Young Syndrome

Complex MONDO:0010220 Pathograph 13 Show in embeddings browser

Young syndrome is the combination of obstructive azoospermia with chronic sinusitis, bronchitis or bronchiectasis in men whose spermatogenesis is normal, whose sweat chloride is normal, and whose respiratory cilia are structurally normal. The azoospermia is caused by obstruction of the head (caput) of the epididymis by inspissated secretions, and lung mucociliary clearance is reduced although ciliary beat frequency and axonemal ultrastructure are normal, which points to abnormal secretions rather than a primary ciliary defect. The only documented aetiological factor is childhood mercury intoxication (pink disease), and the frequency of the syndrome fell in men born after mercurous chloride was withdrawn from teething powders. A single CFAP221 compound-heterozygous patient with the full triad has been reported and classified as primary ciliary dyskinesia, which is the basis of the MONDO causal-gene link; whether Young syndrome is a distinct entity or a phenotype shared by mercury injury and mild central-apparatus primary ciliary dyskinesia is unresolved.

Ask OpenScientist

Ask a research question about Young Syndrome. OpenScientist will conduct autonomous deep research using the Disorder Mechanisms Knowledge Base and PubMed literature (typically 10-30 minutes).

Submitting...

Do not include personal health information in your question. Questions and results are cached in your browser's local storage.

4
Pathophys.
8
Phenotypes
3
Hypotheses
13
Pathograph
2
Genes
4
Medical Actions
2
Differentials
1
References
1
Deep Research
◈

Mechanistic Hypotheses

3
Abnormal viscous secretions with normal cilia
abnormal_secretions CANONICAL
Evidence balance 1 support
The classical account of the syndrome: abnormally viscous airway and epididymal secretions impair mucociliary clearance and obstruct the caput epididymidis, while the cilia are normal. The secretion defect itself has been inferred rather than measured. Childhood mercury exposure is the proposed upstream cause within this account.
Pathograph links
Abnormally Viscous Respiratory and Reproductive Secretions -> Impaired Mucociliary Clearance DIRECT
Abnormally Viscous Respiratory and Reproductive Secretions -> Inspissated Secretion Obstruction of the Caput Epididymidis DIRECT
Show evidence (1 reference)
PMID:6689737 SUPPORT Human Clinical
"the azoospermia is due to obstruction of the epididymis by inspissated secretions"
The founding clinical series attributes the obstruction to inspissated secretions.
Childhood mercury intoxication leading to abnormal airway and epididymal secretions
mercury_secretory_injury ALTERNATIVE
Evidence balance 1 support
Young syndrome as a late consequence of infant exposure to mercurous chloride (pink disease). Supported only by birth-cohort epidemiology; no histological or experimental study shows how the exposure alters secretions.
Show evidence (1 reference)
PMID:19128521 SUPPORT REVIEW SYNTHESIS Other
"The only documented aetiological factor is mercury exposure in childhood, an event that is seldom currently encountered; this would support our theory of the extinction of the condition."
Literature review identifying childhood mercury exposure as the only documented cause.
Unrecognized C1d central-apparatus primary ciliary dyskinesia
c1d_central_apparatus_pcd EMERGING
Evidence balance 1 support
Some patients given the Young syndrome diagnosis may have primary ciliary dyskinesia caused by defects of the C1d projection (CFAP221 and related genes), which leaves ciliary ultrastructure, situs and nasal nitric oxide normal and so evades the tests used to exclude PCD. Supported by one CFAP221 patient with the triad.
Pathograph links
Central Apparatus C1d Projection Defect -> Impaired Mucociliary Clearance DIRECT
Central Apparatus C1d Projection Defect -> Inspissated Secretion Obstruction of the Caput Epididymidis INDIRECT UNKNOWN INTERMEDIATES Proposed route: failure of motile cilia in the efferent ducts impairs sperm transport and produces a proximal obstruction. Not demonstrated for CFAP221; the reported CFAP221 patient had obstructive azoospermia with normal sperm structure.
Show evidence (1 reference)
PMID:38960684 SUPPORT Human Clinical
"Distinguishing PCD from Young's syndrome in patients with the triad of obstructive azoospermia, sinusitis, and bronchiectasis is challenging. Young's syndrome may be a phenotype of PCD."
The reporting authors propose Young syndrome as a PCD phenotype after finding CFAP221 variants.
⚙

Pathophysiology

4
Central Apparatus C1d Projection Defect
Biallelic loss-of-function CFAP221 variants disturb the C1d projection of the ciliary central apparatus. Ultrastructure by electron microscopy, situs and nasal nitric oxide are normal, but beating is asynchronous and ciliary transport is insufficient. Recorded as the upstream lesion of the PCD hypothesis only.
Unrecognized C1d central-apparatus primary ciliary dyskinesia
CFAP221 hgnc:33720 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves CFAP221 (hgnc:33720). hgnc:33720 is a gene from the HUGO Gene Nomenclature Committee.
Downstream
Impaired Mucociliary Clearance Unrecognized C1d central-apparatus primary ciliary dyskinesia
Inspissated Secretion Obstruction of the Caput Epididymidis Proposed route: failure of motile cilia in the efferent ducts impairs sperm transport and produces a proximal obstruction. Not demonstrated for CFAP221; the reported CFAP221 patient had obstructive azoospermia with normal sperm structure. Unrecognized C1d central-apparatus primary ciliary dyskinesia
Show evidence (2 references)
PMID:39362668 SUPPORT Human Clinical
"C1d-defective primary ciliary dyskinesia is associated with normal situs composition, normal nasal nitric oxide production rates, normal ciliary ultrastructure by transmission electron microscopy and normal ciliary beating by high-speed videomicroscopy analysis."
Explains why C1d defects evade the tests used to separate Young syndrome from PCD.
PMID:40250778 SUPPORT Human Clinical
"Subtle abnormalities in the protein composition of the ciliary central apparatus were consistent with the asynchronous, circular motion of cilia and reduced ciliary beat frequency in the proband"
Central-apparatus composition defect and abnormal beating in a CFAP221 patient.
Abnormally Viscous Respiratory and Reproductive Secretions
Respiratory and epididymal secretions are abnormally thick and viscous. The defect has been inferred from the combination of impaired clearance with structurally and functionally normal cilia; no specific mucin or ion-transport lesion has been identified.
Abnormal viscous secretions with normal cilia
mucus secretion GO:0070254 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves mucus secretion (GO:0070254). GO:0070254 is a biological process from the Gene Ontology.
Downstream
Impaired Mucociliary Clearance Abnormal viscous secretions with normal cilia
Inspissated Secretion Obstruction of the Caput Epididymidis Abnormal viscous secretions with normal cilia
Show evidence (3 references)
PMID:30969689 SUPPORT REVIEW SYNTHESIS Other
"Individuals with Young syndrome have structurally normal lung parenchyma and cilia but produce abnormally thick, viscous respiratory and reproductive secretions."
StatPearls synthesis stating the secretion abnormality as the core lesion of the syndrome.
PMID:1387740 SUPPORT INDIRECT Human Clinical
"may be due to a structural defect but is more likely to be a consequence of abnormal mucus"
In 20 patients, the only ciliary finding (distal axoneme disorientation) was attributed by the authors to abnormal mucus rather than a ciliary defect; the abnormal-mucus claim is an inference from this observation.
PMID:1387740 REFUTE BACKGROUND Human Clinical
"No defect of cilia or mucus has been detected in Young's syndrome."
No mucus defect had been directly demonstrated when this study was published; the viscous-secretion lesion remains inferred rather than measured.
Impaired Mucociliary Clearance
Lung mucociliary transport is reduced. In classic series ciliary beat frequency, microtubular structure and dynein arm number are normal, so the defect was attributed to the secretions rather than the cilia; a C1d central-apparatus defect would also impair clearance without visible ultrastructural change.
respiratory tract multiciliated cell CL:4030034 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves respiratory tract multiciliated cell (CL:4030034). CL:4030034 is a cell type from the Cell Ontology.
mucociliary clearance GO:0120197 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased mucociliary clearance (GO:0120197). GO:0120197 is a biological process from the Gene Ontology.
Downstream
Chronic sinusitis
Recurrent lower respiratory tract infections
Show evidence (4 references)
PMID:7307631 SUPPORT Human Clinical
"Lung mucociliary transport was significantly reduced in patients with Young's syndrome compared to 14 control subjects matched for physical characteristics, tobacco consumption and initial topographic distribution of tracer particles within the lungs."
Radioaerosol measurement of reduced lung mucociliary transport in 14 patients versus matched controls.
PMID:1387740 SUPPORT BACKGROUND Human Clinical
"Mucociliary clearance is impaired in patients with Young's syndrome (obstructive azoospermia with recurrent sinobronchial disease), cystic fibrosis, and primary ciliary dyskinesia."
States the clearance impairment as established background to the study.
PMID:1387740 SUPPORT Human Clinical
"Ciliary beat frequency and the incidence of microtubular defects and numbers of dynein arms did not differ between patients with Young's syndrome and control subjects."
Rules out a ciliary cause in classic cases; the cilia beat normally and are ultrastructurally normal.
+ 1 more reference
Inspissated Secretion Obstruction of the Caput Epididymidis
The block lies in the head of the epididymis (a "capital" block), with lipid accumulation in the ductuli efferentes. Spermatogenesis is intact. Capital blocks respond poorly to reconstructive surgery.
epididymis secretory cell CL:1001590 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves epididymis secretory cell (CL:1001590). CL:1001590 is a cell type from the Cell Ontology.
Downstream
Obstructive azoospermia
Show evidence (3 references)
PMID:8292944 SUPPORT Human Clinical
"146 men had hold up in the head of the epididymis (capital blocks): 119 (82%) had Young's syndrome"
In 274 men with obstructive azoospermia, Young syndrome concentrated in obstruction of the epididymal head.
PMID:2241062 SUPPORT Human Clinical
"Poor results were obtained with capital blocks (patency 12%, pregnancy 3%), in which substantial lipid accumulation was demonstrated in the ductuli efferentes; three-quarters of these patients had sinusitis, bronchitis or bronchiectasis (Young's syndrome)."
Histology of capital blocks (lipid accumulation in the efferent ducts) in a cohort mostly with Young syndrome.
PMID:15204683 SUPPORT Human Clinical
"scrotal exploration revealed the distended caput, but atrophic body to tail, of the epididymis. Light microscopy of testicular biopsy showed normal spermatogensis"
Case-level anatomy of a caput epididymidis block with normal spermatogenesis.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Young Syndrome Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

