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Latest Insights on the Etiology and Management of Primary Adrenal Insufficiency in Children.


Primary adrenal insufficiency (PAI) is a relatively rare but potentially lethal clinical condition in which the adrenal cortex cannot produce adequate amounts of steroid hormones, primarily cortisol, but may also include impaired production of aldosterone and adrenal sex steroids. Recent molecular advances have expanded our knowledge of the etiologies of PAI. However, its diagnosis may be missed or delayed unless an illness or stress precipitates a severe cardiovascular collapse resulting in acute adrenal crisis. Early recognition of the clinical findings and treatment with glucocorticoids and rehydration with intravenous fluids, with or without mineralocorticoids and salt, are life-saving while attempts to confirm the diagnosis with extensive work-up are ongoing. Delay in treatment may result in disastrous clinical outcomes.

This review mainly focuses on the recent advances in the etiology, clinical manifestations and management of PAI of genetic origin in children.


PAI in children may arise from abnormalities in the development of adrenal gland, impaired steroidogenesis, resistance to adrenocorticotropin hormone (ACTH) action [familial glucocorticoid deficiency (FGD)] or adrenal destruction. In contrast to the predominance of autoimmune etiologies in adults, most causes of PAI in childhood are inherited and monogenic in origin (1,2,3,4). Table 1 summarises the aetiologies of inherited PAI in children.

Congenital Adrenal Hyperplasia

Congenital adrenal hyperplasia (CAH), which occurs in 1 in 10.000-18.000 live births, accounts for most cases of PAI in childhood (5). CAH represents a group of autosomal recessive disorders associated with deficiencies in the enzymes and cofactor proteins required for cortisol biosynthesis (6). Cortisol deficiency increases ACTH production that subsequently leads to adrenocortical hyperplasia and accumulation of the upstream precursor steroids above the enzyme deficiency. The accumulated upstream steroids and their urinary metabolites present the biochemical fingerprints for the localization of the defect (Figure 1). Additionally, these steroid precursors are generally diverted to androgen producing alternate pathways leading to androgen excess. The accumulation of certain steroid precursors enable differentiation of steroidogenic enzyme deficiencies (except StAR and P450 side-chain cleavage enzyme deficiencies) from the rest of the etiologies leading to PA1, as non-CAH is characterized by elevated ACTH concentrations and low steroidogenic intermediates.

The presence of hyperpigmentation of skin, nail beds, mucous membranes, palmar creases and scars is one of the hallmarks of primary adrenocortical pathology. ACTH and alpha-melanocyte stimulating hormone ([alpha]-MSH) are cleavage products of pro-opiomelanocortin (POMC). 1n patients with low cortisol levels as a consequence of adrenal disorders, POMC synthesis and consequently ACTH and MSH levels rise by negative feedback mechanisms. [alpha]-MSH then binds to the melanocortin 1 receptor on melanocyte cells, inducing a switch from the production of the pale skin pigment pheomelanin to eumelanin which is the darker (brown or black) pigment (7).

Clinical presentation may be mild or severe depending on the degree of impairment of enzyme activity and there may be signs, symptoms and laboratory findings of cortisol deficiency, mineralocorticoid deficiency or excess, undervirilization or androgen excess in males and sexual infantilism or virilization in affected females. The main signs and symptoms of cortisol deficiency include anorexia, weight loss, fatigue, myalgia, joint pain, low blood pressure, orthostatic hypotension, hyponatremia, hypoglycemia, lymphocytosis and eosinophilia and in addition direct hyperbilirubinemia and apnea may be present in newborn babies. Mineralocorticoid synthesis and release is under the control of the renin-angiotensin system, rather than ACTH. Therefore, mineralocorticoid deficiency develops only in adrenocortical abnormalities. Mineralocorticoid deficiency causes failure to thrive, abdominal pain, nausea, vomiting, dizziness, low blood pressure, orthostatic hypotension, hyponatremia, salt craving, hyperkalemia, metabolic acidosis, dehydration and hypovolemic shock. Lack of pubic and/or axillary hair and absent/delayed clinical adrenarche in either sex suggests deficiency of adrenal sex steroids.

More than 95% of all cases of CAH are caused by 21-hydroxylase deficiency (21-OHD). 21-OHD is classified into 3 subtypes according to retained enzyme activity and clinical severity: classic salt wasting, classic simple virilizing, and nonclassic CAH (NCCAH; mild or late onset) (6,8). The classic type affects approximately 1 in 16.000 live births. NCCAH is one of the most common autosomal recessive disorders in humans and affects approximately 1 in 1000 individuals (6). The second most common form of CAH, 11 [beta]-hydroxylase deficiency (11-OHD), occurs in 1 in 100,000 live births and accounts for approximately 5% of cases (9). Other less common forms of CAH include 3[beta]-hydroxysteroid dehydrogenase type 2 deficiency, 17[alpha]-hydroxylase deficiency, POR deficiency, lipoid CAH and cholesterol side-chain cleavage enzyme deficiency. Distinctive clinical and biochemical features and management goals of CAH are presented in Table 2. An expert review on the genetic features of CAH is also available (6).

