Introduction

CHARGE syndrome is a genetic disorder that is caused by a mutation in the gene encoding chromodomain helicase DNA binding protein 7 (CHD7), which is characterised by ocular coloboma (incomplete development of eye tissue), heart malformations, atresia of the choanae (a blocked nasal cavity), retardation of growth, genital hypoplasia (underdevelopment) and ear abnormalities.¹ The prevalence of CHARGE at birth has previously been estimated to range from 1 in 10,000 to 1 in 15,000 live births.² CHARGE also causes temporal bone abnormalities (one of the bones of the skull), cleft lip and/or palate, tracheoesophageal fistula (an opening between the trachea and the oesophagus), balance disorders, dual sensory impairment leading to deafness and blindness and delayed motor development.^1,2,4

What are genitourinary anomalies?

Genitourinary anomalies in CHARGE syndrome describe structural or functional changes that occur in the genital and urinary systems, potentially affecting sexual development, fertility and kidney function. This is caused by a mutation in the CHD7.

Aetiology and pathophysiology

A mutation in the CHD7 gene can cause abnormal gonadotropin signaling (an important hormone for genital development), leading to hypogonadotropic hypogonadism, particularly in males, which affects the hormone production that regulates sexual development, and also affects the development of the kidneys and other structures of the urinary tract, leading to a range of abnormalities such as absent or underdeveloped kidneys, ectopically located kidneys (not in the correct place) or hydronephrosis (excess fluid in the kidneys).⁵ These anomalies can occur due to the broad impact of CHD7 on the development of multiple organ systems. It also causes abnormal sexual differentiation, leads to genital anomalies and impaired fertility.^6,7

Types of genitourinary anomalies in CHARGE syndrome

Genitourinary anomalies in CHARGE syndrome are:

Renal and urinary tract anomalies

• Structural anomalies lead to renal agencies hypoplasia, horseshoe kidney and duplex kidney⁸
• Functional anomalies may lead to hydronephrosis, vesicoureteral reflux (VUR), neurogenic bladder and recurrent UTI¹¹

Genital anomalies

• In males, it may cause micropenis, cryptorchidism, hypospadias and bifid scrotum (a split scrotum)¹²
• In females, it may cause hypoblastic labia (small or absent labia), uterine hypoplasia and vaginal atresia (narrowing)¹³

Clinical presentation

Neonates/infants

• In boys, the presence of undescended testicles may be accompanied by a smaller penis. This is because the final stages of testicular descent and penile development in late pregnancy rely on testosterone produced by the testes.
• In girls, the clitoris and labia minora may be underdeveloped, making them smaller
• Failure of the development of pubic and axillary (armpit) hair
• Infertility

Diagnostic strategies

Genetic

• Karyotype: to confirm chromosomal integrity (if the gene is intact)
• FISH [Fluorescent In Situ Hybridisation]
• CHD7 gene mutation testing

Biochemical

• Blood urea nitrogen, creatinine, electrolytes and calcium are measured to evaluate renal (kidney) function

Hormonal

• Hypogenitalism, luteinizing hormone-releasing hormone (LHRH), and human chorionic gonadotropin (HCG) tests should be performed to evaluate the pituitary-gonadal axis (the gland system involved in producing these hormones, which needs to be tested in the first four months of life or at puberty). Growth hormone (GH) stimulation levels should be investigated to exclude deficiency of GH as a cause for growth retardation³
• X-ray of bone ages
• Screening for hypogonadotrophic hypogonadism in early puberty

Radiological

• CT and/or MRI scans
• Abdominal ultrasound and voiding cystourethrogram are performed to detect renal anomalies
• Ultrasound is performed to evaluate the size of the ovaries and uterus, and to check the location of any undescended testes 
• DEXA (dual x-ray) scan for osteoporosis