8
Genitourinary 3
Obstructive azoospermia OBLIGATE HP:0011962 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Obstructive azoospermia (HP:0011962). HP:0011962 is a phenotype from the Human Phenotype Ontology.
Sequelae: Male infertility
Show evidence (1 reference)
PMID:6689737 SUPPORT Human Clinical
"Men with this syndrome have only mildly impaired respiratory function and normal spermatogenesis; the azoospermia is due to obstruction of the epididymis by inspissated secretions."
Defining finding in a series of 29 men.
Male infertility HP:0003251 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Male infertility (HP:0003251). HP:0003251 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:30969689 SUPPORT REVIEW SYNTHESIS Other
"first described by urologist Dr Donald Young following his observation of a cohort of infertile men with concomitant chronic respiratory disease"
The syndrome was first recognized among infertile men.
PMID:6689737 SUPPORT Human Clinical
"We suggest that Young's syndrome has a prevalence comparable to that of Klinefelter's syndrome and is a common cause of both chronic sinopulmonary infection and azoospermia."
Young syndrome as a common cause of azoospermia, and so of male infertility, in a 29-man series.
Decreased fertility in females HP:0000868 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Decreased fertility in females (HP:0000868). HP:0000868 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30969689 SUPPORT REVIEW SYNTHESIS Other
"Women with Young syndrome may have mildly reduced fertility, with fewer than 50% of pregnancies completing successfully."
Review-level statement of a female reproductive phenotype; no primary series was found.
Head and Neck 2
Chronic sinusitis HP:0011109 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Chronic rhinosinusitis, annotated with Chronic sinusitis (HP:0011109). HP:0011109 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:30969689 SUPPORT REVIEW SYNTHESIS Other
"most often presenting in middle-aged men as the triad of chronic rhinosinusitis, bronchiectasis, and obstructive azoospermia"
Chronic rhinosinusitis is one of the three defining features.
PMID:19128521 REFUTE REVIEW SYNTHESIS Other
"Within the reviewed literature, the diagnosis of sinusitis in Young's syndrome was crude and poorly defined; there was little emphasis on sinus disease in most publications."
A literature review found the sinus component poorly documented, which weakens its status as a defining feature.
Nasal polyposis HP:0100582 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Nasal polyposis (HP:0100582). HP:0100582 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36196705 SUPPORT BACKGROUND Human Clinical
"Young's syndrome (YS) is a rare, inherited syndrome commonly seen in middle-aged men with chronic rhinosinusitis, nasal polyps, decreased fertility due to azoospermia, and bronchiectasis."
Nasal polyps listed among the features of the syndrome in the introduction of a case report; no series reports their frequency.
Immune 1
Recurrent lower respiratory tract infections HP:0002783 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Recurrent lower respiratory tract infections (HP:0002783). HP:0002783 is a phenotype from the Human Phenotype Ontology.
Sequelae: Bronchiectasis
Show evidence (1 reference)
PMID:7551394 SUPPORT Human Clinical
"Most had intermittent bronchial and sinus infections, but none was chronically colonized with Staphylococcus aureus or Pseudomonas aeruginosa."
Intermittent bronchial infections in 13 patients, without the chronic colonization typical of cystic fibrosis.
Respiratory 2
Bronchiectasis HP:0002110 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Bronchiectasis (HP:0002110). HP:0002110 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:30969689 SUPPORT REVIEW SYNTHESIS Other
"most often presenting in middle-aged men as the triad of chronic rhinosinusitis, bronchiectasis, and obstructive azoospermia"
Bronchiectasis is one of the three defining features.
PMID:39119117 SUPPORT Human Clinical
"with cystic and tractional bronchiectasis changes in the bilateral lower lobes"
Case-level CT documentation of bronchiectasis in Young syndrome.
Mildly impaired respiratory function Reduced forced expiratory volume in one second HP:0032342 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is mildly reduced FEV1, annotated with Reduced forced expiratory volume in one second (HP:0032342), qualified as severity mild. HP:0032342 is a phenotype from the Human Phenotype Ontology.
Severity: MILD
Show evidence (1 reference)
PMID:7551394 SUPPORT Human Clinical
"The FEV1 was normal or only mildly reduced in most patients (mean = 74%; range, 48 to 100% predicted)."
Quantifies the mild degree of airflow impairment.
🧬

Genetic Associations

2
CFAP221
Gene: CFAP221 hgnc:33720 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is CFAP221 (hgnc:33720). hgnc:33720 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: UNKNOWN
Show evidence (1 reference)
PMID:38960684 SUPPORT Human Clinical
"Young's syndrome was suspected based on the triad of obstructive azoospermia, sinusitis, and bronchiectasis. He had normal electron microscopy findings, normal nasal nitric oxide levels (116 nL/min), and no situs inversus. However, we found compound heterozygous variants considered pathogenic in..."
Single case linking CFAP221 to the Young syndrome triad; the authors classify it as PCD.
CFTR
Gene: CFTR hgnc:1884 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is CFTR (hgnc:1884). hgnc:1884 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: DISPUTED
Show evidence (2 references)
PMID:7551394 REFUTE Human Clinical
"The incidence of CFTR mutations (1 in 26) did not differ significantly from the expected carrier frequency in this population. In summary, it is unlikely that the typical Young syndrome patient has a clinical disease associated with CFTR mutation on both alleles."
CFTR mutation frequency at carrier background in 13 patients.
PMID:7539448 REFUTE Human Clinical
"In Young's syndrome, no CF mutations were detected."
No CFTR mutations in 12 patients screened, in contrast to 77% in congenital absence of the vas deferens.
💊

Medical Actions

4
Epididymovasostomy
Action: epididymovasostomyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is epididymovasostomy, annotated with Bilateral Epididymovasostomy (NCIT:C219825). NCIT:C219825 is a clinical intervention from the NCI Thesaurus. Ontology label: Bilateral Epididymovasostomy NCIT:C219825
Platform: Surgery
Microsurgical bypass of the epididymal obstruction. Results are poor for the capital blocks typical of Young syndrome.
Target Phenotypes: Obstructive azoospermia HP:0011962 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Obstructive azoospermia (HP:0011962). HP:0011962 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:2241062 SUPPORT Human Clinical
"Poor results were obtained with capital blocks (patency 12%, pregnancy 3%)"
Low patency and pregnancy rates after reconstruction of capital blocks, the block type of Young syndrome.
PMID:753515 SUPPORT Human Clinical
"Thirty had epididymovasostomy, and in only 2 (6.5%) did the sperm count become normal"
Low success of epididymovasostomy in a series where half the obstructions were Young syndrome.
Testicular sperm extraction with intracytoplasmic sperm injection
Action: testicular sperm extraction with intracytoplasmic sperm injectionNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is testicular sperm extraction with intracytoplasmic sperm injection, annotated with Intracytoplasmic Sperm Injection (NCIT:C185482). NCIT:C185482 is a clinical intervention from the NCI Thesaurus. Ontology label: Intracytoplasmic Sperm Injection NCIT:C185482
Platform: Surgery
Spermatogenesis is normal, so sperm can be retrieved surgically for ICSI.
Target Phenotypes: Male infertility HP:0003251 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Male infertility (HP:0003251). HP:0003251 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:15204683 SUPPORT Human Clinical
"motile sperms were easily obtained by testicular sperm extraction"
Sperm retrievable by testicular extraction because spermatogenesis is intact.
PMID:38960684 SUPPORT Human Clinical
"He later successfully fathered a baby through intracytoplasmic sperm injection using his wife's egg."
Successful ICSI with testicular sperm in a patient with the triad.
Antibiotic therapy
Action: antibiotic therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is antibiotic therapy (NCIT:C15620). NCIT:C15620 is a clinical intervention from the NCI Thesaurus. Ontology label: Antibiotic Therapy NCIT:C15620
Platform: Small molecule
Treatment of sinus and lower respiratory infections.
Target Phenotypes: Recurrent lower respiratory tract infections HP:0002783 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Recurrent lower respiratory tract infections (HP:0002783). HP:0002783 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39119117 SUPPORT Human Clinical
"Treatment involves control of sinus, lung infection and surgical/assisted measures for reproduction."
Management is directed at infection control and assisted reproduction.
Mucoregulatory agents
Action: mucoregulatory pharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is mucoregulatory pharmacotherapy, annotated with Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. Ontology label: Pharmacotherapy NCIT:C15986
Mucolytic and mucoregulatory drugs did not improve clearance, lung function or sperm count.
Show evidence (1 reference)
PMID:3047900 REFUTE Human Clinical
"There was no improvement in tracheobronchial clearance, pulmonary function, or sperm count."
Randomised open crossover of four agents in eight patients showed no benefit.
🌍

Environmental Factors

1
Childhood mercury intoxication (pink disease)
exposure to mercury ECTO:0001571 Environmental Conditions, Treatments and Exposures Ontology (ECTO) Relation: this environmental factor is this exposure This environmental factor is exposure to mercury (ECTO:0001571). ECTO:0001571 is an exposure from the Environmental Conditions, Treatments and Exposures Ontology.
Exposure in infancy to mercurous chloride (calomel) in teething powders and worm medication. The frequency of Young syndrome among men with obstructive azoospermia fell for those born after calomel was removed from these products in the United Kingdom, in parallel with the decline of pink disease.
Show evidence (2 references)
PMID:8292944 SUPPORT Human Clinical
"The incidence of Young's syndrome fell significantly from 114 (50%) of 227 men born up to 1955 to eight (17%) of 47 men born since then."
Birth-cohort decline coinciding with withdrawal of calomel from teething powders.
PMID:40287162 SUPPORT Human Clinical
"This report details a case of a man who suffered from pink disease as a child following his mother applying teething powder containing inorganic mercury to his gums for 12 weeks, from the age of 6 months."
Case of childhood mercury intoxication followed by infertility and bronchiectasis; the authors leave open whether the later disease is Young syndrome.
Mechanism Target:
PREDISPOSES Abnormally Viscous Respiratory and Reproductive Secretions — Epidemiological association only; the mechanism by which childhood mercury exposure would alter secretions in adulthood is unknown.
Show evidence (1 reference)
PMID:8292944 SUPPORT Human Clinical
"The decline in incidence of Young's syndrome in those born after 1955 is similar to that observed with pink disease, suggesting that both conditions may have had a similar aetiology--mercury intoxication."
The authors' inference of a shared mercury aetiology from parallel birth-cohort declines.
🔬

Diagnosis

3
Sweat chloride and pancreatic function testing
Normal sweat chloride and pancreatic function exclude cystic fibrosis.
Show evidence (1 reference)
PMID:7551394 SUPPORT Human Clinical
"The sweat chloride concentration was normal in all patients (mean = 29 mEq/L; range, 8 to 43 mEq/L)."
Sweat chloride was normal in all 13 patients.
Nasal potential difference
Normal nasal potential difference argues against a CFTR-related disorder.
Show evidence (1 reference)
PMID:7551394 SUPPORT Human Clinical
"Young syndrome is characterized by obstructive azoospermia associated with chronic sinobronchial disease of an infectious nature, but normal sweat-gland and pancreatic function as well as normal nasal potential differences."
Normal nasal potential difference is part of the characterization.
Ciliary electron microscopy and genetic testing
Normal ciliary ultrastructure is expected, but it does not exclude C1d-defective primary ciliary dyskinesia, which needs genetic testing.
Show evidence (1 reference)
PMID:39362668 SUPPORT Human Clinical
"individuals with C1d-defective primary ciliary dyskinesia elude diagnosis when using the current diagnostic algorithm. To enable diagnosis, genetic testing should be prioritised in future diagnostic guidelines."
Standard PCD tests miss C1d defects, so genetic testing is required to separate them from Young syndrome.
📊