Advances in steroid assays in recent years, particularly the clinical utility of liquid chromatography/tandem mass spectrometry (LC-MS/MS), have allowed more accurate quantitation of key steroids, simultaneous measurement of multiple steroids from small biological samples and identification of novel steroids in the pathogenesis of adrenal disorders. The best example of this is the emerging evidence of 11-oxygenated 19-carbon (11oxC19) adrenal-derived steroids as clinically important androgens. 11oxC19 steroids are synthesized by the action of cytochrome P450 11 [beta]-hydroxylase. Besides the last step of cortisol biosynthesis, cytochrome P450 11 [beta]-hydroxylase mediates the conversion of androstenedione and testosterone into their respective 11-oxygenated products, namely 11 [beta]-hydroxyandrostenedione (11OHA4) and 11 [beta]-hydroxytestosterone (11OHT). These steroids are further converted to small amounts of 11-ketoandrostenedione (11KA4) and 11-ketotestosterone (11KT) respectively, by the action of 11 [beta]-hydroxysteroid dehydrogenase, type 2. 11oxC19 steroids are produced almost exclusively from the adrenal gland and they were shown to be three to four times higher in 21OHD patients than in controls. In addition 11KT was found to be more closely associated with poor control in 21OHD than testosterone levels in both males and females. Therefore it has been hypothesized that 11KT is a major adrenal androgen, responsible for suppression of gonadal functions observed in poorly controlled 21OHD (10). Furthermore, 21-deoxycortisol and 11oxC19 steroids showed the closest correlation with adrenal gland size and 11oxC19 steroids were detected at much higher concentrations in CAH patients with testicular adrenal rest tumor (TART) than those without (11). These findings suggest that 11oxC19 steroids may present clinically promising biomarkers in the treatment monitoring and management of CAH.

Adrenal Dysgenesis/Hypoplasia

During the last two decades, high-throughput sequencing approaches proved very effective in reaching a molecular diagnosis for several forms of primary adrenal hypoplasia and adrenal dysgenesis syndromes. The genetic basis for these disorders involves various cellular and physiologic processes, including metabolism, nuclear protein import, oxidative stress defense mechanisms and regulation of cell cycle (12). Two distinct histological patterns of adrenal hypoplasia have been described; the miniature adult and cytomegalic forms. In the miniature adult form, adrenal cortex has normal structural organization whereas in the cytomegalic form of primary adrenal hypoplasia the residual adrenal cortex is structurally disorganized with scattered irregular nodular formations of eosinophilic cells, with the adult permanent zone absent or nearly absent. The miniature adult form is generally sporadic or inherited in an autosomal recessive manner while the cytomegalic form is generally considered to be X-linked, but there may be one or more autosomal genes associated with this phenotype (12). Regardless of underlying genetic etiology, conditions with adrenal hypoplasia/dysplasia are associated with deficiency of all adrenocortical hormones (aldosterone, cortisol, androgens). Most common is DAX1 deficiency which is due to genetic defects in NR0B1, located on chromosome Xp21.2. DAX1 defects have been detected in two thirds of males with PA1 of unknown etiology by clinical or biochemical phenotype (13). Therefore all male patients with a history of non-CAH PA1 should be screened for DAX1 deficiency, especially those with infertility, delayed/absent puberty or adrenal insufficiency in males from the maternal family. Adrenal insufficiency shows a bimodal distribution pattern of age at presentation ie either around newborn period or after 1 year of age. However late-onset DAX1 deficiency cases are also being increasingly reported from adult clinics (3,14). Patients with DAX1 deficiency present with variable phenotypes. Typically, they develop severe primary adrenal failure with salt-wasting. The hypogonadotropic hypogonadism may manifest as delayed puberty, impaired spermatogenesis or infertility which is explained by the expression of NR0B1 in the hypothalamus and the anterior pituitary, besides the adrenal glands and the gonads. Therefore, long-term focus on puberty and fertility is needed in affected individuals. Ambiguous genitalia is not a feature of DAX1 deficiency. However micropenis and or cryptorchidism may be present. Patients with precocious puberty have also been reported (15,16). Although this is an X-linked condition, females carrying homozygous or heterozygous mutations have also been reported to express phenotypic features of adrenal hypoplasia congenital due to non-random X inactivation (17,18). Genetic counselling can help to identify family members at risk of adrenal insufficiency and female carriers.

The SF1 protein, encoded by the nuclear receptor subfamily 5, group A, member 1 (NR5A1) gene, is expressed in the adrenal gland, gonads, hypothalamus and anterior pituitary. SF1 has a crucial role in adrenal gland, gonads and spleen development in both sexes. Besides, SF1 is involved in the regulation of energy balance and glucose homeostasis in the central nervous system (19). SF1 deficiency develops as a result of pathogenic mutations in NR5A1 gene in both heterozygous or homozygous inheritance. 1n contrast to DAX1-associated diseases, SF-1 deficiency only rarely causes adrenal insufficiency, but generally in combination with testicular dysgenesis. 1solated adrenal failure has rarely been reported (20). However, long-term follow-up for adrenal function is important for those patients with NR5A1 mutations. Phenotypic features in 46,XY individuals with NR5A1 mutations include different forms of disorders of sex differentiation (DSD) ranging from hypospadias to complete female phenotype or late-onset impaired spermatogenesis and infertility. NR5A1 gene defects should also be considered in 46,XY DSD cases with normal testosterone concentrations, similar to androgen receptor (AR) mutations or mild 5-[alpha] reductase, or mild 17-ketosteroid reductase deficiencies. Mutations in NR5A1 were found in 46,XX females with isolated/premature ovarian insufficiency (14). 46,XX testicular/ovotesticular DSD is also described in one case (21,22). Poly/asplenia can be seen in both sexes (23).

The common feature of syndromes associated with adrenal hypoplasia is the severe impairment of growth and tissue development and particularly with a prenatal onset. These disorders specifically impair the machinery involved in cell division and cell cycling. The author suggests evaluation of adrenal function in any patient with severe, prenatal-onset growth retardation and with syndromic features, especially with cerebral and finger malformations (Table 1).

Here, two specific examples of syndromic adrenal hypoplasia are given.

