Young Syndrome

Etiology

The exact cause of Young syndrome is unknown, but in addition to a genetic etiology, some researchers speculate that it could be due to mercury exposure.[3]

Epidemiology

Young syndrome is a rare inherited syndrome. It has correlations with mercury exposure. Since the implementation of restrictions on mercury use, the incidence of Young syndrome has also declined.

Pathophysiology

Pathophysiology is not well known. While it resembles Kartagener syndrome, it is still not clear if ciliary dysfunction is the primary abnormality.[4]

History and Physical

Suspicious clinical features involving different organ systems should be reviewed; 

• Pulmonary: Newborns may suffer from respiratory distress, but the primary manifestations of bronchiectasis present in later life
• Rhinosinusitis: Nasal polyps and chronic sinusitis, which may also present with chronic cough
• Chronic otitis media with recurrent acute otitis media is present in childhood and adolescence.
• Fertility: Men often have living but immotile spermatozoa, which results in infertility, although some have motile spermatozoa and immotile cilia, while others are azoospermic - women may also have decreased fertility, with fewer than 50 percent successful pregnancy completions.[5][6][7][8][9][10]

Evaluation

Evaluation again is based on the presenting complaint and a high index of suspicion. The chest X-ray may show hyperinflated lungs with peribronchial thickening and bronchiectasis in the lower bases. However, a CT scan is more sensitive than a chest X-ray to assess the lung and may reveal alveolar damage and cystic bronchiectasis, which are more significant in the lower lung fields. Plain X-rays of maxillary and frontal sinuses may show central opacification.

Pulmonary function tests will reveal mild airflow obstruction in the smaller airways. In a patient with compatible clinical features, confirmation of the diagnosis is possible with genetic testing that shows homozygosity or compound heterozygosity.

Young syndrome requires differentiation from cystic fibrosis (CF), which can present with similar features, and further evaluation with cystic fibrosis transmembrane conductance regulator (CFTR) mutation carrier testing is highly recommended. While Young syndrome more often presents in males, CF presents equally in either sex. In Young syndrome, chronic sinusitis is the predominant pulmonary abnormality, while in CF, there is progressive bronchiectasis due to recurrent lung Infections and colonization, especially with Pseudomonas. Spermatogenesis is affected in CF patients with abnormal sperm histology.[11]

The diagnostic basis is on the occurrence of recurrent sinopulmonary infections, persistent azoospermia but normal spermatogenesis, and the exclusion of cystic fibrosis and immotile-cilia syndrome.

Treatment / Management

There is no cure for Young syndrome, and the treatment is to control bacterial infection with antibiotics.  Inhaled albuterol and hypertonic saline may help open the blocked airway and loosen mucus in it. The precise management of the sequelae of the disease is not known, so recommendations are based on experience in treating patients with cystic fibrosis and other similar conditions. The treatment must be individualized depending upon the clinical course of a given patient.[12][13](B3)

Bronchiectasis — Clearing the secretions and reducing the microbial load with antibiotics are the mainstay of preventive therapy.  Daily chest physiotherapy is important in compensating for the diminished or absent mucociliary clearance; additionally, other airway clearance techniques available merit consideration. Antitussive and mucolytic agents are useful for cough and sputum.[13][14][15] Vaccination against influenza and pneumococcus is advisable.(A1)

Surgical intervention to remove an area of bronchiectasis is very rarely recommended due to the risks of the procedure and the possibility of developing bronchiectasis in other lung areas.[16](B2)

Chronic rhinosinusitis and nasal polyposis: Medical management of these conditions is by antibiotic therapy, nasal saline lavage, and intranasal glucocorticoids for nasal polyposis.

Surgical interventions for chronic sinusitis and nasal polyposis may be recommended in a subset of patients not responding to medical management.

Otitis media with effusion (OME): Chronic OME is common in children and adolescents, leading to hearing loss.[13][17] Tympanostomy tubes improve hearing loss, at least temporarily.[18] Conductive hearing loss and associated speech delays should undergo assessment in childhood, and hearing aids prescribed, if necessary.[17](B2)

Impaired fertility: Semen analysis should be offered to the patient. In-vitro fertilization techniques, principally intracytoplasmic sperm injection, have been shown effective in this setting. Male patients with Young syndrome might present with infertility secondary to obstructive azoospermia. Followings are step-wise surgical management to address infertility in these patients.

Surgical interventions, including microsurgical reconstruction of the vas and/or epididymis or transurethral resection of the ejaculatory ducts (TURED), might be utilized. However, similar to all couples with the complaint of infertility, before performing the microsurgery in the male partner, diagnostic protocols to evaluate the female partner should not be underestimated. Fertility procedural treatment options might be well categorized into a surgical intervention to ablate the obstruction in the epididymis; A) Vasoepididymostomy or B) Assisted reproduction procedures, including intracytoplasmic sperm injection (ICSI). Generally, the microsurgical interventions, including vasoepididymostomy to address the obstruction, are more cost-effective than IVF/ICSI. However, sperm retrieval with ICSI might be preferred over vasoepididymostomy in patients with a long-term obstructive issue.[19] Moreover, airway and sinus complications, including bronchiectasis and sinusitis, might be treated symptomatically. 