Prevalence

1
Men with obstructive azoospermia (historical clinical series)
Unknown
No population estimate exists. The founding series suggested a frequency comparable to Klinefelter syndrome, and later birth-cohort data show the syndrome becoming much rarer in men born after 1955.
Show evidence (2 references)
PMID:6689737 SUPPORT Human Clinical
"We suggest that Young's syndrome has a prevalence comparable to that of Klinefelter's syndrome and is a common cause of both chronic sinopulmonary infection and azoospermia."
The only stated frequency estimate, offered as a suggestion rather than a measurement.
PMID:8292944 SUPPORT Human Clinical
"The incidence of Young's syndrome fell significantly from 114 (50%) of 227 men born up to 1955 to eight (17%) of 47 men born since then."
Proportion of men with epididymal obstruction who had Young syndrome, by birth cohort.
🔀

Differential Diagnoses

2

Conditions with similar clinical presentations that must be differentiated from Young Syndrome:

Cystic fibrosis MONDO:0009061
Distinguishing Features
  • Normal sweat chloride, normal pancreatic function and normal nasal potential difference in Young syndrome.
Show evidence (1 reference)
PMID:7551394 SUPPORT Human Clinical
"Young syndrome is characterized by obstructive azoospermia associated with chronic sinobronchial disease of an infectious nature, but normal sweat-gland and pancreatic function as well as normal nasal potential differences."
Features that separate Young syndrome from cystic fibrosis.
Primary ciliary dyskinesia MONDO:0016575
Distinguishing Features
  • Normal ciliary ultrastructure and beat frequency in Young syndrome.
  • Azoospermia rather than immotile sperm.
  • Central-apparatus forms of PCD (CFAP221) can also show normal ultrastructure and normal nasal nitric oxide, so genetic testing is needed to separate them.
Show evidence (2 references)
PMID:9213847 SUPPORT Human Clinical
"The seminogram showed azoospermia in cases with YS and hypospermia with marked hypomotility in cases with PCD."
Semen findings separate the two conditions.
PMID:38960684 SUPPORT Human Clinical
"Distinguishing PCD from Young's syndrome in patients with the triad of obstructive azoospermia, sinusitis, and bronchiectasis is challenging. Young's syndrome may be a phenotype of PCD."
Overlap with central-apparatus PCD.
{ }