IMAGe syndrome is a recently described, syndromic adrenal hypoplasia syndrome associated with severe growth failure. This syndrome develops as a result of impaired expression of a cell cycle regulator protein, cyclin dependent kinase inhibitor 1C (CDKN1C). CDKN1C, encoded by the CDKN1C gene, is a negative regulator of cell proliferation maintaining the cell at the non-proliferative state throughout life. The loss-of-function mutations, located at the CDK-binding domain of the CDKN1C gene, are associated with Beckwith-Wiedemann syndrome. Recently, gain-of-function mutations in the PCNA domain of CDKN1C have been have been described in association with various growth-retarded syndromes including 1MAGe syndrome and Russell Silver syndrome as well as a novel undergrowth syndrome that additionally exhibits early adulthood onset diabetes (24). De novo heterozygous CDKN1C mutations or imprinted mode of inheritance with maternal transmission of CDKN1C mutations were reported. Early recognition of metaphyseal dysplasia accompanying early-onset, severe adrenal insufficiency is crucial for the diagnosis 1MAGe syndrome. Delayed endochondral ossification, osteopenia, hypercalcemia, and/or hypercalciuria of variable degree are among the early findings. Dysmorphic craniofacial features including prominent forehead, low-set ears, short nose, flat nasal bridge, rhizomelic shortening and genital abnormalities in males are other associated features.

Another severe growth-restricting pathology associated with adrenal hypoplasia has recently been described in patients due to gain-of-function mutations in the SAMD9 gene. Growth and survival is so impaired in this genetic disorder that affected individuals develop tissue adaptation by progressive loss of mutated SAMD9 in chromosomal structure. This modification is achieved through the development of monosomy 7 (-7), deletions of 7q (7q-), and secondary somatic loss-of-function (nonsense and frameshift) mutations in SAMD9 to rescue the growth-restricting effects of mutant SAMD9 proteins in bone marrow and to increase the length of survival (25). So the use of advanced diagnostic and molecular technologies has helped to define novel mechanisms in human development beyond genetic defects in adrenal development and adrenal steroidogenesis.

Affected individuals with heterozygous gain-of-function mutation in SAMD9 present with MIRAGE syndrome, which is an acronym of myelodysplasia, infection, restriction of growth, adrenal hypoplasia, genital phenotypes, and enteropathy (26).

Adrenocorticotropin Hormone Resistance

Mutations in MC2R (encoding the ACTH receptor protein, MC2R) and MRAP (encoding MC2R accessory protein) are well described causes of inherited disorders of ACTH binding and signaling, namely FGD type 1 (FGD1) and type 2 (FGD2). FGD is characterized by cortisol deficiency together with a preserved renin-aldosterone axis. Children typically present with hypoglycemia or hyperpigmentation in early infancy or in childhood. Some associated phenotypical features may also be present (Table 1). Children with FGD do not typically have salt-loss. However, transient hyponatremia has been reported in several children with severe MC2R defects, sometimes leading to a misdiagnosis of adrenal hypoplasia (3). Plasma ACTH often remains markedly raised despite normal or even supranormal glucocorticoid treatment. Therefore, affected patients remain hyperpigmented. So the clinical aim of glucocorticoid replacement strategies should not be to suppress ACTH or normalization of hyperpigmentation but should rather target normal water and electrolyte balance and a normal physical growth rate.

Mitochondria and Adrenal Gland

Recent advances in molecular studies and application of genome-wide, next-generation sequencing approaches revealed the importance of mitochondrial function for endocrine health and steroid hormone biosynthesis. All steroid hormones are synthesized within mitochondria by tissue-specific steroidogenic enzymes (Figure 2). Mitochondrial dysfunction may affect the capacity for adrenocortical hormone production by impaired mitochondrial ATP production, oxidative stress and/or accelerated apoptosis (27). In particular some of the latest findings have expanded the spectrum of pathogenetic mechanisms causing adrenal disease and imply that the adrenal is highly vulnerable to oxidative stresses (Figure 2) (28,29).

Molecular defects in both mitochondrial and nuclear genomes have been associated with mitochondrial dysfunction (Table 1). Clinicians should have a high level of suspicion for the possibility of an underlying mitochondrial disease in patients with adrenal insufficiency associated with sensorineural hearing loss, lactic acidosis and accompanying endocrine abnormalities (diabetes, hypoparathyroidism, hypogonadism, hypothyroidism) and multisystemic diseases (epilepsy, stroke, encephalopathy, cranial abnormalities, cardiac conduction defects, neuropathy, retinopathy).

Sphingolipids and Adrenal Gland

The essential role of sphingolipid metabolism has recently emerged in adrenal disease. Congenital sphingosine1phosphate (S1P) lyase deficiency due to biallelic mutations in the SGPL1 gene has been described, in association with PAI and steroid-resistant nephrotic syndrome (30,31,32). S1P lyase is the enzyme responsible for irreversible S1P degradation which is the final step in sphingolipid breakdown. Inhibition of S1P lyase activity will lead to accumulation of bioactive signaling molecules upstream of the pathway including S1P and ceramides (Cer). We have recently demonstrated that accumulation of S1P, Cer and potentially other upstream components of the sphingolipid pathway, due to congenital S1P lyase deficiency, leads to a multisystemic disorder including PAI, nephrotic syndrome and ichthyosis, primary hypothyroidism, cryptorchidism, lymphopenia and neurological anomalies.

Establishing a specific genetic diagnosis of PAI is extremely valuable for identifying presymptomatic children who could benefit from treatment before the onset of potentially life-threatening symptoms and for counseling family members appropriately about the risk of passing the condition on to their children. Knowing the genetic etiology can also help to modify treatments, such as the need for long-term mineralocorticoid replacement, and can predict potential co-morbidities, such as impaired puberty or fertility and neurological dysfunction. An etiological approach in children with Inherited Primary Adrenal Insufficiency is suggested in Figure 3.


