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Autosomal dominant pseudohypoaldosteronism type 1(PHA1A)

MedGen UID:
260623
Concept ID:
C1449842
Disease or Syndrome
Synonyms: PHA I, AUTOSOMAL DOMINANT; Pseudohypoaldosteronism Type 1, Dominant; Pseudohypoaldosteronism, Type I, Autosomal Dominant; Pseudohypoaldosteronism, Type I, Dominant
Modes of inheritance:
Autosomal dominant inheritance
MedGen UID:
141047
Concept ID:
C0443147
Intellectual Product
Source: Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in heterozygotes. In the context of medical genetics, an autosomal dominant disorder is caused when a single copy of the mutant allele is present. Males and females are affected equally, and can both transmit the disorder with a risk of 50% for each child of inheriting the mutant allele.
 
Gene (location): NR3C2 (4q31.23)
 
Monarch Initiative: MONDO:0008329
OMIM®: 177735
Orphanet: ORPHA171871

Definition

Autosomal dominant pseudohypoaldosteronism type I (PHA1A) is characterized by salt wasting resulting from renal unresponsiveness to mineralocorticoids. Patients may present with neonatal renal salt wasting with hyperkalaemic acidosis despite high aldosterone levels. These patients improve with age and usually become asymptomatic without treatment. Some adult patients with the disorder may have elevated aldosterone levels, but no history of clinical disease. This observation suggests that only those infants whose salt homeostasis is stressed by intercurrent illness and volume depletion develop clinically recognized PHA I (summary by Geller et al., 1998). Autosomal recessive pseudohypoaldosteronism type I (see PHA1B1, 264350), caused by mutation in any one of 3 genes encoding the epithelial sodium channel (ENaC), is a similar but more severe systemic disorder with persistence into adulthood. [from OMIM]

Additional description

From MedlinePlus Genetics
Pseudohypoaldosteronism type 1 (PHA1) is a condition characterized by problems regulating the amount of sodium in the body. Sodium regulation, which is important for blood pressure and fluid balance, primarily occurs in the kidneys. However, sodium can also be removed from the body through other tissues, such as the sweat glands and colon. Pseudohypoaldosteronism type 1 is named for its characteristic signs and symptoms, which mimic (pseudo) low levels (hypo) of a hormone called aldosterone that helps regulate sodium levels. However, people with PHA1 have high levels of aldosterone.

Infants with autosomal recessive PHA1 can have additional signs and symptoms due to the involvement of multiple organs. Affected individuals may experience episodes of abnormal heartbeat (cardiac arrhythmia) or shock because of the imbalance of salts in the body. They may also have recurrent lung infections or lesions on the skin. Although adults with autosomal recessive PHA1 can have repeated episodes of salt wasting, they do not usually have other signs and symptoms of the condition.

There are two types of PHA1 distinguished by their severity, the genes involved, and how they are inherited. One type, called autosomal dominant PHA1 (also known as renal PHA1) is characterized by excessive sodium loss from the kidneys. This form of the condition is relatively mild and often improves in early childhood. The other type, called autosomal recessive PHA1 (also known as generalized or systemic PHA1) is characterized by sodium loss from the kidneys and other organs, including the sweat glands, salivary glands, and colon. This type of PHA1 is more severe and does not improve with age.

The earliest signs of both types of PHA1 are usually the inability to gain weight and grow at the expected rate (failure to thrive) and dehydration, which are typically seen in infants. The characteristic features of both types of PHA1 are excessive amounts of sodium released in the urine (salt wasting), which leads to low levels of sodium in the blood (hyponatremia), and high levels of potassium in the blood (hyperkalemia). Infants with PHA1 can also have high levels of acid in the blood (metabolic acidosis). Hyponatremia, hyperkalemia, or metabolic acidosis can cause nonspecific symptoms such as nausea, vomiting, extreme tiredness (fatigue), and muscle weakness in infants with PHA1.  https://medlineplus.gov/genetics/condition/pseudohypoaldosteronism-type-1