Source YAML

click to show 
name: Young Syndrome
creation_date: "2026-10-14T16:50:49Z"
category: Complex
disease_term:
  preferred_term: Young syndrome
  term:
    id: MONDO:0010220
    label: Young syndrome
synonyms:
- Young's syndrome
- sinusitis-infertility syndrome
- Barry-Perkins-Young syndrome
description: >-
  Young syndrome is the combination of obstructive azoospermia with chronic sinusitis,
  bronchitis or bronchiectasis in men whose spermatogenesis is normal, whose sweat chloride
  is normal, and whose respiratory cilia are structurally normal. The azoospermia is caused
  by obstruction of the head (caput) of the epididymis by inspissated secretions, and lung
  mucociliary clearance is reduced although ciliary beat frequency and axonemal ultrastructure
  are normal, which points to abnormal secretions rather than a primary ciliary defect. The
  only documented aetiological factor is childhood mercury intoxication (pink disease), and
  the frequency of the syndrome fell in men born after mercurous chloride was withdrawn from
  teething powders. A single CFAP221 compound-heterozygous patient with the full triad has
  been reported and classified as primary ciliary dyskinesia, which is the basis of the
  MONDO causal-gene link; whether Young syndrome is a distinct entity or a phenotype shared
  by mercury injury and mild central-apparatus primary ciliary dyskinesia is unresolved.
notes: >-
  Curated as a Disease for the clinical triad named by MONDO:0010220. The upstream cause is
  heterogeneous (historical childhood mercury exposure; one CFAP221 case), but the
  tissue-level mechanism that defines the syndrome (inspissated secretions obstructing the
  caput epididymidis and impairing mucociliary clearance with structurally normal cilia) is
  shared. CFAP221 is curated as a Definitive primary ciliary dyskinesia gene in
  Primary_Ciliary_Dyskinesia; it is recorded here with relationship_type UNKNOWN because the
  only patient with the Young syndrome phenotype and CFAP221 variants was diagnosed with PCD
  by the reporting authors. CFTR is not causal in typical Young syndrome (no excess of CFTR
  mutations over the carrier frequency in two screened series).
references:
- reference: PMID:30969689
  title: Young Syndrome.
  tags:
  - StatPearls
mechanistic_hypotheses:
- hypothesis_group_id: abnormal_secretions
  hypothesis_label: Abnormal viscous secretions with normal cilia
  status: CANONICAL
  description: >-
    The classical account of the syndrome: abnormally viscous airway and epididymal
    secretions impair mucociliary clearance and obstruct the caput epididymidis, while the
    cilia are normal. The secretion defect itself has been inferred rather than measured.
    Childhood mercury exposure is the proposed upstream cause within this account.
  evidence:
  - reference: PMID:6689737
    reference_title: "Young's syndrome. Obstructive azoospermia and chronic sinopulmonary infections."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the azoospermia is due to obstruction of the epididymis by inspissated secretions"
    explanation: The founding clinical series attributes the obstruction to inspissated secretions.
- hypothesis_group_id: mercury_secretory_injury
  hypothesis_label: Childhood mercury intoxication leading to abnormal airway and epididymal secretions
  status: ALTERNATIVE
  description: >-
    Young syndrome as a late consequence of infant exposure to mercurous chloride (pink
    disease). Supported only by birth-cohort epidemiology; no histological or experimental
    study shows how the exposure alters secretions.
  evidence:
  - reference: PMID:19128521
    reference_title: "Does Young's syndrome exist?"
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "The only documented aetiological factor is mercury exposure in childhood, an event that is seldom currently encountered; this would support our theory of the extinction of the condition."
    explanation: Literature review identifying childhood mercury exposure as the only documented cause.
- hypothesis_group_id: c1d_central_apparatus_pcd
  hypothesis_label: Unrecognized C1d central-apparatus primary ciliary dyskinesia
  status: EMERGING
  description: >-
    Some patients given the Young syndrome diagnosis may have primary ciliary dyskinesia
    caused by defects of the C1d projection (CFAP221 and related genes), which leaves ciliary
    ultrastructure, situs and nasal nitric oxide normal and so evades the tests used to
    exclude PCD. Supported by one CFAP221 patient with the triad.
  evidence:
  - reference: PMID:38960684
    reference_title: "Primary Ciliary Dyskinesia Due to Compound Heterozygous Variants in CFAP221 with Obstructive Azoospermia: Young's Syndrome May Be a Phenotype of Primary Ciliary Dyskinesia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Distinguishing PCD from Young's syndrome in patients with the triad of obstructive azoospermia, sinusitis, and bronchiectasis is challenging. Young's syndrome may be a phenotype of PCD."
    explanation: The reporting authors propose Young syndrome as a PCD phenotype after finding CFAP221 variants.
prevalence:
- population: Men with obstructive azoospermia (historical clinical series)
  measure_type: UNKNOWN
  notes: >-
    No population estimate exists. The founding series suggested a frequency comparable
    to Klinefelter syndrome, and later birth-cohort data show the syndrome becoming much
    rarer in men born after 1955.
  evidence:
  - reference: PMID:6689737
    reference_title: "Young's syndrome. Obstructive azoospermia and chronic sinopulmonary infections."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We suggest that Young's syndrome has a prevalence comparable to that of Klinefelter's syndrome and is a common cause of both chronic sinopulmonary infection and azoospermia."
    explanation: The only stated frequency estimate, offered as a suggestion rather than a measurement.
  - reference: PMID:8292944
    reference_title: "Was Young's syndrome caused by exposure to mercury in childhood?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The incidence of Young's syndrome fell significantly from 114 (50%) of 227 men born up to 1955 to eight (17%) of 47 men born since then."
    explanation: Proportion of men with epididymal obstruction who had Young syndrome, by birth cohort.
diagnosis:
- name: Sweat chloride and pancreatic function testing
  description: Normal sweat chloride and pancreatic function exclude cystic fibrosis.
  evidence:
  - reference: PMID:7551394
    reference_title: "Screening Young syndrome patients for CFTR mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The sweat chloride concentration was normal in all patients (mean = 29 mEq/L; range, 8 to 43 mEq/L)."
    explanation: Sweat chloride was normal in all 13 patients.
- name: Nasal potential difference
  description: Normal nasal potential difference argues against a CFTR-related disorder.
  evidence:
  - reference: PMID:7551394
    reference_title: "Screening Young syndrome patients for CFTR mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Young syndrome is characterized by obstructive azoospermia associated with chronic sinobronchial disease of an infectious nature, but normal sweat-gland and pancreatic function as well as normal nasal potential differences."
    explanation: Normal nasal potential difference is part of the characterization.
- name: Ciliary electron microscopy and genetic testing
  description: >-
    Normal ciliary ultrastructure is expected, but it does not exclude C1d-defective
    primary ciliary dyskinesia, which needs genetic testing.
  evidence:
  - reference: PMID:39362668
    reference_title: "Pathogenic variants in CFAP46, CFAP54, CFAP74 and CFAP221 cause primary ciliary dyskinesia with a defective C1d projection of the central apparatus."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "individuals with C1d-defective primary ciliary dyskinesia elude diagnosis when using the current diagnostic algorithm. To enable diagnosis, genetic testing should be prioritised in future diagnostic guidelines."
    explanation: Standard PCD tests miss C1d defects, so genetic testing is required to separate them from Young syndrome.
pathophysiology:
- name: Central Apparatus C1d Projection Defect
  description: >-
    Biallelic loss-of-function CFAP221 variants disturb the C1d projection of the ciliary
    central apparatus. Ultrastructure by electron microscopy, situs and nasal nitric oxide are
    normal, but beating is asynchronous and ciliary transport is insufficient. Recorded as
    the upstream lesion of the PCD hypothesis only.
  biological_scale: MOLECULAR
  genes:
  - preferred_term: CFAP221
    term:
      id: hgnc:33720
      label: CFAP221
  evidence:
  - reference: PMID:39362668
    reference_title: "Pathogenic variants in CFAP46, CFAP54, CFAP74 and CFAP221 cause primary ciliary dyskinesia with a defective C1d projection of the central apparatus."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "C1d-defective primary ciliary dyskinesia is associated with normal situs composition, normal nasal nitric oxide production rates, normal ciliary ultrastructure by transmission electron microscopy and normal ciliary beating by high-speed videomicroscopy analysis."
    explanation: Explains why C1d defects evade the tests used to separate Young syndrome from PCD.
  - reference: PMID:40250778
    reference_title: "A novel pathogenic variant of CFAP221 is a cause of a mild form of primary ciliary dyskinesia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Subtle abnormalities in the protein composition of the ciliary central apparatus were consistent with the asynchronous, circular motion of cilia and reduced ciliary beat frequency in the proband"
    explanation: Central-apparatus composition defect and abnormal beating in a CFAP221 patient.
  downstream:
  - target: Impaired Mucociliary Clearance
    causal_link_type: DIRECT
    hypothesis_groups:
    - c1d_central_apparatus_pcd
    evidence:
    - reference: PMID:39362668
      reference_title: "Pathogenic variants in CFAP46, CFAP54, CFAP74 and CFAP221 cause primary ciliary dyskinesia with a defective C1d projection of the central apparatus."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "we could show by in vitro ciliary transport assays that affected individuals exhibit insufficient ciliary clearance"
      explanation: Patient-cell transport assays show the C1d defect impairs clearance.
  - target: Inspissated Secretion Obstruction of the Caput Epididymidis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - c1d_central_apparatus_pcd
    description: >-
      Proposed route: failure of motile cilia in the efferent ducts impairs sperm transport
      and produces a proximal obstruction. Not demonstrated for CFAP221; the reported
      CFAP221 patient had obstructive azoospermia with normal sperm structure.
    evidence:
    - reference: PMID:38960684
      reference_title: "Primary Ciliary Dyskinesia Due to Compound Heterozygous Variants in CFAP221 with Obstructive Azoospermia: Young's Syndrome May Be a Phenotype of Primary Ciliary Dyskinesia."
      supports: SUPPORT
      directness: INDIRECT
      quote_role: BACKGROUND
      evidence_source: HUMAN_CLINICAL
      snippet: "recent suggestions indicate that the impairment of efferent duct ciliary motility is also a factor in male infertility"
      explanation: >-
        Background statement that efferent-duct ciliary dysfunction can cause male
        infertility, offered by the authors as the link between PCD and obstructive
        azoospermia in their CFAP221 patient; inference, not a CFAP221-specific result.
- name: Abnormally Viscous Respiratory and Reproductive Secretions
  description: >-
    Respiratory and epididymal secretions are abnormally thick and viscous. The defect has
    been inferred from the combination of impaired clearance with structurally and
    functionally normal cilia; no specific mucin or ion-transport lesion has been identified.
  biological_scale: TISSUE
  biological_processes:
  - preferred_term: mucus secretion
    term:
      id: GO:0070254
      label: mucus secretion
  evidence:
  - reference: PMID:30969689
    reference_title: "Young Syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Individuals with Young syndrome have structurally normal lung parenchyma and cilia but produce abnormally thick, viscous respiratory and reproductive secretions."
    explanation: StatPearls synthesis stating the secretion abnormality as the core lesion of the syndrome.
  - reference: PMID:1387740
    reference_title: "Mucociliary function, ciliary ultrastructure, and ciliary orientation in Young's syndrome."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "may be due to a structural defect but is more likely to be a consequence of abnormal mucus"
    explanation: >-
      In 20 patients, the only ciliary finding (distal axoneme disorientation) was attributed
      by the authors to abnormal mucus rather than a ciliary defect; the abnormal-mucus claim
      is an inference from this observation.
  - reference: PMID:1387740
    reference_title: "Mucociliary function, ciliary ultrastructure, and ciliary orientation in Young's syndrome."
    supports: REFUTE
    quote_role: BACKGROUND
    evidence_source: HUMAN_CLINICAL
    snippet: "No defect of cilia or mucus has been detected in Young's syndrome."
    explanation: >-
      No mucus defect had been directly demonstrated when this study was published; the
      viscous-secretion lesion remains inferred rather than measured.
  downstream:
  - target: Impaired Mucociliary Clearance
    causal_link_type: DIRECT
    hypothesis_groups:
    - abnormal_secretions
    evidence:
    - reference: PMID:30969689
      reference_title: "Young Syndrome."
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: "In the lungs, this thick and tenacious mucus impairs mucociliary clearance, predisposing patients to recurrent lower respiratory tract infections and progressive bronchiectasis."
      explanation: States that the viscous mucus is what impairs mucociliary clearance.
  - target: Inspissated Secretion Obstruction of the Caput Epididymidis
    causal_link_type: DIRECT
    hypothesis_groups:
    - abnormal_secretions
    evidence:
    - reference: PMID:6689737
      reference_title: "Young's syndrome. Obstructive azoospermia and chronic sinopulmonary infections."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "the azoospermia is due to obstruction of the epididymis by inspissated secretions"
      explanation: In 29 men, the epididymal obstruction was attributed to inspissated secretions.
- name: Impaired Mucociliary Clearance
  description: >-
    Lung mucociliary transport is reduced. In classic series ciliary beat frequency,
    microtubular structure and dynein arm number are normal, so the defect was attributed to
    the secretions rather than the cilia; a C1d central-apparatus defect would also impair
    clearance without visible ultrastructural change.
  biological_scale: TISSUE
  cell_types:
  - preferred_term: respiratory tract multiciliated cell
    term:
      id: CL:4030034
      label: respiratory tract multiciliated cell
  biological_processes:
  - preferred_term: mucociliary clearance
    modifier: DECREASED
    term:
      id: GO:0120197
      label: mucociliary clearance
  evidence:
  - reference: PMID:7307631
    reference_title: "Lung mucociliary clearance in patients wit Young's syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Lung mucociliary transport was significantly reduced in patients with Young's syndrome compared to 14 control subjects matched for physical characteristics, tobacco consumption and initial topographic distribution of tracer particles within the lungs."
    explanation: Radioaerosol measurement of reduced lung mucociliary transport in 14 patients versus matched controls.
  - reference: PMID:1387740
    reference_title: "Mucociliary function, ciliary ultrastructure, and ciliary orientation in Young's syndrome."
    supports: SUPPORT
    quote_role: BACKGROUND
    evidence_source: HUMAN_CLINICAL
    snippet: "Mucociliary clearance is impaired in patients with Young's syndrome (obstructive azoospermia with recurrent sinobronchial disease), cystic fibrosis, and primary ciliary dyskinesia."
    explanation: States the clearance impairment as established background to the study.
  - reference: PMID:1387740
    reference_title: "Mucociliary function, ciliary ultrastructure, and ciliary orientation in Young's syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Ciliary beat frequency and the incidence of microtubular defects and numbers of dynein arms did not differ between patients with Young's syndrome and control subjects."
    explanation: Rules out a ciliary cause in classic cases; the cilia beat normally and are ultrastructurally normal.
  - reference: PMID:9213847
    reference_title: "[Clinical features and ultrastructure of primary ciliary dyskinesia and Young syndrome]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients with YS did not have pathognomonic ultrastructural changes, whereas patients with PCD had a large number of ciliary abnormalities"
    explanation: Rules out a ciliary ultrastructural lesion; electron microscopy separates Young syndrome from primary ciliary dyskinesia.
  downstream:
  - target: Chronic sinusitis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Recurrent lower respiratory tract infections
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:30969689
      reference_title: "Young Syndrome."
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: "In the lungs, this thick and tenacious mucus impairs mucociliary clearance, predisposing patients to recurrent lower respiratory tract infections and progressive bronchiectasis."
      explanation: Links impaired clearance to recurrent lower respiratory tract infections.
- name: Inspissated Secretion Obstruction of the Caput Epididymidis
  description: >-
    The block lies in the head of the epididymis (a "capital" block), with lipid
    accumulation in the ductuli efferentes. Spermatogenesis is intact. Capital blocks
    respond poorly to reconstructive surgery.
  biological_scale: TISSUE
  cell_types:
  - preferred_term: epididymis secretory cell
    term:
      id: CL:1001590
      label: epididymis secretory cell
  evidence:
  - reference: PMID:8292944
    reference_title: "Was Young's syndrome caused by exposure to mercury in childhood?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "146 men had hold up in the head of the epididymis (capital blocks): 119 (82%) had Young's syndrome"
    explanation: In 274 men with obstructive azoospermia, Young syndrome concentrated in obstruction of the epididymal head.
  - reference: PMID:2241062
    reference_title: "Testicular obstruction: clinicopathological studies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Poor results were obtained with capital blocks (patency 12%, pregnancy 3%), in which substantial lipid accumulation was demonstrated in the ductuli efferentes; three-quarters of these patients had sinusitis, bronchitis or bronchiectasis (Young's syndrome)."