Replacement of glucocorticoids and mineralocorticoids, particularly by hydrocortisone and fludrocortisone is the mainstay of treatment in adrenal insufficiency. 1ntravenous fluids and salt replacement should be added to the treatment in stressful conditions and adrenal crisis. Principal treatment goals include maintaining a physiologic water and electrolyte homeostasis together with attainment of normal physical and pubertal growth. CAH management should also target reduction of androgen exposure. Additionally, optimization of hydrocortisone treatment is critical to mimic the physiological circadian rhythm of cortisol secretion and to avoid excessive glucocorticoid exposure which is associated with poor long-term health outcomes, including growth suppression, obesity, metabolic syndrome, diabetes and osteoporosis (33). These challenges have led to the development of new glucocorticoid formulations and some adjuvant treatments (34). 1n recent years, investigators have developed two modified-release, oral, glucocorticoid preparations. The first is a dual-release hydrocortisone with an extended-release core surrounded by an immediate-release coating (Plenadren; ViroPharma, Maidenhead, UK), which was developed for once-daily, first-morning administration in patients with PA1. However, it is unable to deliver a sufficient early morning cortisol rise and to suppress ACTH and adrenal androg ens in the morning by once-daily dosing. Plenadren failed to achieve physiologic cortisol replacement in a small case series of children with non-CAH primary adrenal failure and secondary adrenal insufficiency (35,36,37). Plenadren is not yet licensed for use in the management of adrenal insufficiency in children, but is available for use in adult patients with a good safety profile (38). The second formulation is a delayed and sustained release, multiparticulate hydrocortisone, Chronocort[R] (Diurnal, UK). Chronocort given at morning and night doses provides release of hydrocortisone in the early hours of the morning, replicating a physiological cortisol secretion pattern. 1t also appears to achieve better control of excessive androgen synthesis produced via classical and alternative pathways through attenuation of androstenedione and 17OH-progesteron (39). There is an ongoing phase 111 study to evaluate long-term effects of Chronocort treatment. This drug is also not licenced for use in children. There are a few recent trials to evaluate the bioavailability and absorption of modified hydrocortisone formulations, such as granules or sprinkles, for young children (1nfacort[R], Diurnal Ltd) (40). Continuous subcutaneous hydrocortisone infusion (CSH1) via a pump, similar to an insulin pump, is superior in achieving a better cortisol secretion profile and lowering ACTH concentrations in non-CAH PAI and in lowering serum androgens in CAH (41,42). However, certain issues limit the use of CSHI including high cost, complexity of device usage, the need for patient/parent education, the potential for local irritation and the potential for uninterrupted equipment wear and malfunction which would be particularly risky in patients with complete glucocorticoid deficiency. A recent meta-analysis demonstrated that extended-/dual-release and CSHI forms of glucocorticoid treatments are associated with higher life quality scores over the short-term (43).

Non-glucocorticoid adjuvant pharmacologic treatments for adrenal failure mainly target control of hyperandrogenism in CAH (34). Among them, abiraterone may be a promising alternative therapy that decreases the need for supraphysiologic exogenous glucocorticoids. Abiraretone is a potent inhibitor of CYP17A1, required for the synthesis of gonadal and adrenal androgens. Combined use of abiraterone with glucocorticoids can effectively lower androstenedione and testosterone metabolites in adult women with 21OHD without any potential side effects including hypertension and hypokalemia. However, it does not lower ACTH and inhibits gonadal sex-steroid secretion which limits its use in males with TART and for patients who desire fertility (44). A CRH receptor-1 antagonist was used in a Phase 1 trial of eight CAH women at a single dose which showed a 40% reduction in morning ACTH rise to control hyperandrogenism (45).


PAI is a relatively rare but potentially lethal clinical condition in children. Early recognition of adrenal insufficiency can be difficult, although treatment is usually successful once it is initiated and, in most cases, lifelong treatment is necessary. Monogenic conditions, particularly CAH, account for most cases of PAI in childhood. Application of omics-based approaches by LC combined with MS significantly facilitated the recognition of biochemical markers of various steroidogenic enzyme deficiencies. In particular, targeted LC-MS/MS steroid panels, besides being very well suited for the routine laboratory setting, have proven extremely useful in diagnosing CAH subtypes and guiding treatment. However, non-CAH PAI often remains without a definite cause in a substantial number of cases. Detailed clinical phenotyping of such cases is critically important for diagnostic workflow but genotyping is equally important, confirming the diagnosis or carrier state, providing prognostic information on disease severity and is essential for genetic counseling.

Adrenal insufficiency is associated with a reduced quality of life that may be caused by non-physiological glucocorticoid replacement. In recent years, a substantial amount of progress has been made in optimizing glucocorticoid delivery systems, as well as by exploring non-glucocorticoid therapeutic strategies in CAH. However, there is still a long way to go in developing disease-specific and personalized treatments for children with PAI.


Peer-review: Internally peer-reviewed.

Financial Disclosure: The author declared that this study received no financial support.


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Tulay Guran

Marmara University Faculty of Medicine, Department of Pediatric Endocrinology and Diabetes, Istanbul, Turkey

Address for Correspondence: Tulay Guran MD, Marmara University Faculty of Medicine, Department of Pediatric Endocrinology and Diabetes, istanbul, Turkey

E-mail: ORCID ID:

[c]Copyright 2017 by Turkish Pediatric Endocrinology and Diabetes Society

The Journal of Clinical Research in Pediatric Endocrinology published by Galenos Publishing House.

Conflict of interest: None declared

Received: 20.10.2017

Accepted: 18.12.2017

DOI: 10.4274/jcrpe.2017.S002
Table 1. Aetiologies of inherited primary adrenal insufficiency in

Condition/deficiency                           Gene              OMIM

Impaired steroidogenesis
Impaired cholesterol transport
Steroidogenic acute regulatory protein         StAR              201710
(congenital lipoid adrenal
hyperplasia) ([+ or -])
Steroidogenic enzyme / co-factor deficiency causing congenital adrenal
21[alpha]-hydroxylase deficiency               CYP21A2           201910
11 [beta]-hydroxylase deficiency               CYP11B1           202010

17[alpha]-hydroxylase deficiency               CYP17A1           202110

P450 oxidoreductase deficiency                 POR               201750

3[beta]-hydroxysteroid                         HSD3B2            201810
dehydrogenase type 2
P450 side-chain cleavage enzyme                CYP11A1           118485
Defects in cholesterol synthesis or metabolism
Smith-Lemli Opitz disease                      DHCR7             270400

