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Congenital adrenal hypoplasia, X-linked(AHC)

MedGen UID:: 87442
•Concept ID:: C0342482
•: Disease or Syndrome

Synonyms:	Adrenal hypoplasia, congenital; ADRENAL HYPOPLASIA, CONGENITAL, WITH HYPOGONADOTROPIC HYPOGONADISM; AHC; Isolated X-Linked Adrenal Hypoplasia Congenita; X-Linked Adrenal Hypoplasia Congenita; X-linked AHC
SNOMED CT:	Congenital adrenal hypoplasia, X-linked (237764004)
Modes of inheritance:	X-linked recessive inheritance MedGen UID: 375779 •Concept ID: C1845977 • Finding Source: Orphanet A mode of inheritance that is observed for recessive traits related to a gene encoded on the X chromosome. In the context of medical genetics, X-linked recessive disorders manifest in males (who have one copy of the X chromosome and are thus hemizygotes), but generally not in female heterozygotes who have one mutant and one normal allele. See: This record X-linked recessive inheritance (Orphanet)

Gene (location): Gene(s) directly associated with this condition or phenotype.	NR0B1 (Xp21.2)

Monarch Initiative:	MONDO:0010264
OMIM®:	300200
Orphanet:	ORPHA95702

Disease characteristics

Excerpted from the GeneReview: NR0B1-Related Adrenal Hypoplasia Congenita

NR0B1-related adrenal hypoplasia congenita includes both X-linked adrenal hypoplasia congenita (X-linked AHC) and Xp21 deletion (previously called complex glycerol kinase deficiency). X-linked AHC is characterized by primary adrenal insufficiency and/or hypogonadotropic hypogonadism (HH). Adrenal insufficiency is acute infantile onset (average age 3 weeks) in approximately 60% of affected males and childhood onset (ages 1-9 years) in approximately 40%. HH typically manifests in a male with adrenal insufficiency as delayed puberty (i.e., onset age >14 years) and less commonly as arrested puberty at about Tanner Stage 3. Rarely, X-linked AHC manifests initially in early adulthood as delayed-onset adrenal insufficiency, partial HH, and/or infertility. Heterozygous females very occasionally have manifestations of adrenal insufficiency or hypogonadotropic hypogonadism. Xp21 deletion includes deletion of NR0B1 (causing X-linked AHC) and GK (causing glycerol kinase deficiency), and in some cases deletion of DMD (causing Duchenne muscular dystrophy). Developmental delay has been reported in males with Xp21 deletion when the deletion extends proximally to include DMD or when larger deletions extend distally to include IL1RAPL1 and DMD. [from GeneReviews]

Authors:
John C Achermann | Eric J Vilain view full author information

Additional descriptions

From OMIM
Congenital adrenal hypoplasia (AHC) is a rare disorder that can be inherited in an X-linked or autosomal recessive (see 240200) pattern. In X-linked AHC, primary adrenocortical failure occurs because the adrenal glands lack the permanent adult cortical zone. The remaining cells are termed 'cytomegalic' because they are larger than typical fetal adrenal cells (Hay et al., 1981; Reutens et al., 1999). Patients with AHC usually present in early infancy with primary adrenal failure. Hypogonadotropic hypogonadism (HHG) is a hallmark of the disorder, and is recognized during adolescence because of the absence or interruption of normal pubertal development. Abnormal spermatogenesis has also been observed in these patients. Milder forms of the disease have been described, with adrenal insufficiency sometimes occurring in childhood or even early adulthood. A few cases of partial HHG have been reported (summary by Raffin-Sanson et al., 2013). Transient precocious sexual development in infancy or early childhood can be a prominent feature of AHC (Landau et al., 2010). A contiguous gene syndrome involving a combination of congenital adrenal hypoplasia, glycerol kinase deficiency (307030), and Duchenne muscular dystrophy (DMD; 310200) is caused by deletion of multiple genes on chromosome Xp21 (see 300679). http://www.omim.org/entry/300200

From MedlinePlus Genetics
X-linked adrenal hypoplasia congenita is a disorder that is noticeable from birth (congenital) and affects the development of the adrenal glands, which are hormone-producing (endocrine) organs (glands) located on top of each kidney. These glands produce a variety of hormones that regulate many essential functions in the body, such as response to stress.

One of the main signs of this disorder is adrenal insufficiency, which occurs when the adrenal glands do not produce enough hormones. Adrenal insufficiency typically begins in infancy or childhood and can cause vomiting, difficulty with feeding, dehydration, extremely low blood glucose (hypoglycemia), and shock. If untreated, these complications are often life-threatening.

Individuals with X-linked adrenal hypoplasia congenita may also have a shortage of male sex hormones, which leads to underdeveloped reproductive tissues, undescended testicles (cryptorchidism), delayed puberty, and an inability to father children (infertility). Together, these characteristics are known as hypogonadotropic hypogonadism.

The onset and severity of these signs and symptoms can vary, even among affected members of the same family. https://medlineplus.gov/genetics/condition/x-linked-adrenal-hypoplasia-congenita

Clinical features

From HPO

Azoospermia

MedGen UID:: 2150
•Concept ID:: C0004509
•: Disease or Syndrome

Absence of any measurable level of sperm in his semen.

