• 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.

• 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.

• 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.

history

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.

• 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

• 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.

• 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.

• 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

• 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.

• 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.

• 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

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

• 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)

• 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

• 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

• Pathologic evaluation reveals that the zona glomerulosa of the adrenal glands is well preserved.

• The zona fasciculata and zona reticularis are markedly atrophic.

Pathology

presentation

• hypoglycemic seizures.

• failure to thrive.

• recurrent infections.

• respiratory distress.

• Jaundice .

• learning difficulties.

• Hyper pigmentation.

• Tall stature.

Presentation

• 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

• 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

• 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

• 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

• 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

• 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

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

• 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-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

• 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

• 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

neuro

• Severe recurrent prolonged neonatal hypoglycemia can cause :

• brain injury. Epilepsy, mental retardation, cerebral palsy

Neurological sequele

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

• 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 ferritin.

Lab

• 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

• 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 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

• 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

• 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

• Educating parents and patients on the need to increase hydrocortisone

• dosages during illness and emergency management with intramuscular hydrocortisone is vital.

Treatment

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

Prognosis

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 Chromosomal breakage ,NK defect

Associated cardiac

• 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

• 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

• 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

• 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

• 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

• 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

• 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

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

references