Introduction and background
Young's syndrome is a rare disease comprising three components: obstructive azoospermia, bronchiectasis and sinus disease. It is a recognised cause of male infertility and is a well known and accepted diagnosis in the field of infertility. The exact nature and natural history of the sinus disease component is not widely understood.
The aim of this review article was to formulate a current, comprehensive account of the sinus disease component of Young's syndrome. The review will focus on the genetics, aetiology, clinical findings and differential diagnosis of Young's syndrome.
Methods
A literature search was undertaken using limits set to English and humans. The search parameter ‘Young's syndrome’ identified 42 articles; 37 were relevant and seven were review articles. The articles rejected had the following search terms: ‘Young's modulus’ (two), ‘Young's valve’ (one) and ‘Young's operation’ (two). An additional search strategy was undertaken to include books, the internet, theses, libraries, e-mail lists, academic subject gateways, reports and ‘grey literature’, reviews, and citation indexes. This search yielded one further article which was deemed to be relevant. A total of 38 articles were reviewed.
History of Young's syndrome
In 1970, David Young, a Liverpool urologist, observed that 54 per cent of patients with obstructive azoospermia also had evidence of lung defects.Reference Young1 He called the association between azoospermia and pulmonary disease the Berry–Perkins–Young syndrome. The syndrome was shortened to Young's syndrome by Hendry in 1978,Reference Hendry, Knight, Whitfield, Stansfeld, Pryse-Davies and Ryder2 and was described as a triad of obstructive azoospermia, sinusitis, and bronchitis or bronchiectasis.
However, the term Young's syndrome had been used previously, in 1953, to describe a condition in women associated with prolonged fetal growth, high fetal or neonatal mortality, large babies, hyperlactation, obesity and diabetes.Reference Abaza, Varroud-Vial and Rombauts3 Only two case reports were described. The syndrome received no further mention in the literature and has now been disregarded.
Aetiology
The prevalence of Young's syndrome is unknown. In the 1980s, the syndrome was reported to affect one in 500 malesReference Roth and Gleckman4 and was described as being commoner than cystic fibrosis (CF).Reference Handelsman, Conway, Boylan and Turtle5 More recently, only a handful of case reports have been published on this syndrome.Reference Armengot, Juan, Carda, Montalt and Basterra6–Reference Shiraishi, Ono, Eguchi, Mohri, Kamiryo and Takihara8 A reduction in the use of mercury in Europe and the USA has been cited as a potential reason for this decline. Mercury exposure in childhood is likely to be the only aetiological factor identifiable in Young's syndrome. A history of mercury intoxication (Pink's disease) was seen in 10 per cent of Young's syndrome patients in one series.Reference Hendry, Levison, Parkinson, Parslow and Royle9 Mercury inhibits enzymes containing sulphydryl by reacting with thiols to form mercaptides. Mercaptides are thought to inhibit glycolysis, which is necessary for the normal function and energy supply of sperm and cilia.Reference Brown and Kulkarni10
Young's syndrome is rare in the USA, where mercury usage was discouraged by the Food and Drug Administration in 1933.Reference Warkany11 In the UK, mercury-containing calomel was removed from teething powders and worm medications in 1955. It was still used in the UK and Australia (which shares similar prevalences with the UK) until 1966, and it was still reported to be used in ethnic remediesReference Kew, Morris, Aihie, Fysh, Jones and Brooks12 and skin lighteners as recently as 1993.Reference Godlee13 This reduction in mercury exposure was the reason given for Hendry and colleagues' observation that the prevalence of Young's syndrome has greatly declined in recent times – from 114 (50 per cent) of 227 men with obstructive azoospermia born before 1955, to eight (17 per cent) of 47 men born after 1955.Reference Hendry, A'Hern and Cole14 If mercury intoxication is the aetiological factor in Young's syndrome, then it is logical to assume that prevalence of the condition has subsequently declined.