Abetalipoproteinemia ([OMEGA])                 MTP               200100

Familial hypercholesterolemia ([OMEGA])        LDLR              143890
Sitosterolemia (phytosterolemia) ([OMEGA])     ABCG5             210250

Adrenal dysgenesis/hypoplasia
Without syndromic features
X-linked adrenal hypoplasia congenital         NR0B1 (DAX1)      300200

Xp21contiguous gene deletion syndrome          Deletion of
(5% of cases)                                  genes for
                                               and NR0B1
Adrenal hypoplasia steroidogenic factor-1      NR5A1 (SF1)       184757
With syndromic features
IMAGe syndrome                                 CDKN1C            300290

MIRAGE syndrome                                SAMD9             617053

Pallister-Hall syndrome                        GLI3              165240

Meckel syndrome                                MKS1              249000

Pena-Shokeir syndrome 1                        DOK7              208150

Pseudotrisomy 13                               RAPSN             264480

Hydrolethalus syndrome                         HYLS1             236680

Galloway-Mowat syndrome                        WDR73             251300

Chromosomal abnormalities                      Tetraploidy,
                                               18, trisomy
                                               21, 5p
                                               and 11q
ACTH resistance
Familial glucocorticoid deficiency type 1      MC2R              202200

Familial glucocorticoid deficiency type 2      MRAP              607398

Adrenal destruction
Impaired redox homeostasis
Nuclear envelope defects
Triple A syndrome (Allgrove syndrome)          AAAS              231550

Mitochondrial defects
Nicotinamide nucleotide                        NNT               614736
transhydrogenase deficiency

Thioredoxin reductase deficiency ([section])   TXNRD2            606448
Glutathione peroxidase deficiency +            GPX1 + PRDX3
peroxiredoxine deficiency (*)

Defects in complex lipid metabolism
a) Peroxisomal defects
X-linked adrenoleukodystrophy                  ABCD1             300100
(X-linked ALD)                                 ABCD2             300371
Neonatal adrenoleukodystrophy                  PEX1              601539
(autosomal recessive)

Zellweger syndrome                             PEX1, 2, 3, 5,    214100
                                               6, 12, 14, 26

Refsum disease                                 PHYH, PEX7        266500

b) Lysosomal defects
Wolman disease                                 LIPA              278000
(lysosomal acid lipase
deficiency, cholesterol
ester storage disease)
c) Endoplasmic reticulum                       defects
Sphingosine-1-phosphate                        SGPL1             603723
lyase deficiency

Autoimmune destruction
Isolated autoimmune                            Association with
adrenalitis                                    CLTA-4, HLA-DR3,
                                               HLA-DR4, HLA-B8
Autoimmune polyglandular syndromes (APS)
APS type 1                                     AIRE

APS type 2                                     Association with
                                               HLA-DR3, CTLA-4
APS type 4                                     Association with
                                               HLA-DR3, CTLA-4
DNA repair defects                             MCM4 ([yen])      609981

Bioinactive ACTH (*)                           POMC

Mitochondrial diseases
Kearns-Sayre syndrome                          Mitochondrial     530000
                                               DNA deletions,

Mitochondrial DNA                              POLG1             203700
polymerase deficiency

Impaired mitochondrial                         GFER              613076
disulfide relay system

MELAS syndrome                                 MTTL1, MTTQ,      540000
                                               MTTH, MTTK,
                                               MTTC, MTTS1-2,
                                               MTND1, 5, 6
Impaired complex I                             NDUFAF5           252010
Impaired translation                           MRPS7, QRSL1      611974,
Pearson syndrome                               Contiguous gene   557000
                                               /duplication of
                                               several mtDNA

Condition/deficiency                           Associated clinical signs
                                               and symptoms

