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Surfactant metabolism dysfunction, pulmonary, 4(SMDP4)

MedGen UID:: 393858
•Concept ID:: C2677877
•: Disease or Syndrome

Synonyms:	CSF2RA DEFICIENCY; CSF2RA-Related Pulmonary Surfactant Metabolism Dysfunction; PAP DUE TO CSF2RA DEFICIENCY; PULMONARY ALVEOLAR PROTEINOSIS, CONGENITAL, 4; SMDP4

Gene (location): Gene(s) directly associated with this condition or phenotype.	CSF2RA (Xp22.33;Yp11.2)

Monarch Initiative:	MONDO:0010424
OMIM®:	300770

Definition

Pulmonary alveolar proteinosis (PAP) is a rare lung disorder in which surfactant-derived lipoproteins accumulate excessively within pulmonary alveoli, causing severe respiratory distress. Three forms of PAP have been described: hereditary (usually congenital), secondary, and acquired. Hereditary PAP is associated with mutations in the CSF2RA gene or in genes encoding surfactant proteins. Secondary PAP develops in conditions in which there are reduced numbers or functional impairment of alveolar macrophages and is associated with inhalation of inorganic dust (silica) or toxic fumes, hematologic malignancies, pharmacologic immunosuppression, infections, and impaired CSF2RB (138960) expression. Acquired PAP (610910), the most common form, usually occurs in adults and is caused by neutralizing autoantibodies to CSF2 (138960) (Martinez-Moczygemba et al., 2008). For a general phenotypic description and a discussion of genetic heterogeneity of congenital pulmonary surfactant metabolism dysfunction, see SMDP1 (265120). [from OMIM]

Additional description

From MedlinePlus Genetics
Surfactant dysfunction is a lung disorder that causes breathing problems. This condition results from abnormalities in the composition or function of surfactant, a mixture of certain fats (called phospholipids) and proteins that lines the lung tissue and makes breathing easy. Without normal surfactant, the tissue surrounding the air sacs in the lungs (the alveoli) sticks together (because of a force called surface tension) after exhalation, causing the alveoli to collapse. As a result, filling the lungs with air on each breath becomes very difficult, and the delivery of oxygen to the body is impaired.

The signs and symptoms of surfactant dysfunction can vary in severity. The most severe form of this condition causes respiratory distress syndrome in newborns. Affected babies have extreme difficulty breathing and are unable to get enough oxygen. The lack of oxygen can damage the baby's brain and other organs. This syndrome leads to respiratory failure, and most babies with this form of the condition do not survive more than a few months.

Less severe forms of surfactant dysfunction cause gradual onset of breathing problems in children or adults. Signs and symptoms of these milder forms are abnormally rapid breathing (tachypnea); low concentrations of oxygen in the blood (hypoxemia); and an inability to grow or gain weight at the expected rate (failure to thrive).

There are several types of surfactant dysfunction, which are identified by the genetic cause of the condition. One type, called SP-B deficiency, causes respiratory distress syndrome in newborns. Other types, known as SP-C dysfunction and ABCA3 deficiency, have signs and symptoms that range from mild to severe. https://medlineplus.gov/genetics/condition/surfactant-dysfunction

Clinical features

From HPO

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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Tachypnea

MedGen UID:: 66669
•Concept ID:: C0231835
•: Finding

Very rapid breathing.

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Reduced forced vital capacity

MedGen UID:: 337630
•Concept ID:: C1846678
•: Finding

An abnormal reduction in the amount of air a person can expel following maximal inspiration.

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Restrictive ventilatory defect

MedGen UID:: 478856
•Concept ID:: C3277226
•: Finding

A functional defect characterized by reduced total lung capacity (TLC) not associated with abnormalities of expiratory airflow or airway resistance. Spirometrically, a restrictive defect is defined as FEV1 (forced expiratory volume in 1 second) and FVC (forced vital capacity) less than 80 per cent. Restrictive lung disease may be caused by alterations in lung parenchyma or because of a disease of the pleura, chest wall, or neuromuscular apparatus.