Clinical features

From HPO
Hypotension
MedGen UID:
5715
Concept ID:
C0020649
Finding
Low Blood Pressure, vascular hypotension.
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.
Diarrhea
MedGen UID:
8360
Concept ID:
C0011991
Sign or Symptom
Abnormally increased frequency (usually defined as three or more) loose or watery bowel movements a day.
Vomiting
MedGen UID:
12124
Concept ID:
C0042963
Sign or Symptom
Forceful ejection of the contents of the stomach through the mouth by means of a series of involuntary spasmic contractions.
Feeding difficulties
MedGen UID:
65429
Concept ID:
C0232466
Finding
Impaired ability to eat related to problems gathering food and getting ready to suck, chew, or swallow it.
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.
Hyperkalemia
MedGen UID:
5691
Concept ID:
C0020461
Finding
An abnormally increased potassium concentration in the blood.
Hyponatremia
MedGen UID:
6984
Concept ID:
C0020625
Finding
An abnormally decreased sodium concentration in the blood.
Metabolic acidosis
MedGen UID:
65117
Concept ID:
C0220981
Pathologic Function
Metabolic acidosis (MA) is characterized by a fall in blood pH due to a reduction of serum bicarbonate concentration. This can occur as a result of either the accumulation of acids (high anion gap MA) or the loss of bicarbonate from the gastrointestinal tract or the kidney (hyperchloremic MA). By definition, MA is not due to a respirary cause.
Increased circulating aldosterone concentration
MedGen UID:
6960
Concept ID:
C0020428
Disease or Syndrome
Overproduction of the mineralocorticoid aldosterone by the adrenal cortex.
Pseudohypoaldosteronism
MedGen UID:
18721
Concept ID:
C0033805
Disease or Syndrome
A state of renal tubular unresponsiveness or resistance to the action of aldosterone.
Increased circulating renin concentration
MedGen UID:
66818
Concept ID:
C0240783
Finding
An increased level of renin in the blood.
Hyperactive renin-angiotensin system
MedGen UID:
335401
Concept ID:
C1846345
Finding
An abnormally increased activity of the renin-angiotensin system, causing hypertension by a combination of volume excess and vasoconstrictor mechanisms.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVAutosomal dominant pseudohypoaldosteronism type 1
Follow this link to review classifications for Autosomal dominant pseudohypoaldosteronism type 1 in Orphanet.

Recent clinical studies

Etiology

Riepe FG, Holterhus PM
Am J Nephrol 2007;27(2):164-9. Epub 2007 Feb 23 doi: 10.1159/000100107. PMID: 17317952
Riepe FG, Finkeldei J, de Sanctis L, Einaudi S, Testa A, Karges B, Peter M, Viemann M, Grötzinger J, Sippell WG, Fejes-Toth G, Krone N
J Clin Endocrinol Metab 2006 Nov;91(11):4552-61. Epub 2006 Sep 5 doi: 10.1210/jc.2006-1161. PMID: 16954160
Geller DS, Zhang J, Zennaro MC, Vallo-Boado A, Rodriguez-Soriano J, Furu L, Haws R, Metzger D, Botelho B, Karaviti L, Haqq AM, Corey H, Janssens S, Corvol P, Lifton RP
J Am Soc Nephrol 2006 May;17(5):1429-36. Epub 2006 Apr 12 doi: 10.1681/ASN.2005111188. PMID: 16611713

Diagnosis

Loomba-Albrecht LA, Nagel M, Bremer AA
Horm Res Paediatr 2010;73(6):482-6. Epub 2010 Apr 24 doi: 10.1159/000281290. PMID: 20453518
Kanda K, Nozu K, Yokoyama N, Morioka I, Miwa A, Hashimura Y, Kaito H, Iijima K, Matsuo M
BMC Nephrol 2009 Nov 14;10:37. doi: 10.1186/1471-2369-10-37. PMID: 19912655Free PMC Article
Riepe FG, Krone N, Morlot M, Ludwig M, Sippell WG, Partsch CJ
J Clin Endocrinol Metab 2003 Apr;88(4):1683-6. doi: 10.1210/jc.2002-021556. PMID: 12679457

Prognosis

Loomba-Albrecht LA, Nagel M, Bremer AA
Horm Res Paediatr 2010;73(6):482-6. Epub 2010 Apr 24 doi: 10.1159/000281290. PMID: 20453518
Geller DS, Zhang J, Zennaro MC, Vallo-Boado A, Rodriguez-Soriano J, Furu L, Haws R, Metzger D, Botelho B, Karaviti L, Haqq AM, Corey H, Janssens S, Corvol P, Lifton RP
J Am Soc Nephrol 2006 May;17(5):1429-36. Epub 2006 Apr 12 doi: 10.1681/ASN.2005111188. PMID: 16611713

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