    explanation: Histology of capital blocks (lipid accumulation in the efferent ducts) in a cohort mostly with Young syndrome.
  - reference: PMID:15204683
    reference_title: "Young's syndrome associated with situs inversus totalis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "scrotal exploration revealed the distended caput, but atrophic body to tail, of the epididymis. Light microscopy of testicular biopsy showed normal spermatogensis"
    explanation: Case-level anatomy of a caput epididymidis block with normal spermatogenesis.
  downstream:
  - target: Obstructive azoospermia
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:30969689
      reference_title: "Young Syndrome."
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: "Spermatogenesis itself is intact, and functional obstruction prevents sperm from reaching the ejaculate, resulting in obstructive azoospermia."
      explanation: Obstruction rather than failed spermatogenesis produces the azoospermia.
phenotypes:
- name: Obstructive azoospermia
  category: Reproductive
  frequency: OBLIGATE
  description: Azoospermia with normal spermatogenesis, due to epididymal obstruction.
  phenotype_term:
    preferred_term: Obstructive azoospermia
    term:
      id: HP:0011962
      label: Obstructive azoospermia
  evidence:
  - reference: PMID:6689737
    reference_title: "Young's syndrome. Obstructive azoospermia and chronic sinopulmonary infections."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Men with this syndrome have only mildly impaired respiratory function and normal spermatogenesis; the azoospermia is due to obstruction of the epididymis by inspissated secretions."
    explanation: Defining finding in a series of 29 men.
  sequelae:
  - target: Male infertility
- name: Male infertility
  category: Reproductive
  phenotype_term:
    preferred_term: Male infertility
    term:
      id: HP:0003251
      label: Male infertility
  evidence:
  - reference: PMID:30969689
    reference_title: "Young Syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "first described by urologist Dr Donald Young following his observation of a cohort of infertile men with concomitant chronic respiratory disease"
    explanation: The syndrome was first recognized among infertile men.
  - reference: PMID:6689737
    reference_title: "Young's syndrome. Obstructive azoospermia and chronic sinopulmonary infections."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We suggest that Young's syndrome has a prevalence comparable to that of Klinefelter's syndrome and is a common cause of both chronic sinopulmonary infection and azoospermia."
    explanation: Young syndrome as a common cause of azoospermia, and so of male infertility, in a 29-man series.
- name: Chronic sinusitis
  category: Respiratory
  phenotype_term:
    preferred_term: Chronic rhinosinusitis
    term:
      id: HP:0011109
      label: Chronic sinusitis
  evidence:
  - reference: PMID:30969689
    reference_title: "Young Syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "most often presenting in middle-aged men as the triad of chronic rhinosinusitis, bronchiectasis, and obstructive azoospermia"
    explanation: Chronic rhinosinusitis is one of the three defining features.
  - reference: PMID:19128521
    reference_title: "Does Young's syndrome exist?"
    supports: REFUTE
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Within the reviewed literature, the diagnosis of sinusitis in Young's syndrome was crude and poorly defined; there was little emphasis on sinus disease in most publications."
    explanation: A literature review found the sinus component poorly documented, which weakens its status as a defining feature.
- name: Bronchiectasis
  category: Respiratory
  phenotype_term:
    preferred_term: Bronchiectasis
    term:
      id: HP:0002110
      label: Bronchiectasis
  evidence:
  - reference: PMID:30969689
    reference_title: "Young Syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "most often presenting in middle-aged men as the triad of chronic rhinosinusitis, bronchiectasis, and obstructive azoospermia"
    explanation: Bronchiectasis is one of the three defining features.
  - reference: PMID:39119117
    reference_title: "Barry-Perkins-Young syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "with cystic and tractional bronchiectasis changes in the bilateral lower lobes"
    explanation: Case-level CT documentation of bronchiectasis in Young syndrome.
- name: Recurrent lower respiratory tract infections
  category: Respiratory
  phenotype_term:
    preferred_term: Recurrent lower respiratory tract infections
    term:
      id: HP:0002783
      label: Recurrent lower respiratory tract infections
  evidence:
  - reference: PMID:7551394
    reference_title: "Screening Young syndrome patients for CFTR mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Most had intermittent bronchial and sinus infections, but none was chronically colonized with Staphylococcus aureus or Pseudomonas aeruginosa."
    explanation: Intermittent bronchial infections in 13 patients, without the chronic colonization typical of cystic fibrosis.
  sequelae:
  - target: Bronchiectasis
    evidence:
    - reference: PMID:30969689
      reference_title: "Young Syndrome."
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: "In the lungs, this thick and tenacious mucus impairs mucociliary clearance, predisposing patients to recurrent lower respiratory tract infections and progressive bronchiectasis."
      explanation: Places progressive bronchiectasis downstream of recurrent lower respiratory infection.
- name: Mildly impaired respiratory function
  category: Respiratory
  description: Lung function is normal or only mildly reduced.
  phenotype_term:
    preferred_term: mildly reduced FEV1
    severity: MILD
    term:
      id: HP:0032342
      label: Reduced forced expiratory volume in one second
  evidence:
  - reference: PMID:7551394
    reference_title: "Screening Young syndrome patients for CFTR mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The FEV1 was normal or only mildly reduced in most patients (mean = 74%; range, 48 to 100% predicted)."
    explanation: Quantifies the mild degree of airflow impairment.
- name: Nasal polyposis
  category: Respiratory
  phenotype_term:
    preferred_term: Nasal polyposis
    term:
      id: HP:0100582
      label: Nasal polyposis
  evidence:
  - reference: PMID:36196705
    reference_title: "Young's syndrome, a rare syndrome that can cause infertility and mimics cystic fibrosis and immotile-cilia syndrome: a case report."
    supports: SUPPORT
    quote_role: BACKGROUND
    evidence_source: HUMAN_CLINICAL
    snippet: "Young's syndrome (YS) is a rare, inherited syndrome commonly seen in middle-aged men with chronic rhinosinusitis, nasal polyps, decreased fertility due to azoospermia, and bronchiectasis."
    explanation: >-
      Nasal polyps listed among the features of the syndrome in the introduction of a case
      report; no series reports their frequency.
- name: Decreased fertility in females
  category: Reproductive
  description: Women may have mildly reduced fertility; the female phenotype is poorly characterized.
  phenotype_term:
    preferred_term: Decreased fertility in females
    term:
      id: HP:0000868
      label: Decreased fertility in females
  evidence:
  - reference: PMID:30969689
    reference_title: "Young Syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Women with Young syndrome may have mildly reduced fertility, with fewer than 50% of pregnancies completing successfully."
    explanation: Review-level statement of a female reproductive phenotype; no primary series was found.
genetic:
- name: CFAP221
  gene_term:
    preferred_term: CFAP221
    term:
      id: hgnc:33720
      label: CFAP221
  relationship_type: UNKNOWN
  notes: >-
    MONDO's causal-gene assertion. The only reported patient with the Young syndrome triad
    and CFAP221 variants carried compound heterozygous loss-of-function alleles, had normal
    ciliary ultrastructure and normal nasal nitric oxide, and was diagnosed with primary
    ciliary dyskinesia by the reporting authors. CFAP221 is a component of the C1d projection
    of the ciliary central apparatus.
  evidence:
  - reference: PMID:38960684
    reference_title: "Primary Ciliary Dyskinesia Due to Compound Heterozygous Variants in CFAP221 with Obstructive Azoospermia: Young's Syndrome May Be a Phenotype of Primary Ciliary Dyskinesia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Young's syndrome was suspected based on the triad of obstructive azoospermia, sinusitis, and bronchiectasis. He had normal electron microscopy findings, normal nasal nitric oxide levels (116 nL/min), and no situs inversus. However, we found compound heterozygous variants considered pathogenic in CFAP221. This led to a diagnosis of primary ciliary dyskinesia (PCD)."
    explanation: Single case linking CFAP221 to the Young syndrome triad; the authors classify it as PCD.
- name: CFTR
  gene_term:
    preferred_term: CFTR
    term:
      id: hgnc:1884
      label: CFTR
  relationship_type: DISPUTED
  notes: >-
    Screened because CFTR causes congenital bilateral absence of the vas deferens; no excess
    of CFTR mutations was found in two series of Young syndrome patients. Both screened
    panels of common mutations or selected exons rather than the whole gene, so rare CFTR
    alleles are not excluded.
  evidence:
  - reference: PMID:7551394
    reference_title: "Screening Young syndrome patients for CFTR mutations."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "The incidence of CFTR mutations (1 in 26) did not differ significantly from the expected carrier frequency in this population. In summary, it is unlikely that the typical Young syndrome patient has a clinical disease associated with CFTR mutation on both alleles."
    explanation: CFTR mutation frequency at carrier background in 13 patients.
  - reference: PMID:7539448
    reference_title: "Obstructive azoospermia with agenesis of vas deferens or with bronchiectasia (Young's syndrome): a genetic approach."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "In Young's syndrome, no CF mutations were detected."
    explanation: No CFTR mutations in 12 patients screened, in contrast to 77% in congenital absence of the vas deferens.
environmental:
- name: Childhood mercury intoxication (pink disease)
  description: >-
    Exposure in infancy to mercurous chloride (calomel) in teething powders and worm
    medication. The frequency of Young syndrome among men with obstructive azoospermia fell
    for those born after calomel was removed from these products in the United Kingdom,
    in parallel with the decline of pink disease.
  exposure_term:
    preferred_term: exposure to mercury
    term:
      id: ECTO:0001571
      label: exposure to mercury
  evidence:
  - reference: PMID:8292944
    reference_title: "Was Young's syndrome caused by exposure to mercury in childhood?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The incidence of Young's syndrome fell significantly from 114 (50%) of 227 men born up to 1955 to eight (17%) of 47 men born since then."
    explanation: Birth-cohort decline coinciding with withdrawal of calomel from teething powders.
  - reference: PMID:40287162
    reference_title: "Mercury exposure, pink disease and Young's syndrome: a forgotten public health disaster."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This report details a case of a man who suffered from pink disease as a child following his mother applying teething powder containing inorganic mercury to his gums for 12 weeks, from the age of 6 months."
    explanation: >-
      Case of childhood mercury intoxication followed by infertility and bronchiectasis; the
      authors leave open whether the later disease is Young syndrome.
  influences_mechanisms:
  - target: Abnormally Viscous Respiratory and Reproductive Secretions
    environmental_effect: PREDISPOSES
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Epidemiological association only; the mechanism by which childhood mercury exposure
      would alter secretions in adulthood is unknown.
    evidence:
    - reference: PMID:8292944
      reference_title: "Was Young's syndrome caused by exposure to mercury in childhood?"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The decline in incidence of Young's syndrome in those born after 1955 is similar to that observed with pink disease, suggesting that both conditions may have had a similar aetiology--mercury intoxication."
      explanation: The authors' inference of a shared mercury aetiology from parallel birth-cohort declines.
treatments:
- name: Epididymovasostomy
  description: >-
    Microsurgical bypass of the epididymal obstruction. Results are poor for the capital
    blocks typical of Young syndrome.
  therapeutic_modality: SURGERY
  notes: >-
    Bound to the bilateral NCIT term because NCIT has no unqualified epididymovasostomy
    concept (OLS search "epididymovasostomy" in ncit returned only NCIT:C219825); the
    obstruction in Young syndrome is bilateral.
  treatment_term:
    preferred_term: epididymovasostomy
    term:
      id: NCIT:C219825
      label: Bilateral Epididymovasostomy
  target_phenotypes:
  - preferred_term: Obstructive azoospermia
    term:
      id: HP:0011962
      label: Obstructive azoospermia
  evidence:
  - reference: PMID:2241062
    reference_title: "Testicular obstruction: clinicopathological studies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Poor results were obtained with capital blocks (patency 12%, pregnancy 3%)"
    explanation: Low patency and pregnancy rates after reconstruction of capital blocks, the block type of Young syndrome.
  - reference: PMID:753515
    reference_title: "Obstructive azoospermia: respiratory function tests, electron microscopy and the results of surgery."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Thirty had epididymovasostomy, and in only 2 (6.5%) did the sperm count become normal"
    explanation: Low success of epididymovasostomy in a series where half the obstructions were Young syndrome.
- name: Testicular sperm extraction with intracytoplasmic sperm injection
  description: Spermatogenesis is normal, so sperm can be retrieved surgically for ICSI.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: testicular sperm extraction with intracytoplasmic sperm injection
    term:
      id: NCIT:C185482
      label: Intracytoplasmic Sperm Injection
  target_phenotypes:
  - preferred_term: Male infertility
    term:
      id: HP:0003251
      label: Male infertility
  evidence:
  - reference: PMID:15204683
    reference_title: "Young's syndrome associated with situs inversus totalis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "motile sperms were easily obtained by testicular sperm extraction"
    explanation: Sperm retrievable by testicular extraction because spermatogenesis is intact.
  - reference: PMID:38960684
    reference_title: "Primary Ciliary Dyskinesia Due to Compound Heterozygous Variants in CFAP221 with Obstructive Azoospermia: Young's Syndrome May Be a Phenotype of Primary Ciliary Dyskinesia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "He later successfully fathered a baby through intracytoplasmic sperm injection using his wife's egg."
    explanation: Successful ICSI with testicular sperm in a patient with the triad.
- name: Antibiotic therapy
  description: Treatment of sinus and lower respiratory infections.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: antibiotic therapy
    term:
      id: NCIT:C15620
      label: Antibiotic Therapy
  target_phenotypes:
  - preferred_term: Recurrent lower respiratory tract infections
    term:
      id: HP:0002783
      label: Recurrent lower respiratory tract infections
  evidence:
  - reference: PMID:39119117
    reference_title: "Barry-Perkins-Young syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Treatment involves control of sinus, lung infection and surgical/assisted measures for reproduction."
    explanation: Management is directed at infection control and assisted reproduction.
- name: Mucoregulatory agents
  description: Mucolytic and mucoregulatory drugs did not improve clearance, lung function or sperm count.
  treatment_term:
    preferred_term: mucoregulatory pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  evidence:
  - reference: PMID:3047900
    reference_title: "Efficacy of \"mucoregulatory\" agents in Young's syndrome."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "There was no improvement in tracheobronchial clearance, pulmonary function, or sperm count."
    explanation: Randomised open crossover of four agents in eight patients showed no benefit.
differential_diagnoses:
- name: Cystic fibrosis
  disease_term:
    preferred_term: cystic fibrosis
    term:
      id: MONDO:0009061
      label: cystic fibrosis
  distinguishing_features:
  - Normal sweat chloride, normal pancreatic function and normal nasal potential difference in Young syndrome.
  evidence:
  - reference: PMID:7551394
    reference_title: "Screening Young syndrome patients for CFTR mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Young syndrome is characterized by obstructive azoospermia associated with chronic sinobronchial disease of an infectious nature, but normal sweat-gland and pancreatic function as well as normal nasal potential differences."
    explanation: Features that separate Young syndrome from cystic fibrosis.
- name: Primary ciliary dyskinesia
  disease_term:
    preferred_term: primary ciliary dyskinesia
    term:
      id: MONDO:0016575
      label: primary ciliary dyskinesia
  distinguishing_features:
  - Normal ciliary ultrastructure and beat frequency in Young syndrome.
  - Azoospermia rather than immotile sperm.
  - Central-apparatus forms of PCD (CFAP221) can also show normal ultrastructure and normal nasal nitric oxide, so genetic testing is needed to separate them.
  evidence:
  - reference: PMID:9213847
    reference_title: "[Clinical features and ultrastructure of primary ciliary dyskinesia and Young syndrome]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The seminogram showed azoospermia in cases with YS and hypospermia with marked hypomotility in cases with PCD."
    explanation: Semen findings separate the two conditions.
  - reference: PMID:38960684
    reference_title: "Primary Ciliary Dyskinesia Due to Compound Heterozygous Variants in CFAP221 with Obstructive Azoospermia: Young's Syndrome May Be a Phenotype of Primary Ciliary Dyskinesia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Distinguishing PCD from Young's syndrome in patients with the triad of obstructive azoospermia, sinusitis, and bronchiectasis is challenging. Young's syndrome may be a phenotype of PCD."
    explanation: Overlap with central-apparatus PCD.
📚