Genetics
Although there has been a reported case of identical twins diagnosed with the condition,Reference Teichtahl, Temple-Smith, Johnson, Southwick and de Kretser15 no hereditary factors for Young's syndrome have been identified. A positive family history is not indicative of the disease. Genetic studies carried out in Young's syndrome patients found that only a few subjects tested positive for CF transmembrane conductance regulator mutations.Reference Hirsch, Williams and Williamson16, Reference Le Lannou, Jezequel, Blayau, Dorval, Lemoine and Dabadie17 A link was made in a case report describing Young's syndrome in association with the hereditary disease medullary sponge kidney; the latter disease is characterised by a dilatation of the distal collecting tubules of the kidneys similar to that found in the head of the epididymis in Young's syndromeReference Umeki, Soejima and Kawane18 (due to the accumulation of impacted sperm). This possible genetic link has not been mentioned further in the literature.
Characteristics of Young's syndrome
Young's syndrome affects young males. Sinus symptoms usually disappear after adolescence,Reference Armengot, Juan, Carda, Montalt and Basterra6–Reference Shiraishi, Ono, Eguchi, Mohri, Kamiryo and Takihara8, Reference Hughes, Skolnick and Belker19, Reference Lau and Lieberman20 whereas pulmonary symptoms may persist. Patients usually seek help for infertility rather than sino-pulmonary problems, and only rarely are patients diagnosed with the condition after initially presenting to an ENT specialist.Reference Hasegawa, Ohe, Yamazaki, Kobayashi, Fujita and Munakata7, Reference Umeki, Soejima and Kawane18, Reference Khan, Noah, Bashi, Joharjy, Obaid and Young's21 Patients frequently give a history of antibiotic treatment for sinusitis, but surgical intervention is not usually required. Young's syndrome is essentially a diagnosis of exclusion in any patient presenting with infertility and sino-pulmonary infections. Handelsman et al. Reference Handelsman, Conway, Boylan and Turtle5 identified a cohort of patients with similar characteristics who were considered to have Young's syndrome. All had sino-pulmonary infections, azoospermia with normal spermatogenesis and dilation of the epididymal heads; other conditions such as CF and primary ciliary dyskinesia (then known as immotile cilia syndrome) had been excluded.
In Young's syndrome patients, prolonged nasal mucociliary clearance (tested by placing saccharin on the inferior turbinate) may be the only abnormality identified within the nose, but this finding is not specific for Young's syndrome.Reference Greenstone, Rutman, Hendry and Cole22
The nasal cilia of Young's syndrome patients have been studied with regard to function and ultrastructure; subtle defects in ciliary structure have been described,Reference Teichtahl, Temple-Smith, Johnson, Southwick and de Kretser15, Reference Wilton, Teichtahl, Temple-Smith, Johnson, Southwick and Burger23, Reference de Iongh, Ing and Rutland24 but ciliary beat frequency has appeared normal.Reference de Iongh, Ing and Rutland24 Investigators have reported a reduction in the mean frequency of inner dynein arms and an increased incidence of abnormalities of the nine plus two microtubular organisation, when compared with controls. However, the in vivo and in vitro function of respiratory cilia did not differ from controls.Reference Teichtahl, Temple-Smith, Johnson, Southwick and de Kretser15 Electron microscopy studies of nasal cilia demonstrated abnormal inner dynein arms when compared with controls.Reference Wilton, Teichtahl, Temple-Smith, Johnson, Southwick and Burger23 Other studies examining nasal ciliary ultrastructure found normal inner dynein arms but a greater deviation of the ciliary tip, compared with controls.Reference de Iongh, Ing and Rutland24 However, it is thought that abnormal mucus accounts for these structural abnormalities rather than a primary ciliary defect.
Diagnostic criteria for sinus disease in Young's syndrome
Over the last decade, attempts have been made to establish ideal diagnostic criteria for both rhinitis and sinusitis. A diagnosis of chronic rhinitis relies on a history of nasal irritation, sneezing, rhinorrhoea and nasal blockage lasting for at least one hour a day on most days. A diagnosis of chronic sinusitis requires two or more of the following symptoms: nasal discharge, nasal blockage or congestion, facial pain or pressure, and reduction or loss of sense of smell. Sinusitis is invariably accompanied by rhinitis; the term ‘rhinosinusitis’ was therefore recommended by the 1997 Task Force of the Rhinology and Paranasal Sinus Committee.Reference Masood, Moumoulidis and Panesar25 The term ‘chronic’ implies that symptoms have been present for more than 12 weeks. None of these criteria existed when Young's syndrome was initially described, and the diagnosis of sino-nasal disorders within this cohort of patients has been at best crude.
