Introduction

Bardet-Biedl syndrome(BBS) is a rare inherited ciliopathy, a disorder of one of the components of the cell called the primary cilia(PC). It has widespread manifestation in different body systems including the genital and urinary systems. Among these, hypogonadism, a condition marked by reduced function of the gonads, leading to diminished sex hormone production is a significant concern, particularly concerning reproductive health. There are about 35 ciliopathies that have been described and the disease shares the same clinical history with patients who have other ciliopathies. The clinical manifestations can range from multiorgan dysfunction in the developing baby to manifestations in later life. 

Distribution of Bardet-Biedl syndrome

The distribution of the disease varies in many localities with a higher incidence in localities where there are consanguineous marriages (intermarriage of blood relatives). Higher figures are noted in the Arab population of Kuwait than in North America and Europe. The figures can be as low as 1:140,000 in European populations to 1:13,500 in Kuwait and 1:17,500 in Newfoundland.¹

How does the disease develop?

Bardet-Biedl syndrome is an autosomal recessive disease. This means that both parents must have the trait for it to manifest in the offspring. The basis of the manifestation of the disease is the malfunction of the cilia, one of the organelles in the human cell. 

The cilia are organelles that protrude from the cell surface. They are an extension of the cell membrane. There are two types of cilia

• Motile cilia
• Immotile cilia (primary cilia)

While the motile cilia generate the flow or movement of fluid in the cell, the immotile cilia are thought to have a sensory function. The primary cilia contain many different proteins and act as the anchoring structure for the cell. They play an important role in several pathways regulating important cellular functions, including cell division, and metabolism.²

BBS arises from problems in the genes that code for proteins involved in the function of the primary cilia. The major genes involved are the BBS1 and BBS10 genes.

These proteins perform signalling functions in many steps in the reproduction process. The dysfunction results in reproductive problems in patients with BBS.

Apart from the reproductive system, BBS manifests in different organ systems.^3,4,5 

The clinical features include: 

• Retinal dystrophy. This may lead to blindness
• Postaxial polydactyly (Having an extra digit on the border of the 5th finger or toe)-This is specifically characteristic of this disease. There may also be brachydactyly (short digits) or syndactyly (fused digits) in some patients
• Kidney problems
• Truncal obesity
• Diabetes
• Dental problems
• Learning difficulties
• Speech deficit
• Developmental delays or cognitive deficit
• Hypogonadism (reduced sex hormone levels) in males and females. This leads to reproductive dysfunction

Polydactyly may be the only feature at birth but the disease slowly evolves as the individual ages. over a decade. The pattern of progression differs in individuals. However, the majority of the patients are diagnosed in late childhood or early adulthood

Hypogonadism in Bardet-Biedl syndrome

Hypogonadism refers to a condition in which little or no hormones are produced by the testis or ovary in males and females respectively.⁶

Hypogonadism and problems in the genital and urinary organs have been reported in 59% of cases of BBS.⁵ 

Hypogonadism can be:

• Primary
• Secondary

Primary, also referred to as Hypergonadotrophic hypogonadism results from failure to produce hormones from the gonad(testis/ovary)

Secondary hypogonadism(Hypogonadotropic hypogonadism) refers to a situation where the testis or ovary does not produce enough hormones because of a problem with the release of sex organ-stimulating hormones from the brain(pituitary gland or hypothalamus).

Reproductive abnormalities may exist as abnormalities in the sexual organs alone or in conjunction with reduced sex hormones. They usually manifest at puberty.

The majority of persons with Bardet-Biedl syndrome have hypogonadotropic hypogonadism(secondary hypogonadism) 

Secondary hypogonadism could result from impaired function of the Kisspeptin receptor in the hypothalamus(a part of the brain). Kisspeptin is involved in Gonadotropin-releasing hormone(GnRH) activity in the fetus(developing baby), at puberty and during the process of reproduction. This results in reduced stimulation of the pituitary gland by the GnRH.⁵ Occasional reversal of the disease has been reported.⁷

It could also be due to other abnormalities in the pituitary gland leading to:

• High prolactin level
• Low follicle-stimulating hormone(FSH) and Luteinizing hormone(LH)
• Growth hormone abnormalities

Some of the patients have primary hypogonadism (hypergonadotropic hypogonadism). This may be due to undescended testis and obesity, both of which affect the function of the testis in males. In females, the ovaries may be small and poorly functional.