References & Deep Research

References

1
PMID:30969689
Young Syndrome.
No top-level findings curated for this source.

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (1)

Create: Young_Syndrome · 2026-10-14T17:07:21Z · View source

New Disease entry for Young syndrome (MONDO:0010220), claimed in #14160. Entry type decided as DISEASE rather than a has_subtypes row on Primary_Ciliary_Dyskinesia: the clinical triad is defined by a shared tissue-level mechanism (inspissated secretions obstructing the caput epididymidis; reduced mucociliary clearance with normal ciliary ultrastructure and beat frequency), while its upstream causes differ. Two competing upstream causes are modelled as hypothesis groups: childhood mercury exposure (birth-cohort epidemiology, PMID:8292944) and unrecognized C1d central-apparatus PCD (one CFAP221 patient with the triad, PMID:38960684). CFAP221 is recorded as relationship_type UNKNOWN and CFTR as DISPUTED (no excess of CFTR mutations, PMID:7551394, PMID:7539448). Deep research: falcon was requested by default but failed authentication (503) on two attempts, including with --fallback, which did not hand off; the claude_code provider was run instead (research/Young_Syndrome-deep-research-claude_code.md; 24/24 references resolved, 10/10 quotes valid, 3 off-topic references not cited). preflight-dr WARN on CFTR mentions was read: they are refutation and differential content for this disease, not a second entity. No GeneReviews chapter exists (check-genereviews --online: NO_CHAPTER); the StatPearls chapter is cited and tagged. An independent subagent review was run before the PR; its findings (reference titles, hypothesis-group scoping, a reproductive branch for the C1d hypothesis, a qualifying REFUTE item on the inferred mucus defect, FEV1 binding, quote_role on background quotes, prevalence and diagnosis rows) were applied. Validation: just validate passes (schema, terms, 53/53 snippets), plus check-entity-refs, check-causal-targets, check-duplicate-keys, check-snippet-grading, check-title-snippets, check-reference-titles and check-coarse-phenotypes.

Claude Code ▸
Young Syndrome: Research Report
claude-haiku-5-5, claude-opus-5-5 18 citations 2026-10-14T12:55:44.083569

Young Syndrome: Research Report

Target: Young syndrome (MONDO:0010220) · Category: Complex · Report date: 2026-10-14

How the citations were checked. 19 PMIDs already have a references_cache/ file on this branch. Quotes from those PMIDs were copied from the cached abstract or full text. Sources that are not cached are marked [not cached], so fetch them with just fetch-reference before quoting them in the KB. Ontology CURIEs marked ✓ were read from the repository's cache/<prefix>/terms.csv during this session. Unmarked CURIEs are leads, and each one needs a lookup before it is used.

Summary of the evidence (read this first)

Whether Young syndrome is a distinct disease is itself disputed. The literature supports three positions:

  1. A real clinical entity of unknown cause. Obstructive azoospermia comes from the epididymis being blocked by thick secretions, and occurs alongside chronic sinopulmonary infection. Handelsman 1984 (PMID:6689737) is the main source.
  2. A mostly historical condition caused by childhood mercury exposure. Incidence dropped sharply in men born after mercury (calomel) was removed from UK teething powders in 1955 (Hendry 1993, PMID:8292944 [not cached]; Arya 2009, PMID:19128521; Brown 2025, PMID:40287162).
  3. A misdiagnosed form of primary ciliary dyskinesia (PCD). In particular, PCD caused by defects in the C1d projection of the ciliary central apparatus (for example CFAP221) gives normal electron microscopy (EM), normal nasal NO and normal situs. It is therefore missed by the classical tests that were used to "exclude" PCD when Young syndrome was defined (Ito 2025, PMID:38960684; Wohlgemuth 2024, PMID:39362668).

Two lines of evidence count against Young syndrome being a mild form of cystic fibrosis (CF): normal sweat chloride, and a CFTR mutation rate no higher than the background carrier rate (PMID:7551394).

What this means for curation: the stub's entry_type decision is not obvious, and the notes should record the reasoning. A defensible choice is a DISEASE entry with low-confidence, hypothesis-grouped mechanisms, namely mercury toxicity versus an undiagnosed motile ciliopathy. Each grouping should be marked EMERGING or HYPOTHETICAL rather than ESTABLISHED.

1. Disease Information

Overview. Young syndrome is a triad found mainly in middle-aged men: - obstructive azoospermia, with normal spermatogenesis and an enlarged, sperm-filled caput epididymis; - chronic or recurrent rhinosinusitis; - recurrent bronchitis or bronchiectasis.

It is diagnosed by exclusion, after CF and PCD have been ruled out.

"We studied 29 men with Young's syndrome, a combination of obstructive azoospermia and chronic sinopulmonary infections. Men with this syndrome have only mildly impaired respiratory function and normal spermatogenesis; the azoospermia is due to obstruction of the epididymis by inspissated secretions." — PMID:6689737 (Handelsman et al., NEJM 1984)

"The diagnosis is based on the occurrence of chronic sinopulmonary infections, persistent azoospermia, normal spermatogenesis, and characteristic epididymal findings, as well as exclusion of cystic fibrosis and the immotile-cilia syndrome." — PMID:6689737

Identifiers.

System ID Note
MONDO MONDO:0010220 Not in cache/mondo/terms.csv, so confirm the label via OLS
OMIM 279000 Per MedGen. omim.org returned 403 to a fetch
Orphanet ORPHA:3471 Per MedGen. Run just fetch-reference ORPHA:3471 to get a quotable record
MedGen C0221040 / 137934
ICD-10 No specific code Usually coded through its components (N46 male infertility, J47 bronchiectasis)

Synonyms: Young's syndrome; sinusitis–infertility syndrome; Barry–Perkins–Young syndrome; azoospermia–sinusitis–bronchiectasis.

"Young´s syndrome also known as Barry-Perkins-Young syndrome or sinusitis-infertility syndrome is a rare, inherited syndrome commonly seen in middle-aged men with chronic rhinosinusitis, nasal polyps, infertility and bronchiectasis." — PMID:39119117

Name collision (a Named Entity Confusion risk). "Young syndrome" also names an unrelated condition:

"As an incidental finding, we found that the term Young's syndrome refers to two different medical conditions." — PMID:19128521

When searching, filter out the Young–Simpson / Say–Barber–Biesecker–Young–Simpson (KAT6B) syndrome, which is a different disease.

Source of the information: case series and aggregated reviews. There are no registries or EHR cohorts.

2. Etiology

Causal factors (unresolved)

(a) Childhood mercury exposure (environmental hypothesis). This is the only cause any source documents. Hendry et al. 1993 (BMJ 307:1579; PMID:8292944 [not cached]) followed 274 men who had epididymovasostomy for obstructive azoospermia. Young syndrome was diagnosed in 114 of 227 men (50%) born up to 1955, against 8 of 47 men (17%) born afterwards. 1955 is the year calomel (mercurous chloride) was withdrawn from UK teething powders and worm treatments, and the drop parallels the disappearance of pink disease (acrodynia). See also Hendry et al. 1996, BMJ, "Declining sperm count. Increasing evidence that Young's syndrome is associated with mercury" (PMID:8664779). That PMID is cached, but its content is unavailable, so it cannot be quoted.

"The only documented aetiological factor is mercury exposure in childhood, an event that is seldom currently encountered; this would support our theory of the extinction of the condition." — PMID:19128521

"This report details a case of a man who suffered from pink disease as a child following his mother applying teething powder containing inorganic mercury to his gums for 12 weeks, from the age of 6 months. … Throughout his lifetime, however, the man (in his 70s) has been diagnosed as infertile, and with bronchiectasis…" — PMID:40287162

The Ito 2025 full text summarises a second Hendry series: "In a prospective study conducted between 1975 and 1993 on 146 subfertile men with epididymal obstruction, 82% were diagnosed with Young's syndrome and mercury exposure was identified in 11 cases" (PMID:38960684, discussion). This sentence is a BACKGROUND quote: Ito restates another group's result.

(b) Undiagnosed motile ciliopathy, i.e. PCD with normal EM (genetic hypothesis).