Impaired steroidogenesis
Impaired cholesterol transport
Steroidogenic acute regulatory protein         46,XY DSD, gonadal
(congenital lipoid adrenal                     insufficiency
hyperplasia) ([+ or -])
Steroidogenic enzyme / co-factor deficiency causing congenital adrenal
21[alpha]-hydroxylase deficiency               46,XX DSD,
11 [beta]-hydroxylase deficiency               46,XX DSD,
                                               arterial hypertension
17[alpha]-hydroxylase deficiency               46,XY DSD, arterial
                                               hypertension, gonadal
P450 oxidoreductase deficiency                 46,XX and 46,XY DSD,
                                               gonadal insufficiency,
                                               bone malformations,
                                               affects all endoplasmic
                                               CYP450 enzyme functions
3[beta]-hydroxysteroid                         46,XX and 46,XY DSD,
dehydrogenase type 2                           premature adrenarche,
                                               hyperandrogenism in
P450 side-chain cleavage enzyme                46,XY DSD, gonadal
(P450scc)                                      insufficiency
Defects in cholesterol synthesis or metabolism
Smith-Lemli Opitz disease                      Mental retardation,
                                               malformations, growth
Abetalipoproteinemia ([OMEGA])                 Ataxia, retinopathy,
                                               malabsorption of fat
Familial hypercholesterolemia ([OMEGA])        Tendon xanthomas,
                                               xanthelasma, corneal
Sitosterolemia (phytosterolemia) ([OMEGA])     Short stature, gonadal
                                               failure, xanthomas,
                                               hemolytic anemia,
                                               arthritis, accelerated
                                               atherosclerosis and
                                               premature cardiac death
Adrenal dysgenesis/hypoplasia
Without syndromic features
X-linked adrenal hypoplasia congenital         Hypogonadotropic
                                               hypogonadism in boys. In
                                               some cases gonadotropin
                                               independent precocious
Xp21contiguous gene deletion syndrome          Duchenne muscular
(5% of cases)                                  dystrophy, glycerol
                                               kinase deficiency,
                                               psychomotor retardation
                                               (if deletions extend to
                                               the IL1RAPL1 gene)
Adrenal hypoplasia steroidogenic factor-1      46,XY and 46,XX sex
deficiency                                     reversal, 46,XY DSD,
                                               46,XX DSD, primary
                                               ovarian failure,
                                               spermatogenic failure
With syndromic features
IMAGe syndrome                                 Intrauterine growth
                                               retardation, metaphyseal
                                               dysplasia, adrenal
                                               insufficiency, genital
MIRAGE syndrome                                Myelodysplasia,
                                               infection, restriction of
                                               growth, adrenal
                                               hypoplasia, genital
                                               phenotypes, and
Pallister-Hall syndrome                        Hypothalamic
                                               imperforate anus,
                                               mesoaxial and postaxial
                                               laryngotracheal cleft,
                                               bifid epiglottis
Meckel syndrome                                Central nervous system
                                               malformation (occipital
                                               polycystic kidney,
                                               hepatic fibrosis,
Pena-Shokeir syndrome 1                        Arhrogryposis, fetal
                                               akinesia, intrauterine
                                               growth retardation,
                                               cystic hygroma, pulmonary
                                               hypoplasia, cleft palate,
                                               cryptorchidism, cardiac
                                               defects, camptodactyly,
                                               intestinal malrotation,
                                               pterygiums in extremities
Pseudotrisomy 13                               Holoprosencephaly, facial
                                               abnormalities, postaxial
Hydrolethalus syndrome                         Prenatal-onset severe
                                               micrognathia, abnormal
                                               genitalia, congenital
                                               heart and pulmonary
Galloway-Mowat syndrome                        Early-onset severe
                                               encephalopathy, severe
                                               epilepsy, nephrotic
                                               syndrome, microcephaly,
                                               hiatal hernia
Chromosomal abnormalities                      Often associated with
                                               central nervous system
                                               abnormalities and
                                               prenatal-onset growth
ACTH resistance
Familial glucocorticoid deficiency type 1      Generally isolated
                                               glucocorticoid deficiency
                                               without mineralocorticoid
                                               deficiency, tall stature,
                                               characteristic facial
                                               features, such as
                                               hypertelorism, medial
                                               epicanthus and frontal
Familial glucocorticoid deficiency type 2      Generally isolated
                                               glucocorticoid deficiency
                                               without mineralocorticoid
Adrenal destruction
Impaired redox homeostasis
Nuclear envelope defects
Triple A syndrome (Allgrove syndrome)          Alacrimia, achalasia,
                                               dysfunction of autonomic
                                               nervous system;
                                               additional symptoms,
                                               including neurologic
                                               impairment, deafness,
                                               mental retardation,
Mitochondrial defects
Nicotinamide nucleotide                        Generally isolated
transhydrogenase deficiency                    glucocorticoid deficiency
                                               without mineralocorticoid
                                               deficiency, subclinical
                                               diabetes mellitus
Thioredoxin reductase deficiency ([section])   Isolated glucocorticoid
Glutathione peroxidase deficiency +            A single patient with
peroxiredoxine deficiency (*)                  homozygous gene defects
                                               in both genes was
                                               described. Patient had
                                               isolated glucocorticoid
Defects in complex lipid metabolism
a) Peroxisomal defects
X-linked adrenoleukodystrophy                  Progressive
(X-linked ALD)                                 neurodegeneration,
                                               cognitive and behavioral
                                               changes, progressive loss
                                               of hearing and vision;
                                               dementia, spasticity,
Neonatal adrenoleukodystrophy                  Severe hypotonia,
(autosomal recessive)                          seizures and
                                               encephalopathy, blindness
                                               and deafness, hepatic
                                               dysfunction, peroxysomal
Zellweger syndrome                             Severe neuromotor and
                                               growth retardation,
                                               hypotonia, deafness,
                                               blindness, craniofacial
                                               hepatovmegaly, stippled
                                               epiphysis, genitourinary
                                               anomalies, infants
                                               occasionally mistaken as
                                               having Down syndrome
Refsum disease                                 Multiple epiphyseal
                                               cardiomyopathy, anosmia,
                                               retinitis pigmentosa,
                                               neuropathy, deafness,
                                               ataxia, ichthyosis
b) Lysosomal defects
Wolman disease                                 Diffuse punctate adrenal
(lysosomal acid lipase                         calcification,
deficiency, cholesterol                        xanthomatous changes in
ester storage disease)                         liver, adrenals, spleen,
                                               lymph nodes, bone marrow,
                                               small intestine, lungs
                                               and thymus and slight
                                               changes in skin, retina,
                                               and central nervous
c) Endoplasmic reticulum
Sphingosine-1-phosphate                        Steroid-resistant
lyase deficiency                               nephrotic syndrome,
                                               ichthyosis, lymphopenia,
                                               neurological defects,
                                               primary hypothyroidism,
Autoimmune destruction
Isolated autoimmune

Autoimmune polyglandular syndromes (APS)
APS type 1                                     Chronic mucocutaneous
                                               hypoparathyroidism, other
                                               autoimmune disorders,
                                               rarely lymphomas
APS type 2                                     Hypothyroidism,
                                               premature ovarian
                                               failure, vitiligo, type 1
                                               diabetes mellitus,
                                               pernicious anemia
APS type 4                                     Other autoimmune
                                               diseases, excluding
                                               thyroid disease or
                                               diabetes (unusual in