The most accurate imaging modality for sinusitis is computerised tomography (CT); plain sinus radiographs are unreliable, inaccurate and yield significant numbers of false negative and false positive results.Reference Iiuma, Hirota and Kase26, Reference Jonas and Mann27
When we considered the accuracy of the diagnosis of sinusitis in patients with Young's syndrome, it became apparent that most authors based their diagnosis upon a history of subjective sino-nasal symptoms (n = 65 patients).Reference Shiraishi, Ono, Eguchi, Mohri, Kamiryo and Takihara8, Reference Teichtahl, Temple-Smith, Johnson, Southwick and de Kretser15, Reference Le Lannou, Jezequel, Blayau, Dorval, Lemoine and Dabadie17–Reference Lau and Lieberman20, Reference Wilton, Teichtahl, Temple-Smith, Johnson, Southwick and Burger23, Reference Wodehouse, Kharitonov, Mackay, Barnes, Wilson and Cole28, Reference Pavia, Agnew, Bateman, Sheahan, Knight and Hendry29 Unfortunately, these publications did not provide precise descriptions of individual symptoms. However, there are reports which describe a history of sinus surgery with positive findings on sinus radiographs, covering a total of 69 patients with Young's syndrome;Reference Handelsman, Conway, Boylan and Turtle5, Reference Greenstone, Rutman, Hendry and Cole22, Reference Neville, Brewis, Yeates and Burridge30, Reference Alton, Hay, Munro and Geddes31 a further six patients were reported to have undergone sinus surgery without evidence of sinusitis on sinus radiographs.Reference Pasteur, Helliwell, Houghton, Webb, Foweraker and Coulden32, Reference Matsuda, Horii, Nishimura, Amitani, Matsui and Yoshida33 Positive findings on sinus radiographs, without any other detail, were described in 19 patients.Reference Hendry, Knight, Whitfield, Stansfeld, Pryse-Davies and Ryder2, Reference Hasegawa, Ohe, Yamazaki, Kobayashi, Fujita and Munakata7, Reference Verra, Escudier, Bignon, Pinchon, Boucherat and Bernaudin34 Only three patients were reported to have undergone sinus CT scanning.Reference Armengot, Juan, Carda, Montalt and Basterra6 One study conceded that sinus radiographs were abnormal in both patients and controls.Reference Neville, Brewis, Yeates and Burridge30 Only two reports used a reduction in mucociliary clearance to confirm the diagnosis of Young's syndrome, in 27 patients.Reference de Iongh, Ing and Rutland24, Reference Eliasson, Mossberg, Camner and Afzelius35 The most thorough description of sinus disease in patients with Young's syndrome was given by Wang et al.,Reference Wang, So, Wong, So and Chan36 who documented a history of sinusitis, sinus surgery and sinus radiographs, skin prick tests, family history of sinusitis and use of medication that may have affected mucociliary clearance, in four out of 23 patients with obstructive azoospermia.
The respiratory aspects of Young's syndrome have been studied much more extensively. However, we consider that Young's syndrome may have been incorrectly diagnosed in two of the reviewed papers, if it is accepted that sino-nasal disease is a necessary part of the diagnosis: JequierReference Jequier37 failed to mention any sino-nasal component in 23 patients, and Khan et al. Reference Khan, Noah, Bashi, Joharjy, Obaid and Young's21 described two patients but reported that nasal mucociliary clearance was normal.
Differential diagnosis
The characteristics of Young's syndrome are similar to those of other syndromes associated with obstructive azoospermia. The differential diagnosis includes CF, congenital bilateral absence of the vas deferens, Kartagener's syndrome and primary ciliary dyskinesia.