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Cryptorchidism

MedGen UID:: 8192
•Concept ID:: C0010417
•: Congenital Abnormality

Cryptorchidism, or failure of testicular descent, is a common human congenital abnormality with a multifactorial etiology that likely reflects the involvement of endocrine, environmental, and hereditary factors. Cryptorchidism can result in infertility and increases risk for testicular tumors. Testicular descent from abdomen to scrotum occurs in 2 distinct phases: the transabdominal phase and the inguinoscrotal phase (summary by Gorlov et al., 2002).

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Oligozoospermia

MedGen UID:: 18162
•Concept ID:: C0028960
•: Disease or Syndrome

Reduced count of spermatozoa in the semen, defined as a sperm count below 20 million per milliliter semen.

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Renal salt wasting

MedGen UID:: 375868
•Concept ID:: C1846347
•: Finding

A high concentration of one or more electrolytes in the urine in the presence of low serum concentrations of the electrolyte(s).

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Failure to thrive

MedGen UID:: 746019
•Concept ID:: C2315100
•: Disease or Syndrome

Failure to thrive (FTT) refers to a child whose physical growth is substantially below the norm.

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Muscular dystrophy

MedGen UID:: 44527
•Concept ID:: C0026850
•: Disease or Syndrome

The term dystrophy means abnormal growth. However, muscular dystrophy is used to describe primary myopathies with a genetic basis and a progressive course characterized by progressive skeletal muscle weakness and wasting, defects in muscle proteins, and histological features of muscle fiber degeneration (necrosis) and regeneration. If possible, it is preferred to use other HPO terms to describe the precise phenotypic abnormalities.

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Dehydration

MedGen UID:: 8273
•Concept ID:: C0011175
•: Disease or Syndrome

A condition resulting from the excessive loss of water from the body. It is usually caused by severe diarrhea, vomiting or diaphoresis.

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Hyponatremia

MedGen UID:: 6984
•Concept ID:: C0020625
•: Finding

An abnormally decreased sodium concentration in the blood.

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Hyperpigmentation of the skin

MedGen UID:: 57992
•Concept ID:: C0162834
•: Pathologic Function

A darkening of the skin related to an increase in melanin production and deposition.

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Primary adrenocortical insufficiency

MedGen UID:: 1324
•Concept ID:: C0001403
•: Disease or Syndrome

Insufficient production of steroid hormones (primarily cortisol) by the adrenal glands as a result of a primary defect in the glands themselves.

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Adrenal insufficiency

MedGen UID:: 1351
•Concept ID:: C0001623
•: Disease or Syndrome

Insufficient production of steroid hormones (primarily cortisol) by the adrenal glands.

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Delayed puberty

MedGen UID:: 46203
•Concept ID:: C0034012
•: Pathologic Function

Passing the age when puberty normally occurs with no physical or hormonal signs of the onset of puberty.

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Precocious puberty

MedGen UID:: 18752
•Concept ID:: C0034013
•: Disease or Syndrome

The onset of secondary sexual characteristics before a normal age. Although it is difficult to define normal age ranges because of the marked variation with which puberty begins in normal children, precocious puberty can be defined as the onset of puberty before the age of 8 years in girls or 9 years in boys.

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Hypogonadotropic hypogonadism

MedGen UID:: 82883
•Concept ID:: C0271623
•: Disease or Syndrome

Hypogonadotropic hypogonadism is characterized by reduced function of the gonads (testes in males or ovaries in females) and results from the absence of the gonadal stimulating pituitary hormones

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Decreased circulating aldosterone level

MedGen UID:: 208996
•Concept ID:: C0857899
•: Finding

Abnormally reduced levels of aldosterone.

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Decreased circulating cortisol level

MedGen UID:: 322961
•Concept ID:: C1836623
•: Finding

Abnormally reduced concentration of cortisol in the blood.

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Adrenal hypoplasia

MedGen UID:: 337539
•Concept ID:: C1846223
•: Pathologic Function

Developmental hypoplasia of the adrenal glands.

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Absence of pubertal development

MedGen UID:: 375841
•Concept ID:: C1846228
•: Finding

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Abnormality of metabolism/homeostasis
- Dehydration
- Hyponatremia
Abnormality of the endocrine system
Abnormality of the genitourinary system
Abnormality of the integument
- Hyperpigmentation of the skin
Abnormality of the musculoskeletal system
- Muscular dystrophy
Growth abnormality
- Failure to thrive

Term Hierarchy

GTR
MeSH

CClinical test, RResearch test, OOMIM, GGeneReviews, VClinVar

CROGVCongenital adrenal hypoplasia, X-linked

Phenotypic abnormality
- Abnormality of the endocrine system
  - Abnormal endocrine morphology
    - Abnormality of adrenal morphology
      - Adrenal hypoplasia
        Congenital adrenal hypoplasia
        Congenital adrenal hypoplasia, X-linked

Professional guidelines

PubMed

Evaluation of the genetic basis of primary hypoadrenocorticism in Standard Poodles using SNP array genotyping and whole-genome sequencing.

Friedenberg SG, Lunn KF, Meurs KM
Mamm Genome 2017 Feb;28(1-2):56-65. Epub 2016 Nov 18 doi: 10.1007/s00335-016-9671-6. PMID: 27864587 Free PMC Article

Diagnosis and treatment of Addison's disease.

SIMPSON SL
Proc R Soc Med 1953 Jul;46(7):566-71; discussion, 577-8. PMID: 13074224

The diagnosis and treatment of Addison's disease.

DUNLOP DM
Proc R Soc Med 1953 Jul;46(7):565-6; discussion, 577-8. PMID: 13074223 Free PMC Article

See all (18)