Serkal syndrome

Overview

Serkal syndrome is an extremely rare autosomal recessive genetic disorder characterized by abnormalities in sexual development and early-onset adrenal insufficiency. The condition is classified as a disorder of sex development (DSD), where individuals with a typical 46,XX karyotype (genetically female) present with external male genitalia or ambiguous genitalia. Serkal syndrome was first described in a few consanguineous families, and due to its rarity, it remains poorly understood and underreported in the medical literature. The syndrome reflects a failure of normal female sexual differentiation along with adrenal gland dysfunction, which can be life-threatening if not recognized and managed promptly.

Causes

Serkal syndrome is caused by homozygous mutations in the WNT4 gene, which plays a crucial role in the development of the female reproductive system and the proper formation of the adrenal glands. WNT4 is a member of the WNT gene family, involved in key signaling pathways that regulate embryogenesis and organ development. In individuals with Serkal syndrome, the loss of WNT4 function disrupts ovarian development and allows for partial or complete masculinization of the external genitalia despite a 46,XX chromosomal makeup. Additionally, the WNT4 mutation impairs the normal function of the adrenal cortex, leading to early-onset adrenal insufficiency. The condition follows an autosomal recessive inheritance pattern, meaning two copies of the mutated gene (one from each parent) are required to cause the syndrome.

Symptoms

The clinical features of Serkal syndrome appear in early life and involve both sexual development and adrenal function. Key symptoms include:

Disorders of Sex Development (DSD):

• 46,XX individuals with male or ambiguous external genitalia

• Absent or underdeveloped uterus and upper vaginal tract

• Ovarian dysgenesis or complete absence of ovaries

• Primary amenorrhea (absence of menstruation)

Adrenal Insufficiency:

• Hypoglycemia

• Hypotension (low blood pressure)

• Failure to thrive in infancy

• Vomiting, dehydration, and salt-wasting crises

Symptoms typically manifest shortly after birth or within the first few months of life. If left untreated, adrenal crises can be life-threatening. The genital ambiguity may also lead to challenges in gender assignment and require careful medical and psychological evaluation.

Diagnosis

Diagnosis of Serkal syndrome involves a combination of genetic, endocrine, and imaging studies. Given its rarity, a high index of suspicion is necessary, especially in infants with ambiguous genitalia and signs of adrenal insufficiency.

• Karyotyping: Reveals a 46,XX chromosomal pattern in individuals with masculinized genitalia

• Hormonal assays: Demonstrate low cortisol levels and abnormal adrenal steroid profiles

• Pelvic ultrasound or MRI: May show absence of Müllerian structures (uterus and upper vagina)

• Genetic testing: Confirms mutations in the WNT4 gene, which is diagnostic for Serkal syndrome

Differentiating Serkal syndrome from other causes of adrenal insufficiency and DSD, such as congenital adrenal hyperplasia (CAH), is essential for proper management.

Treatment

There is no cure for Serkal syndrome, and treatment focuses on managing adrenal insufficiency and addressing the DSD aspects. A multidisciplinary team is critical for comprehensive care.

Endocrine Management:

• Life-long glucocorticoid replacement therapy (e.g., hydrocortisone) to manage adrenal insufficiency

• Mineralocorticoid therapy if salt-wasting is present

• Monitoring of electrolytes, glucose levels, and growth parameters

Management of DSD:

• Thorough evaluation by a DSD specialist team including endocrinologists, geneticists, surgeons, and psychologists

• Individualized approach to gender assignment and potential surgical correction, based on family discussions and long-term outcomes

• Supportive psychological counseling for the individual and family

Other Supportive Care:

• Regular follow-ups with a pediatric endocrinologist

• Monitoring for puberty-related issues and potential hormone replacement therapy in adolescence

Prognosis

The long-term outlook for individuals with Serkal syndrome depends on early diagnosis and appropriate management of adrenal insufficiency, which is critical to prevent life-threatening complications. With proper hormone replacement therapy and supportive care, individuals can live healthy lives. However, issues related to gender identity, fertility, and psychosocial well-being may pose challenges and require ongoing support.

Due to the syndrome’s rarity, limited data is available on long-term outcomes. Continued documentation of new cases and advancements in genetic and hormonal research are essential for improving understanding and care for individuals with Serkal syndrome.