"He had normal electron microscopy findings, normal nasal nitric oxide levels (116 nL/min), and no situs inversus. However, we found compound heterozygous variants considered pathogenic in CFAP221. This led to a diagnosis of primary ciliary dyskinesia (PCD). … Young's syndrome may be a phenotype of PCD." — PMID:38960684

"C1d-defective primary ciliary dyskinesia is associated with normal situs composition, normal nasal nitric oxide production rates, normal ciliary ultrastructure by transmission electron microscopy and normal ciliary beating by high-speed videomicroscopy analysis." — PMID:39362668

This matters because the original definition excluded PCD by EM, which every C1d-defective form passes. Some historical Young syndrome cases may therefore have been C1d-defective PCD. That conclusion is inferred: no study has re-genotyped a historical Young syndrome cohort.

(c) CFTR: not supported as a cause.

"Of 26 Young syndrome chromosomes, we identified one with the recognized CF mutation delta F508. The incidence of CFTR mutations (1 in 26) did not differ significantly from the expected carrier frequency in this population. In summary, it is unlikely that the typical Young syndrome patient has a clinical disease associated with CFTR mutation on both alleles." — PMID:7551394 (Friedman et al., AJRCCM 1995)

Related cached letters that cannot be quoted (content unavailable): PMID:8100886 (Lancet 1993, ΔF508) and PMID:9800754 (Lancet 1998, "Cystic fibrosis, Young's syndrome, and normal sweat chloride"). Ito 2025 notes that isolated cases of Young syndrome with CFTR mutations have been reported, so CF should still be excluded.

Risk factors

  • Environmental: mercurous chloride in teething powder or vermifuges during infancy; exposure to mercury, ECTO:0001571 ✓.
  • Sex: the defining feature, obstructive azoospermia, applies only to men. StatPearls says women may have mildly reduced fertility (PMID:30969689). That claim is weakly sourced.
  • Age and birth cohort: men born before 1955 in the UK and northern Europe.
  • Genetic: no confirmed locus. Orphanet and MedGen list autosomal recessive inheritance (HP:0000007 ✓). That listing reflects the older "inherited" framing and has no supporting linkage data.

Protective factors and gene–environment interaction

There are no data. The mercury hypothesis implies that withdrawing calomel was a primary-prevention event at population level.

3. Phenotypes

Phenotype Suggested HPO Frequency / notes Source
Obstructive azoospermia HP:0000027 Azoospermia ✓ (no "obstructive azoospermia" row in the cache, so search HPO for a narrower term) Defining, about 100% PMID:6689737
Enlarged caput epididymis with inspissated material HP:0009714 Abnormal epididymis morphology ✓ Characteristic PMID:6689737; PMID:38960684 discussion
Normal spermatogenesis Not a phenotype; diagnostic qualifier — PMID:6689737
Male infertility HP:0003251 ✓ Defining PMID:19128521
Chronic rhinosinusitis HP:0011109 Chronic sinusitis ✓ / HP:0011108 Recurrent sinusitis ✓ Common but poorly defined PMID:19128521
Nasal polyps HP:0100582 Nasal polyposis ✓ Reported, frequency unknown PMID:36196705; PMID:8922141
Bronchiectasis HP:0002110 ✓ Variable, often mild PMID:39119117; PMID:38960684
Recurrent bronchitis / lower respiratory infection HP:0004469 ✓ / HP:0002783 ✓ Most patients PMID:7551394
Productive cough HP:0031245 ✓ Common PMID:36196705
Impaired lung mucociliary clearance (lab/physiologic) No HP row cached; bind GO:0120197 mucociliary clearance ✓ with DECREASED on a pathophysiology node n=14, significantly reduced PMID:7307631
Mildly reduced FEV1 Look up an HP term Mean 74% predicted (range 48–100%) PMID:7551394

On the sinus component, Arya 2009 (PMID:19128521) found that "the diagnosis of sinusitis in Young's syndrome was crude and poorly defined." Frequencies for the sinus features should be treated as unreliable.

Onset and course: onset is adult, usually first recognised during an infertility work-up in the 30s or 40s. In the Friedman cohort the mean age was 43 (range 32–50) (PMID:7551394). Respiratory disease is chronic, mild and slowly progressive. There was no chronic S. aureus or P. aeruginosa colonisation, which distinguishes it from CF.

Quality of life: no instrument-based data exist. One case report states: "An accurate diagnosis of YS is usually made late, which reduces patients' quality of life and leads to chronic respiratory problems" (PMID:36196705).

4. Genetic / Molecular Information

  • No causal gene has been established. Do not add a CAUSATIVE gene row.
  • CFAP221 (hgnc:33720 ✓): one compound-heterozygous case with a Young phenotype that was reclassified as PCD (PMID:38960684). Should a CFAP221 row be included, the defensible framing is a phenocopy or differential diagnosis, or a SUSCEPTIBILITY-style lead in notes. It should not be causal. On the MalaCards claim that OMIM's CILD55 (CFAP221) entry mentions a Young syndrome presentation (MalaCards): verify it against OMIM before citing.
  • Supporting evidence for CFAP221 in mild PCD: "Subtle abnormalities in the protein composition of the ciliary central apparatus were consistent with the asynchronous, circular motion of cilia and reduced ciliary beat frequency in the proband; importantly, the motility of proband's sperm cells was within the normal range." (PMID:40250778). Normal sperm motility fits the Young pattern, because the obstruction lies outside the sperm and the sperm themselves are normal.
  • Other C1d genes (CFAP46, CFAP54, CFAP74; PMID:39362668) are plausible candidates by the same logic. None has been reported in Young syndrome.
  • DNAH5 (hgnc:2950 ✓): PCD caused by DNAH5 gives epididymal-head dilation and oligozoospermia with motile sperm, "similar to Young's syndrome" (Ito 2025 discussion; this is background).
  • CFTR (hgnc:1884 ✓): tested and not enriched (PMID:7551394). This is a negative finding and suits a REFUTE evidence item on any CF-mechanism claim.
  • No ClinGen classification, no ClinVar disease assertion, no epigenetic data and no chromosomal abnormality has been reported.

5. Environmental Information

  • Exposure: inorganic mercury, as mercurous chloride (calomel), in teething powders and anthelmintics. Exposure to mercury is ECTO:0001571 ✓. Search ECTO further for an ingestion-route or calomel-specific term and record the queries. The CHEBI CURIEs for mercury and calomel are not cached and need a lookup.
  • Linked childhood disease: pink disease (acrodynia). PMID:40287162 links the two.
  • Infectious agents: none causal. Secondary infections are intermittent and non-specific. In the Friedman cohort "none was chronically colonized with Staphylococcus aureus or Pseudomonas aeruginosa" (PMID:7551394).
  • Lifestyle: tobacco was matched in the clearance study (PMID:7307631). No independent role has been shown.

6. Mechanism / Pathophysiology

Ordered causal chain

Branch A: mercury hypothesis (epidemiological; mechanism inferred) 1. Infant exposure to inorganic mercury (calomel teething powder) → (inferred) lasting injury to secretory or ciliated epithelium in the airway and the excurrent ducts of the male reproductive tract. No histological study shows this. 2. → Abnormal, thickened (inspissated) mucus in the airways and in the epididymal lumen. Handelsman reports the epididymal secretions directly. For the airway mucus, the evidence is indirect: tip disorientation is "more likely to be a consequence of abnormal mucus", PMID:1387740. 3. → Impaired mucociliary clearance, even though cilia are structurally and kinetically normal (shown, PMID:7307631, PMID:1387740). 4a. → Mucus stasis → recurrent sinobronchial infection → chronic rhinosinusitis and bronchiectasis. 4b. → Obstruction at the caput epididymis → sperm cannot reach the ejaculate → obstructive azoospermia, with spermatogenesis intact (shown, PMID:6689737).

Branch B: occult motile-ciliopathy hypothesis (genetic; one case plus model data) 1. Biallelic loss-of-function variants in a central-apparatus C1d gene (e.g. CFAP221) → subtle C1d defect (shown in PCD, PMID:39362668, PMID:40250778). 2. → Abnormal (circular, asynchronous) ciliary waveform. Beat frequency and EM are normal or near normal, so classical PCD tests are negative. 3a. → Reduced airway ciliary transport → chronic airway infection and mild bronchiectasis (shown in PCD; inferred for Young syndrome). 3b. → (inferred from mouse models) Defective motile cilia in the efferent ducts → sperm are not kept in suspension → sperm agglutinate and obstruct the efferent ducts or caput epididymis → obstructive azoospermia with normal sperm motility. - Mouse support: Yuan et al. 2019 PNAS (PMID:30659149 [not cached], PMC6397526). In miR-34b/c / miR-449 knockout mice, loss of efferent-duct motile cilia causes sperm agglutination, luminal obstruction and sperm granulomas. The efferent-duct cilia beat in changing directions to keep sperm suspended. - Further support: Terré et al. 2019 Development (GEMC1/MCIDAS/CCNO; dev162628; PMID to be resolved) and DNAH5-deficient mice with immotile efferent-duct cilia (PMC8269963; PMID to be resolved). - Ito 2025 summarises: "Impaired ciliary motility of the efferent duct may explain the obstructive azoospermia observed in patients with Young's syndrome."

Branch C: CF-spectrum (refuted for the typical patient). Sweat chloride is normal, pancreatic function and nasal potential difference are normal, and CFTR mutations are no more frequent than background (PMID:7551394). Model this as a REFUTE item or a discussions entry, not as a node.

Ciliary and mucus findings in detail

"Ciliary beat frequency and the incidence of microtubular defects and numbers of dynein arms did not differ between patients with Young's syndrome and control subjects. … at the ciliary tip ciliary deviation (21.9 degrees) was greater than in healthy subjects (14.5 degrees)." — PMID:1387740

"Lung mucociliary transport was significantly reduced in patients with Young's syndrome compared to 14 control subjects…" — PMID:7307631

"Patients with YS did not have pathognomonic ultrastructural changes, whereas patients with PCD had a large number of ciliary abnormalities…" — PMID:9213847

Suggested bindings

Kind Term
GO GO:0120197 mucociliary clearance ✓ (DECREASED)
GO GO:0003351 epithelial cilium movement involved in extracellular fluid movement ✓ (Branch B)
GO GO:0003341 cilium movement ✓
GO GO:0070254 mucus secretion ✓ (ALTERED or INCREASED viscosity; the qualitative claim is about secretion character, so justify the modifier)
CL CL:0000019 sperm ✓
CL CL:0000160 goblet cell ✓
CL CL:0002480 nasal mucosa goblet cell ✓
CL Multiciliated epithelial cell / efferent-duct ciliated cell: look up (not cached)

Biological scale tags: the exposure and variant nodes are MOLECULAR; ciliary waveform and mucus are CELLULAR; epididymal obstruction and bronchiectasis are TISSUE.

Omics: none. There are no GEO, proteomic or single-cell datasets specific to Young syndrome; the datasets: section should stay empty.