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Decreased DLCO

MedGen UID:: 892993
•Concept ID:: C4073175
•: Finding

Reduced ability of the lungs to transfer gas from inspired air to the bloodstream as measured by the diffusing capacity of the lungs for carbon monoxide (DLCO) test.

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Reduced forced expiratory volume in one second

MedGen UID:: 1687063
•Concept ID:: C5139283
•: Finding

An abnormal reduction in the amount of air a person can forcefully expel in one second.

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Pulmonary alveolar proteinosis

MedGen UID:: 1763046
•Concept ID:: C5400698
•: Finding

Accumulation of amorphous PAS-positive material in the space between alveolar macrophages, sometimes as condensed form (oval bodies) are typically found in alveolar proteinosis.

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Ground-glass opacification

MedGen UID:: 1779663
•Concept ID:: C5539411
•: Finding

On chest radiographs, ground-glass opacity appears as an area of hazy increased lung opacity, usually extensive, within which margins of pulmonary vessels may be indistinct. On CT scans, it appears as hazy increased opacity of lung, with preservation of bronchial and vascular margins. It is caused by partial filling of airspaces, interstitial thickening (due to fluid, cells, and/or fibrosis), partial collapse of alveoli, increased capillary blood volume, or a combination of these, the common factor being the partial displacement of air. Ground-glass opacity is less opaque than consolidation, in which bronchovascular margins are obscured.

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Abnormality of the respiratory system
Growth abnormality
- Failure to thrive

Term Hierarchy

GTR
MeSH

CClinical test, RResearch test, OOMIM, GGeneReviews, VClinVar

CROGVHereditary pulmonary alveolar proteinosis
- CROGVInterstitial lung disease due to ABCA3 deficiency
- CROGVSurfactant metabolism dysfunction, pulmonary, 1
- CROGVSurfactant metabolism dysfunction, pulmonary, 2
- CROGVSurfactant metabolism dysfunction, pulmonary, 4

Primary interstitial lung disease specific to childhood due to pulmonary surfactant protein anomalies
- Hereditary pulmonary alveolar proteinosis
  - Surfactant metabolism dysfunction, pulmonary, 4

Recent clinical studies

Therapy

Use of induced pluripotent stem cells to recapitulate pulmonary alveolar proteinosis pathogenesis.

Suzuki T, Mayhew C, Sallese A, Chalk C, Carey BC, Malik P, Wood RE, Trapnell BC
Am J Respir Crit Care Med 2014 Jan 15;189(2):183-93. doi: 10.1164/rccm.201306-1039OC. PMID: 24279752 Free PMC Article

Gene correction of human induced pluripotent stem cells repairs the cellular phenotype in pulmonary alveolar proteinosis.

Lachmann N, Happle C, Ackermann M, Lüttge D, Wetzke M, Merkert S, Hetzel M, Kensah G, Jara-Avaca M, Mucci A, Skuljec J, Dittrich AM, Pfaff N, Brennig S, Schambach A, Steinemann D, Göhring G, Cantz T, Martin U, Schwerk N, Hansen G, Moritz T
Am J Respir Crit Care Med 2014 Jan 15;189(2):167-82. doi: 10.1164/rccm.201306-1012OC. PMID: 24279725

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Clinical prediction guides

Quantitative Lipidomics in Pulmonary Alveolar Proteinosis.

Griese M, Bonella F, Costabel U, de Blic J, Tran NB, Liebisch G
Am J Respir Crit Care Med 2019 Oct 1;200(7):881-887. doi: 10.1164/rccm.201901-0086OC. PMID: 31002528

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Surfactant metabolism dysfunction, pulmonary, 4(SMDP4)

Definition

Additional description

Clinical features

Term Hierarchy

Recent clinical studies

Therapy

Clinical prediction guides

Supplemental Content

Table of contents

Genetic Testing Registry

Clinical resources

Molecular resources

Consumer resources

Reviews

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