A) Microsurgical Reconstruction of the Reproductive Tract

Performing microsurgical reconstruction of the reproductive tract might be considered in patients with Young syndrome as a contributing factor for genetic and or environmental causality of obstructive azoospermia. Vasoepididymostomy might be undertaken, and although the success rate to achieve pregnancy through intercourse for all-cause of congenital, infectious, postvasectomy, or idiopathic epididymal obstruction has been reported for up to 40% of couples, the specific success rate of the procedure for Young syndrome has not been well studied yet. The surgical outcome of a successful pregnancy with intercourse in Young syndrome is mainly operator-dependent in terms of the level of accuracy and delicacy of the utilized microsurgical technique.

B) Intracytoplasmic Sperm Injection

Intracytoplasmic sperm injection is considered an adjunct to other standard in-vitro fertilization (IVF) methods in patients with Young syndrome. Other assisted reproduction procedures, including intrauterine insemination (IUI) or standard IVF, might be rarely successful in the fertilization management of Young syndrome, as the sperms retrieved via sperm retrieval techniques to proceed with intrauterine insemination (IUI) or standard IVF in these patients are hardly enough motile, however, utilizing ICSI provides fertilization rates of up to 75% per injected oocyte when surgically retrieved epididymal or testicular spermatozoa are obtained. Clinical pregnancy rates vary from almost 25 to 57%, and delivery rates are up to 75%.[20][21](A1)

Sperm Retrieval

Sperm retrieval for use in assistive reproductive techniques may be viewed as the pivot treatment to address obstructive azoospermia in Young syndrome or considered as an adjunct to microsurgical reconstructive procedures of vasoepididymostomy. Common methods of sperm retrieval are microsurgical epididymal sperm aspiration (MESA), percutaneous epididymal sperm aspiration (PESA), and testicular sperm extraction (TESE), and micro TESE. While open surgical testicular sperm retrieval with (TESE) or without microscopic magnification (microTESE) are preferred methods of sperm retrieval in patients with nonobstructive azoospermia, method of sperm retrieval in patients with obstructive azoospermia, including those with Young syndrome, would rarely alter the outcomes of IVF with ICSI. Thus, the route of sperm retrieval should be selected by either percutaneous or open surgery to provide the best quality sperm possible in adequate numbers. Consequently, the retrieved sperms will be utilized for immediate and/or delayed use with potential cryopreservation. Considering recent studies, evidence of direct correlation among fertilization or pregnancy rates with either immediate or delayed utilization of harvested sperms in patients with obstructive azoospermia, including Young syndrome, is lacking. On the contrary, utilizing freshly harvested sperms is highly recommended in patients with the non-obstructive causes of azoospermia. Finally, it would be more cost-effective to proceed with the cryopreserved sperms before the oocyte retrieval in the management of either obstructive or non-obstructive azoospermia. This step-wise management might preclude imposing the unnecessary risk of superovulation on the female partner with the uncertainty of a favorable sperm for conception.  

•  Female patients of child-bearing age should be informed about the possibility of reduced fertility and rarely increased risk of ectopic pregnancy.[22]

(B3)

Differential Diagnosis

• Cystic Fibrosis
  • Men with complaints of infertility, who have congenital obstructive azoospermia, and evidence of bilateral absence of the vas deferens should be further evaluated for cystic fibrosis (CF). While Young syndrome should be suspected in middle-aged male patients, who present with complaints of infertility, the median age for the diagnosis of cystic fibrosis is 6-8 months. The exact causality of Young syndrome has not been well-established yet, and environmental factors, including past exposure to mercury, or genetic factors, are considered suspicious causalities. On the other hand, several well-established mutations in the CF Transmembrane Conductance Regulator (CFTR) gene are present in up to four-fifths of men with congenital bilateral absence of vas deferens.  Therefore, gene sequencing, and specifically request a test for the 5-thymidine (5T)allele of CFTR, would be requested for further diagnostic purposes. [23]
• Kartagener Syndrome 
  • KS is categorized as a rare cause of male infertility, which is characterized by multi-organ clinical presentations, including bronchiectasis, sinusitis, and a subset of situs inversus, called situs inversus totalis (SIT). Patients with KS often are complicated with episodes of respiratory tract infection and acute exacerbation of bronchiectasis. Moreover, a sub-group of male patients with KS also present with infertility due to dyskinesia of the spermatozoa. [24]

Prognosis

Patients with Young syndrome generally live an active life with a normal lifespan. The rate of lung function decline is slower than with cystic fibrosis. However, repeated infections like sinusitis may prove frustrating and negatively influence the quality of life. The lung function variation is not related to the age at the time of diagnosis.[25][26]

Complications

Potential complications from Young syndrome include:

• Chronic and/or recurrent respiratory, sinus, and ear infections
• Infertility[27]