Cystic fibrosis
Cystic fibrosis is one of the commonest genetic disorders among Caucasians and affects one in 2500 children.Reference Welsh and Smith38 The condition is associated with a defect of the CF transmembrane conductance regulator protein located on the long arm of chromosome seven (ΔF508 mutation is the commonest occurring mutation). Clinically, patients have exocrine pancreatic insufficiency and chronic obstruction and infection of the respiratory tract. These effects are caused by ductal obstruction with thickened, viscous mucus. The obstructive azoospermia is secondary to maldevelopment of the mesonephric ducts, leading to absence or degeneration of the vas deferens, epididymis or seminal vesicles. It is unknown whether this is due to mucus obstruction or secondary to the disease itself.Reference Heaton and Pryor39 Chronic polypoidal rhinosinusitis is a major component of the syndrome and presents during childhood.Reference Gysin, Alothman and Papsin40 Cystic fibrosis has historically been diagnosed using the sweat test, which detects raised concentrations of sodium and chloride in sweat (>40 mm/l in children under 10 years; the test is less conclusive in those over 10 years). More recently, genetic screening has been used to provide more accurate diagnostic information.
Congenital bilateral absence of the vas deferens
Congenital bilateral absence of the vas deferens accounts for up to 2 per cent of male infertility cases,Reference Dublin and Amelar41 and is considered to be an incomplete form of CF without the pancreatic and respiratory components. This premise is supported by the detection of a similar defect of CF transmembrane conductance regulator protein,Reference Hirsch, Williams and Williamson16 but not in all cases; some may have a different, undetected mutation (at present, over 400 different CF transmembrane conductance regulator mutations have been detected). Patients with congenital bilateral absence of the vas deferens may have a positive sweat test, but complete absence of the vas deferens is pathognomonic for the condition. Spermatogenesis is normal among these patients, although the level of sperm antibodies is high.
Primary ciliary dyskinesia
Primary ciliary dyskinesia is an autosomal recessive condition in which abnormal ciliary beating impairs normal mucociliary clearance. Typically, cilia show ultrastructural abnormalities, including inner and outer dynein arm deficiency, microtubular transposition and radial spoke defects.Reference Wodehouse, Kharitonov, Mackay, Barnes, Wilson and Cole28 When associated with situs inversus (as occurs sporadically in up to 50 per cent of patients), the condition is known as Kartagener's syndrome. The clinical manifestations of obstructive azoospermia and recurrent pulmonary infections are caused by mucus retention. Nasal nitric oxide production has been shown to be an excellent indicator of primary ciliary dyskinesia; low concentrations are typically observed, compared with controls and patients with other sino-nasal disorders.Reference Wodehouse, Kharitonov, Mackay, Barnes, Wilson and Cole28
Patients with obstructive azoospermia of other origin have many clinical features similar to those found in Young's syndrome; however, there is no underlying genetic abnormality associated with the latter condition. The features of Young's syndrome are caused by impairment of ciliary function, rather than a specific anatomical abnormality, and this is probably related to a dysfunction in glycolysis caused by exposure to mercury. Other genetic conditions cause similar abnormalities, but these are due to thickened secretions (e.g. in CF and congenital bilateral absence of the vas deferens) or to abnormal ciliary structure (e.g. in primary ciliary dyskinesia and Kartagener's syndrome) (see Table I).
Table I Key diagnostic features of conditions causing obstructive azoospermia
PCD = primary ciliary dyskinesia; AR = autosomal recessive; CF = cystic fibrosis; CBAVD = congenital bilateral absence of vas deferens
Summary and conclusions
We can find no convincing evidence that Young's syndrome currently exists. The lack of convincing evidence describing the sinusitic component of Young's syndrome raises doubts over whether the condition remains a true cause of chronic sinusitis.
Although it seems logical to assume that thickened mucus would lead to abnormal ciliary function and thus cause recurrent sinus disease, the actual evidence for this is lacking. It appears more likely that other syndromes associated with obstructive azoospermia are the cause of sinus disease, and these syndromes should be considered instead of Young's syndrome. If the aetiology behind Young's syndrome is mercury intoxication then it would seem likely that the syndrome is in decline, further supporting the view that other syndromes are more common. Further studies are required which are properly designed to accurately diagnose and assess sinus disease in patients with infertility. Such studies should include a thorough sino-nasal history, nasal endoscopy and possibly sinus CT scans. All patients with obstructive azoospermia should be investigated with a combination of NO measurements, sweat testing, ciliary ultrastructure examination and nasal mucociliary clearance time. This would enable an accurate and correct diagnosis in this particular group of patients, and would thus facilitate a deeper understanding of the sino-nasal processes in such infertile patients.
