoglycemia can cause :
• brain injury. Epilepsy, mental retardation,
cerebra...
puberty
• Patients with FGD have no adrenarche
and often have undetectable levels of
adrenal androgens.
• androstenedione ...
• Triple A.
• congenital adrenal hyperplasia.
• Adrenoleucodystrophy.
• Addison’s disease.
DDX
lab
• elevated ACTH.
• low serum cortisol.
• no response to ACTH stimulation.
• normal renin-aldosterone levels.
• high fe...
• ACTH remained elevated despite cortisol
substitution.
• This incomplete ACTH suppression may
be explained by the ineffec...
• Bone age : advanced
• Adrenal MRI or CT scans: reveal small
adrenal glands in FGD.
Imaging
Treatment
• CBA: Managing of Shock .
• Correction of Hypoglycemia.
• Glucocorticoids:
• replacement with hydrocortisone at...
• The adequacy of a treatment regimen may
be clinically judged by noting decreased
hyperpigmentation, absence of weakness,...
• Administer the lowest dosage of
glucocorticoid sufficient to control
symptoms of adrenal insufficiency to
permit normal ...
• Educating parents and patients on the
need to increase hydrocortisone
• dosages during illness and emergency
management ...
• As long as a diagnosis of adrenal failure is
considered, treatment is relatively
straightforward and the long-term
progn...
MC2R MRAP MCM4 NNT TXNRD2
prevalence 25-40% 15-20% 5% 10% -
Age of
presentation
Infant to
childhood
infant Late
childhood
...
• FGD is a rare, treatable disease that can
be easily missed due to its nonspecific
presentation.
• delayed diagnosis are ...
• 1- Eirini Meimaridou,Familial
glucocorticoid deficiency: New genes and
mechanisms. Molecular and Cellular
Endocrinology ...
• 3- Hessa M. al Kandari, Familial Glucocorticoid
Deficiency in Five Arab Kindreds with
Homozygous Point Mutations of the ...
• 5- H Rumie, Clinical and biological phenotype
of a patient with familial glucocorticoid
deficiency type 2 caused by a mu...
• 5- Serap tauran. An Atypical Case of Familial
Glucocorticoid Deficiency without
Pigmentation Caused by Coexistent
Homozy...
• 7- K. S. shivaprasad, Familial glucocorticoid
deficiency presenting with generalized
hyperpigmentation in adolescence. R...
• 9- Rathi Prasad, Thioredoxin Reductase 2
(TXNRD2) Mutation Associated With Familial
Glucocorticoid Deficiency (FGD). (J ...
• 11-abdulrahman al-hussaini, Isolated
Cortisol Deficiency: A Rare Cause of
Neonatal Cholestasis. Saudi J
Gastroenterol. 2...
familial glucocorticoid defceincy.pptx
familial glucocorticoid defceincy.pptx
familial glucocorticoid defceincy.pptx
familial glucocorticoid defceincy.pptx
familial glucocorticoid defceincy.pptx
familial glucocorticoid defceincy.pptx
familial glucocorticoid defceincy.pptx
familial glucocorticoid defceincy.pptx
familial glucocorticoid defceincy.pptx
familial glucocorticoid defceincy.pptx
familial glucocorticoid defceincy.pptx
familial glucocorticoid defceincy.pptx
familial glucocorticoid defceincy.pptx
familial glucocorticoid defceincy.pptx
familial glucocorticoid defceincy.pptx
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familial glucocorticoid defceincy.pptx

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familial glucocorticoid defceincy in pediatric

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familial glucocorticoid defceincy.pptx

  1. 1. • 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.
  2. 2. • 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.
  3. 3. • 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.
  4. 4. history
  5. 5. 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.
  6. 6. • 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
  7. 7. • 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.
  8. 8. • 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.
  9. 9. • 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
  10. 10. • 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.
  11. 11. • 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.
  12. 12. • 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
  13. 13. • MCM4 is one part of a heterohexameric complex responsible for normal DNA replication and genome stability in all eukaryotes.
  14. 14. • 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)
  15. 15. • 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
  16. 16. • 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
  17. 17. • Pathologic evaluation reveals that the zona glomerulosa of the adrenal glands is well preserved. • The zona fasciculata and zona reticularis are markedly atrophic. Pathology
  18. 18. presentation • hypoglycemic seizures. • failure to thrive. • recurrent infections. • respiratory distress. • Jaundice . • learning difficulties. • Hyper pigmentation. • Tall stature. Presentation
  19. 19. • 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
  20. 20. • 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
  21. 21. • 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
  22. 22. • 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
  23. 23. • 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
  24. 24. • 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
  25. 25. 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
  26. 26. • case of FGD without hyperpigmentation due to coexistent MC1R/MC2R mutations.
  27. 27. • 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
  28. 28. • 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
  29. 29. • 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
  30. 30. neuro • Severe recurrent prolonged neonatal hypoglycemia can cause : • brain injury. Epilepsy, mental retardation, cerebral palsy Neurological sequele
  31. 31. 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
  32. 32. • Triple A. • congenital adrenal hyperplasia. • Adrenoleucodystrophy. • Addison’s disease. DDX
  33. 33. lab • elevated ACTH. • low serum cortisol. • no response to ACTH stimulation. • normal renin-aldosterone levels. • high ferritin. Lab
  34. 34. • 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
  35. 35. • Bone age : advanced • Adrenal MRI or CT scans: reveal small adrenal glands in FGD. Imaging
  36. 36. 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
  37. 37. • 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
  38. 38. • 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
  39. 39. • Educating parents and patients on the need to increase hydrocortisone • dosages during illness and emergency management with intramuscular hydrocortisone is vital. Treatment
  40. 40. • As long as a diagnosis of adrenal failure is considered, treatment is relatively straightforward and the long-term prognosis is good. Prognosis
  41. 41. 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
  42. 42. • 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
  43. 43. • 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
  44. 44. • 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
  45. 45. • 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
  46. 46. • 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
  47. 47. • 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
  48. 48. • 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
  49. 49. • 11-abdulrahman al-hussaini, Isolated Cortisol Deficiency: A Rare Cause of Neonatal Cholestasis. Saudi J Gastroenterol. 2012 Sep-Oct; 18(5): 339– 341 references

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