DNA repair defects                             Natural killer cell
                                               deficiency, short
                                               stature, microcephaly,
                                               recurrent viral
                                               infections, chromosomal
                                               breakage, susceptibility
                                               for neoplastic lesions
Bioinactive ACTH (*)                           Signs and symptoms of
                                               POMC deficiency (obesity
                                               and red hair), high ACTH
                                               and low cortisol.
                                               Bioinactive but
                                               immunoreactive ACTH
Mitochondrial diseases
Kearns-Sayre syndrome                          Progressive external
                                               ophthalmoplegia, ptosis,
                                               retinal degeneration, and
                                               cardiac conduction
                                               defects, microcephaly,
                                               other endocrinopathies,
                                               lactic acidosis,
                                               neuropathy, myopathy,
                                               ragged-red fibers seen on
                                               muscle biopsy
Mitochondrial DNA                              Infantile epilepsy,
polymerase deficiency                          metabolic strokes,
                                               chronic ataxia,
                                               neuropathy, and
                                               ophthalmoplegia, type I
                                               diabetes, hypothyroidism
                                               and psychiatric problems
Impaired mitochondrial                         Encephalomyopathy,
disulfide relay system                         congenital cataracts,
                                               hypotonia, developmental
                                               delay and sensorineural
                                               hearing loss, lactic
                                               acidosis, respiratory
MELAS syndrome                                 Mitochondrial myopathy,
                                               encephalopathy, lactic
                                               acidosis, stroke-like
Impaired complex I                             Agenesis of the corpus
assembly                                       callosum and ventricular
                                               septation, congenital
                                               left diaphragmatic hernia
                                               and lactic acidosis
Impaired translation                           Sensorineural deafness,
                                               primary ovarian failure,
                                               progressive hepatic and
                                               renal failure and lactic
Pearson syndrome                               Low birth weight, failure
                                               to thrive, sideroblastic
                                               anemia, exocrine
                                               pancreatic dysfunction

([+ or -]) Mild defects may present like familial glucocorticoid
deficiency (known mutations of StAR causing non-classic deficiency are
p.R192C, p.R188C), ([OMEGA]) Asssociated with mild biochemical cortisol
deficiency but not clinically significant adrenal failure, ([section])
Described only in seven individuals from a consanguineous Kashmiri
kindred, to date, ([yen]) Described only in the Irish traveler
population, to date, (*) Described in a single patient
StAR: steroidogenic acute regulatory protein, CYP21A2: cytochrome P450,
family 21, subfamily A, polypeptide 2, CYP11B1: cytochrome P450, family
11, subfamily B, polypeptide 1, CYP17A1: cytochrome P450, family 17,
subfamily A, polypeptide 1, POR: cytochrome P450, oxidoreductase,
HSD3B2: 3[beta]-hydroxysteroid dehydrogenase 2, CYP11A1: cytochrome
P450, family 11, subfamily A, polypeptide 1, DHCR7:
7-dehydrocholesterol reductase, MTP: microsomal triglyceride transfer
protein, LDLR: low density lipoprotein receptor, ABCG8: ATP-binding
cassette, subfamily G, member 8, NR0B1: nuclear receptor subfamily 0,
group B, member 1, DAX1: dosage sensitive sex reversal, adrenal
hypoplasia congenita, critical region on X chromosome, gene 1, NR5A1:
nuclear receptor subfamily 5 group A member 1, SF1: steroidogenic
factor 1, CDKN1C: cyclin dependent kinase inhibitor 1C, SAMD9: sterile
alpha motif domain-containing protein 9, GL13: gene responsible for
Greig cephalopolysyndactyly syndrome, MKS1: gene responsible for Meckel
syndrome, type 1 and Bardet-Biedl syndrome type 13, DOX7: docking
protein 7, RAPSN: receptor associated protein of the synapse, HYLS1:
hydrolethalus syndrome protein 1, WDR73: WD repeat domain 73, MC2R:
melanocortin 2 receptor, MRAP: melanocortin 2 receptor accessory
protein, AAAS: achalasia-alacrima-addisonianism, NNT: nicotinamide
nucleotide transhydrogenase, TXNRD2: thioredoxin reductase 2, GPX1:
glutathione peroxidase 3, PRDX3: peroxiredoxin 3, ABCD1: ATP-binding
cassette, subfamily D, member 1, PEX: peroxisome biogenesis factor,
PHYH: phytanoyl-CoA hydroxylase, L1PA: lipase A, SGPL1:
sphingosine-1-phosphate lyase, BACH2: BTB and CNC homology 2, AIRE:
autoimmune regulator, MCM4: minichromosome maintenance complex
component 4, POMC: proopiomelanocortin, POLG1: polymerase, DNA,
gamma-1: GFER1: growth factor, ERV1-like, NDUFAF5: NADH dehydrogenase
(ubiquinone) complex 1, assembly factor 5, MRPS7: mitochondrial
ribosomal protein S7, QRSL1: glutaminyl t-RNA-synthase like protein 1,
MIRAGE: myelodysplasia, infection, restriction of growth, adrenal
hypoplasia, genital

Table 2. Clinical and laboratory findings of different forms of
congenital adrenal hyperplasia and treatment goals

Condition                 Clinical landmarks            Impaired

21[alpha]-hydroxylase     Cortisol deficiency           Adrenal
deficiency                mineralocorticoid
                          deficiency (salt-wasting
                          crisis), 46,XX DSD,
                          postnatal virilization
                          in both sexes

11 [beta]-hydroxylase     Cortisol deficiency           Adrenal
deficiency                in both 46,XX DSD,
                          postnatal virilization
3[beta]-hydroxysteroid    Cortisol deficiency           Adrenal, gonadal
dehydrogenase type 2      Mineralocorticoid
                          deficiency (salt-wasting
                          crisis) 46,XX and 46,XY
                          DSD, pubertal disorders
                          and premature adrenarche
                          in both sexes
17[alpha]-hydroxylase /   Cortisol deficiency           Adrenal, gonadal
17,20 lyase deficiency    (excessive
                          masks clinical findings of
                          glucocorticoid deficiency),
                          46,XY DSD, Absence of
                          pubertal development,
Congenital lipoid         Cortisol and                  Adrenal, gonadal
adrenal hyperplasia       mineralocorticoid
(StAR deficiency),        deficiency (salt-wasting
P450 side chain           crisis), 46,XY DSD,
cleavage (CYP11A1)        absence of pubertal
deficiency                development and premature
                          ovarian failure in females
P450 oxidoreductase       Cortisol deficiency           Adrenal, gonadal
deficiency                46,XX and 46,XY DSD,
                          Antley-Bixler syndrome,
                          maternal virilization