7. Anatomical Structures Affected

Level Structures
Primary sites Epididymis UBERON:0001301 ✓ (caput; look up "head of epididymis" and "efferent duct"); bronchus UBERON:0002185 ✓; respiratory airway UBERON:0001005 ✓; paranasal sinus UBERON:0001825 ✓; nasal cavity epithelium UBERON:0005384 ✓
Spared Testis (spermatogenesis normal), vas deferens (patent, unlike CBAVD in CF), pancreas, sweat gland
Subcellular Motile cilium axoneme and central apparatus (Branch B); extracellular mucus
Laterality Bilateral epididymal involvement; bronchiectasis often bilateral and lower-lobe (PMID:39119117 CT description)

8. Temporal Development

  • Onset: adult, presenting at roughly 30–50 years. Respiratory symptoms often date from childhood: in one case report, "cough, sputum, recurrent nasal congestion, and shortness of breath lasting for more than ten years" (PMID:36196705).
  • Course: chronic, mild and slowly progressive on the airway side, with stable azoospermia.
  • Remission: none spontaneous. Fertility can be restored with surgery or ART.
  • Critical period (mercury hypothesis): infancy, during teething, around 6 months of age (PMID:40287162).
  • Suggested progression: phases: childhood sinopulmonary symptoms → adult infertility presentation → established bronchiectasis.

9. Inheritance and Population

  • Prevalence: the only estimate is Handelsman's 1984 claim of a "prevalence comparable to that of Klinefelter's syndrome" (PMID:6689737), roughly 1 in 500–1,000 men. That claim is speculative and predates the post-1955 decline. Model it as measure_type: UNKNOWN with a qualitative class, or CASES_IN_LITERATURE, and record the original phrasing in notes. A more defensible statement is that the condition is now rare or possibly extinct (PMID:19128521).
  • Share of obstructive azoospermia: 50% in men born up to 1955 versus 17% in men born after (Hendry 1993 [not cached]).
  • Inheritance: stated as autosomal recessive by Orphanet and MedGen, but unproven. Familial case reports are lacking.
  • Population: northern European men: "all were of northern European extraction" (PMID:7551394). A UK-centred literature, with case reports from Turkey, Japan and India.
  • Sex ratio: defined in men.

10. Diagnostics

Clinical criteria (Handelsman 1984): - chronic sinopulmonary infection; - persistent azoospermia; - normal spermatogenesis on testicular biopsy; - characteristic epididymal findings (distended caput, inspissated material); - exclusion of CF and of PCD.

Tests:

Test Finding in Young syndrome
Semen analysis Azoospermia, normal volume and pH (distinguishes it from CBAVD)
Hormones FSH, LH and testosterone normal (PMID:38960684)
Testicular biopsy / TESE Normal spermatogenesis
Scrotal or transrectal ultrasound Obstructive pattern (PMID:39119117)
Sweat chloride Normal; mean 29 mEq/L (PMID:7551394). Use a LOINC code here, via just loinc-seed-cache; never type the label
Nasal potential difference Normal
Chest HRCT Bronchiectasis
Nasal brushing: TEM / CBF Normal (PMID:1387740, PMID:9213847)
Radioaerosol mucociliary clearance Reduced (PMID:7307631)

Genetic testing (the change since 2024): run a PCD gene panel or exome that includes the C1d genes CFAP221, CFAP46, CFAP54 and CFAP74, plus CFTR. Normal nNO, TEM and HSVM no longer exclude PCD:

"Despite chronic respiratory disease, PICADAR does not reliably detect this primary ciliary dyskinesia type. … To enable diagnosis, genetic testing should be prioritised in future diagnostic guidelines." — PMID:39362668

Differential diagnosis: - CF / CFTR-related disorder (CBAVD, abnormal sweat test); - PCD (situs inversus, low nNO, sperm immotility in most genotypes); - immunodeficiency (CVID); - ADGRG2-related CBAVD; - post-infectious epididymal obstruction.

Screening: none applicable.

11. Outcome / Prognosis

  • Life expectancy: no data. Respiratory function is "only mildly impaired" (PMID:6689737), and the prognosis is considered benign compared with CF.
  • Morbidity: infertility, plus chronic sinopulmonary infection with hospitalisations if the diagnosis is delayed (PMID:36196705).
  • Fertility: "Pregnancies had occurred in five couples; in three paternity was documented by genotyping. Thus, improved microsurgical and medical therapy might restore fertility." (PMID:6689737). Surgical results are generally worse than for other causes of obstruction. Hendry's series could support that claim but is not cached.

12. Treatment

Treatment NCIT ✓ Modality Evidence
Antibiotics for exacerbations NCIT:C15620 Antibiotic Therapy ✓ SMALL_MOLECULE PMID:39119117 ("treated with intravenous antibiotics")
Airway clearance / chest physiotherapy Look up (no cached row) BEHAVIORAL Extrapolated from bronchiectasis care
Endoscopic sinus surgery NCIT:C157836 ✓ SURGERY Case-level only
Vasoepididymostomy (epididymovasostomy) Look up; fallback NCIT:C15329 Surgical Procedure SURGERY PMID:39119117 ("advised vasoepididymostomy"); Hendry series
Sperm retrieval (TESE / MESA) NCIT:C94427 Sperm Retrieval ✓ SURGERY PMID:38960684
ICSI NCIT:C185482 Intracytoplasmic Sperm Injection ✓ (or NCIT:C93282 ART ✓) OTHER PMID:38960684 ("successfully fathered a baby through intracytoplasmic sperm injection")

There are no disease-specific trials and no pharmacogenomic or advanced therapies. NCT05631509 (genetic study of obstructive azoospermia, CFTR/ADGRG2/WES) is observational. It is not specific to Young syndrome, so it should not be added under clinical_trials:.

13. Prevention

  • Primary prevention (historical): removing mercury from infant teething powders (UK, 1955). This is the best example of public-health prevention, if the mercury hypothesis holds.
  • Secondary prevention: early recognition in men with bronchiectasis and infertility, and genetic testing for PCD and CF.
  • Tertiary prevention: airway clearance, treating exacerbations, vaccination as for bronchiectasis (extrapolated).
  • Counselling: offer genetic counselling once a PCD or CFTR genotype has been found. Otherwise the recurrence risk is unknown.

14. Other Species

There is no naturally occurring Young syndrome in animals (no OMIA entry found). Mercury reproductive toxicity in animals is a separate literature and should not be used as disease evidence.

15. Model Organisms

There are no Young syndrome-specific models. The relevant mechanistic models for Branch B are below.

Model Relationship Fidelity Caveat
miR-34b/c;miR-449 double-KO mouse (Yuan 2019, PMID:30659149 [not cached]) PARTIALLY_RECAPITULATES the efferent-duct obstruction node LOW–MODERATE Global ciliogenesis loss, unlike the subtle C1d defect; also causes airway disease
GEMC1 / MCIDAS / CCNO mutant mice (Terré 2019, Development) PARTIALLY_RECAPITULATES LOW Multiciliogenesis failure rather than a waveform defect
DNAH5-deficient mice (PMC8269963) PARTIALLY_RECAPITULATES MODERATE ODA loss; human DNAH5-PCD gives oligozoospermia, not strict azoospermia
Schmidtea mediterranea Smed-cfap221 RNAi (PMID:40250778) PERTURBS ciliary motility LOW Locomotory cilia; no reproductive-tract readout

These links would be animal_models: entries with SPECIES_MISMATCH / BOUNDARY_OMISSION divergences. A HUMAN_MODEL_MISMATCH discussion is also appropriate, because the efferent-duct cilia hypothesis has not been tested in human Young syndrome epididymal tissue.

Gaps to record as KNOWLEDGE_GAP discussions

  1. Re-genotyping: no historical or new Young syndrome cohort has been tested with a PCD panel that includes the C1d genes.
  2. Mercury mechanism: there is no histology or toxicology linking calomel exposure to epididymal or airway secretion changes. The evidence is birth-cohort epidemiology and case reports only.
  3. Prevalence: the "Klinefelter-comparable" estimate (1984) has never been revisited.
  4. Sinus phenotype: poorly defined (PMID:19128521).
  5. Female phenotype: unsupported beyond StatPearls.

Sources

Cached and quotable (in references_cache/ on this branch): PMID:6689737, 7307631, 1387740, 7551394, 9213847, 8922141, 19128521, 30969689 (StatPearls), 36196705, 38960684 (full text), 39362668 (full text), 39119117, 40250778, 40287162.

Cached but with no content (cite the PMID only; no snippet possible): PMID:8100886, 82711, 8664779, 9800754, 16817397.

Not cached; fetch before use: - PMID:8292944 Hendry 1993 - PMID:30659149 Yuan 2019 - Terré 2019 (Development, dev162628) - DNAH5 efferent-duct mouse study (PMC8269963)

Web sources: - MedGen 137934 - PubMed 8292944 - PMC1697782 (Hendry 1993) - Wikipedia: Young's syndrome - PMC11308939 - PhenoDis - MalaCards CILD55 - NORD - SAIL concept library MONDO:0010220 - StatPearls - Mayo Clinic: Friedman 1995 - NCT05631509 - AIIMS Rishikesh pulmogenetics, Feb 2025 - PMC6397526 (Yuan 2019) - PMC6397547 - PMC8269963 - Development dev162628 - SATH library note on Brown 2025

Reference Validation

Checked with linkml-reference-validator 0.3.0.

Outcome Count
References checked 24
Resolved 24
Unresolved (possible confabulation) 0
Unverifiable 0
Quoted claims checked 10
Quoted claims found in source 10
Quoted claims not found in source 0
References weighed for topical relevance 24
On topic 15
Off topic 3

References that may not be about this subject

These identifiers resolve, so they are not fabrications, but the records they resolve to share almost none of this report's vocabulary. That is a clue and not a verdict - a paper can be relevant in ways its title and abstract do not spell out - so read them before deciding:

  • PMID:30659149 (3 mentions) - Motile cilia of the male reproductive system require miR-34/miR-449 for development and function to generate luminal turbulence.
  • shared terms: obstruction, genetic
  • PMC:PMC8269963 (8 mentions) - CEP164 is essential for efferent duct multiciliogenesis and male fertility.
  • shared terms: obstruction
  • PMC:PMC6397547 (3 mentions) - Motile cilia of the male reproductive system require miR-34/miR-449 for development and function to generate luminal turbulence.
  • shared terms: obstruction, genetic

Weighed against this report's own most characteristic terms: syndrome, young, cached, mercury, azoospermia, bronchiectasis, pcd, normal, disease, obstructive, nasal, ciliary, cftr, epididymal, obstruction, chronic, airway, exposure, genetic, infection.

All extracted references resolved successfully. Resolving is not the same as being relevant, though - see the references listed above as possibly off topic.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome Count
Terms checked 32
Resolved 31
Unresolved (possible confabulation) 0
Obsolete 0
Unverifiable 1
Terms whose name was checked 1
Terms named correctly 0
Terms named as a different term 1

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

  • MONDO:0010220 (5 mentions) - the report calls it "MONDO"; MONDO calls it Young syndrome

Prefixes with no resolver

Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: ORPHA.