Clinical manifestations of hypogonadism in BBS

The disease can have varying reproductive manifestations in males and females.^3,8,9,10

Manifestation in males

• Delayed puberty 
• Micropenis
• Short scrotum
• Cryptorchidism(Undescended testis)
• Impaired sperm production
• Reduced testosterone(male sex hormone) levels
• The predisposition to cyst formation with obstruction of the ejaculatory ducts

Manifestation in females

• hypoplastic(underdeveloped) fallopian tubes, uterus and ovaries
• partial and complete vaginal atresia( lack of development)
• Septate vagina(Vagina divided into two by a membrane) 
• Duplex uterus(double uterus)
• Hydrocolpos & hydrometrocolpos(collection of fluid and blood in the vagina) 
• Persistent urogenital sinus(non-separation of the urinary and reproductive tracts)
• Polycystic ovarian syndrome(PCOS)
• Precocious(early puberty) has also been reported in a female patient with the syndrome 
• Delayed onset of menses 
• Irregular cycles
• Infertility
• Pregnancy problems

Diagnosis of hypogonadism in Bardet-Biedl syndrome

The diagnosis is made by clinical history, examination and investigation.⁵

The history and examination would reveal some of the functional and structural abnormalities associated with the disease.

The investigations to be done include:

• Sex hormone tests: Follicle stimulating hormone, Luteinising Hormone, Estrogen, Testosterone
• Imaging studies: These are used to access the reproductive and urinary organs for abnormalities. They include Ultrasound and Magnetic resonance imaging(MRI)
• Genetic studies: To check the structure and arrangement of the genes. This is the confirmatory diagnostic test

The clinical diagnosis of the disease is made by the presence of four major features or three major and two minor features.

The major features include;

• Red cone(retinal) dystrophy
• Polydactyly
• Central obesity
• Kidney problems
• Hypogonadism/urogenital anomalies
• Cognitive impairment

The minor features include; 

• Speech delay
• Developmental delay
• Diabetes mellitus
• Dental anomalies
• Heart disease
• Brachydactyly/Syndactyly
• Ataxia( loss of coordination)
• Anosmia(lack of sense of smell) 

Management of Hypogonadism in BBS

The management of reproductive problems in Bardet Biedl syndrome requires a multidisciplinary approach. Urologists., Endocrinologists, Cardiologists, Gynaecologists, Ophthalmologists and Clinical Psychologists would be involved.

Hormonal therapy

This involves the replacement of the sex hormones in males and females.

In males, this typically means administering testosterone to induce and maintain the development of the sexual organs and hairs and support sperm production.

In females, estrogen and progesterone therapy can help induce menstruation and support the development of sexual organs, breasts and hairs in the armpit and pelvic regions.

Fertility treatment

Infertility is prevalent in patients with BBS, though some can conceive on their own. 

When conception is not possible by natural or conventional infertility treatment, assisted reproductive technique(ART) becomes the option

This would involve In vitro fertilisation (IVF). Because of the abnormalities in sperm production, which affect sperm quality and count, intracytoplasmic sperm injection (ICSI) would be required. 

Some patients would require surrogacy if the womb is poorly developed and cannot sustain a pregnancy. 

Because of the underlying genetic nature of BBS, pre-implantation genetic diagnosis (PGD) may also be considered. This involves evaluating the embryo for genetic traits of BBS to prevent the transmission of the disorder to offspring.

Surgery may also be needed to correct some of the abnormalities like undescended testis and abnormally shaped uterus.

Supportive care

Counselling and psychological support are needed by these patients to be able to cope with the multiple manifestations of the disease.

Given the hereditary nature of BBS, genetic counselling is essential for affected individuals and their families This provides information on the risk of transmitting the disorder and reproductive options. 

Reproductive issues beyond hypogonadism

Pregnancy considerations in BBS 

Because of the multisystem abnormalities in BBS, there is a high risk of death of the baby, the mother or both. Kidney abnormalities, Diabetes, heart problems and obesity are usually linked to pregnancy problems. A multidisciplinary approach is needed to ensure a successful pregnancy outcome.

Summary

Hypogonadism has a substantial impact on the reproductive health of people with Bardet-Biedl Syndrome, creating issues that necessitate a multidisciplinary approach to management. Hormonal therapy, assisted reproductive technologies, and genetic counselling are all essential components of care. As technology advances, a better knowledge of the genetic and molecular pathways causing BBS should lead to better therapies and outcomes for patients suffering from this complicated condition.