Condition                 Steroid status

21[alpha]-hydroxylase     Glucocorticoids and
deficiency                mineraocorticoids[down arrow],
                          adrenal sex steroids [up arrow]

11 [beta]-hydroxylase     Glucocorticoids[down arrow],
deficiency                mineralocorticoids and
                          adrenal sex steroids [up arrow]

3[beta]-hydroxysteroid    Glucocorticoids,
dehydrogenase type 2      mineralocorticoids and
                          adrenal sex steroids [down arrow]

17[alpha]-hydroxylase /   Glucocorticoids and
17,20 lyase deficiency    adrenal sex steroids [down arrow],
                          mineralocorticoids [up arrow]

Congenital lipoid         Glucocorticoids,
adrenal hyperplasia       mineralocorticoids and
(StAR deficiency),        adrenal sex steroids [down arrow]
P450 side chain
cleavage (CYP11A1)

P450 oxidoreductase

Condition                 Laboratory findings

21[alpha]-hydroxylase     Serum/plasma: Cortisol [down arrow] ACTH
deficiency                [up arrow] serum basal and ACTH-stimulated
                          170HP[up arrow] 21-deoxycortisol (*)
                          [up arrow], 4AS[up arrow] testosterone
                          [up arrow] hyponatremia, hyperkalemia, plasma
                          renin activity[up arrow]
                          Urine: Pregnanetriolone ([section])[up arrow],
                          Pregnanetriol[up arrow],
                          17[alpha]OH-Pregnanolone[up arrow]
11 [beta]-hydroxylase     Cortisol[down arrow] ACTH[up arrow] serum
deficiency                basal and ACTH-stimulated 11-deoxycortisol (*)
                          and deoxycorticoserone[up arrow], 4AS
                          [up arrow], testosterone[up arrow]
                          hypokalemia, plasma renin activity
                          [down arrow]
                          Urine: Tetrahydrodeoxycortisol ([section])
                          [up arrow]
3[beta]-hydroxysteroid    Cortisol[down arrow] ACTH[up arrow] serum
dehydrogenase type 2      basal and ACTH-stimulated [DELTA]5 steroids
                          (pregnenolone, 17-hydroxypregnenolone (*),
                          DHEA)[up arrow], 4AS[down arrow]
                          testosterone[down arrow] hyponatremia,
                          hyperkalemia, plasma renin activity[up arrow]
                          Urine: Pregnenetriol ([section])[up arrow],
                          pregnenediol[up arrow]

17[alpha]-hydroxylase /   Cortisol[down arrow] ACTH[up arrow] serum
17,20 lyase deficiency    basal and ACTH-stimulated corticosterone and
                          11 -deoxycorticosterone (*) [up arrow],
                          17[alpha]-hydroxylated steroids[down arrow],
                          4AS[down arrow] testosterone[down arrow]
                          hypokalemia, plasma renin activity[down arrow]
                          Urine: (5[alpha])
                          Tetrahydrodehydrocorticosterone[up arrow],
                          (5[beta])Tetrahydrocorticosterone [up arrow]
                          Androsterone[down arrow],
                          Etiocholanolone[down arrow]
Congenital lipoid         Cortisol[down arrow] ACTH[up arrow] serum
adrenal hyperplasia       basal and ACTH-stimulated steroids and their
(StAR deficiency),        precursors are low, hyponatremia,
P450 side chain           hyperkalemia, plasma renin activity[up arrow],
cleavage (CYP11A1)        FSH and LH[up arrow], testosterone and
deficiency                estradiol [down arrow]

P450 oxidoreductase       Cortisol[down arrow] ACTH[up arrow]
deficiency                pregnenolone[up arrow], progesterone
                          [up arrow], prenatal androgens[up arrow],
                          androgen and estrogens at puberty [down arrow]
                          Urine: Pregnanetriol[up arrow],
                          17[alpha]OH-pregnanolone[up arrow],
                          androsterone[down arrow], etiocholanolone
                          [down arrow]

Condition                 Treatment

21[alpha]-hydroxylase     Glucocorticoid (hydrocortisone),
deficiency                mineralocorticoid and salt
                          replacement, vaginoplasty
                          cliteroplasty, suppression
                          of hyperandrogenism by

11 [beta]-hydroxylase     Glucocorticoid (hydrocortisone)
deficiency                replacement, vaginoplasty
                          cliteroplasty, suppression
                          of hyperandrogenism by
3[beta]-hydroxysteroid    Glucocorticoid (hydrocortisone),
dehydrogenase type 2      mineralocorticoid and salt
                          replacement, genitoplasty
                          sex steroid replacement
                          at puberty, suppression
                          of hyperandrogenism by
17[alpha]-hydroxylase /   Glucocorticoid (hydrocortisone),
17,20 lyase deficiency    replacement, genitoplasty, sex
                          steroid replacement at puberty

Congenital lipoid         Glucocorticoid (hydrocortisone),
adrenal hyperplasia       mineralocorticoid and salt
(StAR deficiency),        replacement, genitoplasty, sex
P450 side chain           steroid replacement at puberty
cleavage (CYP11A1)

P450 oxidoreductase       Glucocorticoid (hydrocortisone)
deficiency                mineralocorticoid and salt
                          replacement, genitoplasty, sex
                          steroid replacement at puberty

(*) Best diagnostic biochemical marker in serum, ([section]) Best
diagnostic biochemical marker in urine
ACTH: adrenocorticotropin hormone, StAR: steroidogenic acute regulatory
protein, LH: Luteinizing hormone, FSH: follicle stimulating hormone,
DHEA: dehydroepiandrosterone
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Article Details
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Author:Guran, Tulay
Publication:Journal of Clinical Research in Pediatric Endocrinology
Article Type:Report
Date:Dec 1, 2017
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