Treatment and management

Genital anomalies

Micropenis

Hypogonadotrophic hypogonadism

• Testosterone replacement may be given as intramuscular injection, usually with testosterone enanthate or propionate in doses of 12.5-25mg repeated every 3 to 4 weeks for about 3 to 4 doses 
• Alternatively, a 2% testosterone cream can be applied topically once or twice daily, generally continued for up to three months ^9,10

Cryptorchidism

• Changes in the microscopic structure of the testes may develop as early as the first one to two years of life. However, early surgical intervention may be technically more challenging.
• Despite this, orchidopexy is often performed to lower the risk of later malignant transformation⁹
• Hormonal treatment with hCG (human chorionic gonadotropin) may be considered. A usual regimen consists of 500-1000 IU administered intramuscularly twice weekly for 5-6 weeks, which may stimulate penile enlargement and aid in testicular descent⁹

Delayed/absent puberty

In boys:       

• Intramuscular testosterone enanthate or propionate, 50-250 mg monthly
• Oral testosterone undecanoate 20-120 mg daily
• In hypogonadal boys, treatment options have included transdermal patches and long-acting subcutaneous testosterone pellets^9,10

In girls:

• Oral estrogen is started in small amounts, and the dose is gradually increased
• Once pubertal changes are complete, progesterone is added either as part of hormone replacement therapy (HRT) or through a low-dose oral contraceptive pill (OCP). If the uterus is sufficiently developed, this combination will result in menstrual bleeding¹⁰

Renal and urinary tract anomalies

• Recurrent UTIs are treated with prophylactic antibiotics (a preventative treatment)
• Bladder dysfunction is treated with anticholinergics (medications that reduce bladder contraction)¹⁵
• Monitor the regular renal ultrasound, blood pressure check and renal function assessment

Surgery

• Pyeloplasty (for obstruction)
• Ureteral reimplantation is performed for severe VUR
• Orchidopexy for cryptorchidism¹⁴

FAQs

What are the clinical manifestations of genitourinary anomalies?

• Urinary system: it may cause symptoms like urine leakage, abdominal swelling, pain and difficulty urinating, low or high urine flow, frequent appearance of UTI and burning sensation
• Genital system: in boys, it is micropenia. In girls, it manifests as irregular menstrual cycles, infertility, pain in the pelvis and abnormal opening of the urethra

Can patients with CHARGE syndrome go through normal puberty?

Yes, in CHARGE syndrome, puberty can be normalised with treatment of hormone replacement therapy (testosterone or oestrogen/progesterone).

Why is multidisciplinary care important for patients with CHARGE syndrome?

• Paediatric urologists & nephrologists are involved in  structural and renal management
• Endocrinologists provide hormonal evaluation and treatment
• Geneticists provide counselling and family planning
• Psychologists provide psychosocial and sexual health concerns

Does CHARGE syndrome cause any other health issues?

Yes. It can lead to repeated urine infections, kidney damage, deafness and delayed puberty or fertility in ongoing life.

How to diagnose hypogonadism?

It can be diagnosed by hormone testing like LH, FSH and GnRH stimulation tests, as well as imaging studies like MRI for pituitary/olfactory bulb abnormalities and ultrasound. 

What is the long-term outlook for children with GU anomalies in CHARGE syndrome?

When it is identified early, it can be managed with hormone therapy and surgical procedures, allowing many patients to achieve normal growth, timely pubertal development and improved quality of life. Fertility may remain challenging. However, advances in assisted reproductive technologies provide new possibilities for affected individuals.

What are the causes of CHARGE syndrome?

It is mainly caused by a mutation in the CHD7 gene.

How to take care of children with CHARGE Syndrome?

Keep tracking the development of children based on the milestones of their ages. With early diagnosis, good family support and medical management, children can live with a better quality of life.

Summary

CHARGE syndrome is a genetic disorder caused by a gene mutation which leads to GU anomalies in children. The most common problems in CHARGE syndrome with the kidneys and reproductive system are those that can affect a person’s health in the long term. Early detection of conditions with diagnosis, regular follow-up, and the right treatment can help manage patients and improve their quality of life.