Not as rare as previously thought, babies born with differences in sex development can present a vast array of challenges to clinicians, as well as to parents and the patients themselves. These cases require an experienced team of specialists from a variety of disciplines to ensure healthy and normal development.
Each year, Nayla Leon, MD, and Alejandra Reyes, MD, clinical geneticists based in Mexico City, Mexico, encounter more than 50 families with babies born with ambiguous genitalia – cases that can be challenging for clinicians, as diagnosis and management involves myriad decisions and precise diagnosis is essential for management of a slew of issues the child may face.
Difference in sex development (DSD) cases are complex genetically and clinically, potentially with a hundred different causes. They can be present at birth with ambiguous genitalia. Some forms are life-threatening and should be treated immediately. Other forms are not a medical emergency and require assessment by the multidisciplinary team over the first few weeks. Other forms are not a medical emergency and require assessment by the multidisciplinary team over the first few weeks. Variations in more than 40 genes have been associated with DSD, but most cases do not receive a definitive diagnosis.
Increasing genetic information is improving DSD diagnosis and patient management, and while previous studies have shown that about one in 4,500 babies are born with ambiguous genitalia, recent research has shown that ambiguous genitalia in newborns may be more common than previously thought.
Leon and Reyes traveled to the Hudson Institute of Medical Research in Clayton, Victoria, Australia, to work with Vincent Harley, PhD, to develop a clinical algorithm to diagnose DSD based on a systematic review of the literature, which they published earlier this year in The Lancet. “We felt there was a need to describe the many forms of the condition (some 48 forms are described) and to provide a pathway for clinicians to navigate to achieve a diagnosis,” Harley says. “In the past four years, five diagnostic algorithms have been published, being mainly clinical in scope or focused on molecular aspects. We designed a diagnostic tree that integrates traditional clinical practice with molecular diagnosis and emerging technologies.”
Around this time, Banu Kucukemre Aydin, MD, of Istanbul University in Turkey, was studying the frequency of DSD with ambiguous genitalia in babies born in her country and found that not only was the frequency of ambiguous genitalia higher than in previous studies, there may be a connection between the health of the mother and DSD. She and her colleagues published their work in the Journal of the Endocrine Society. “There was limited data available on the exact incidence of DSD with genital ambiguity at birth and most of the published studies were coming from Western countries, in which consanguinity rates are lower than our country,” Aydin says. “That’s why we wanted to determine the frequency of ambiguous genitalia in our population.”
Here, we’ll take a look at both papers and what they mean for babies born with ambiguous genitalia and DSD patients, their families, and the (ideally) multidisciplinary teams who care for them.
Quick, Definitive Diagnosis
Rapid diagnosis is of the utmost importance in children born with ambiguous genitalia. A quick, definitive diagnosis minimizes unnecessary testing, such as the battery of endocrine tests, multiple physical examinations, and imaging studies. At the heart of it is that parents want to know whether their baby is a girl or a boy. A faster diagnosis of a baby with a DSD can shorten this period of anxiety.
“There was limited data available on the exact incidence of DSD with genital ambiguity at birth and most of the published studies were coming from Western countries, in which consanguinity rates are lower than our country. That’s why we wanted to determine the frequency of ambiguous genitalia in our population.” – Banu Kucukemre Aydin, MD, Istanbul University, Istanbul, Turkey
The good news is that technological advances have opened up several avenues to reaching a faster diagnosis. “We are in a genome revolution and in the DSD field, genetic testing is fast becoming the first-line approach,” Harley says. “The standard battery of endocrine tests and imaging analysis as first-line studies is being superseded by genetic analyses.”
However, Harley and his colleagues are fully aware that there are vulnerable communities, such as those in developing countries with no access to large-scale genetic testing. “We have suggested the classical approaches of endocrine analysis and imaging evaluation, but also detailed their limitations when used in isolation,” Harley says. “We recommended that clinicians in vulnerable communities align with international consortia (e.g., DSD-TRN in the U.S., I-DSD in Europe) and research institutes or centers of excellence in DSD research to access genetic testing.”
The algorithm developed by Leon, Reyes, and Harley captures 48 different possible DSD diagnoses into a single tree, and while it won’t increase the number of patients identified with ambiguous genitalia (which can be easily diagnosed through clinical examination), Harley says that his hope for these babies is that the algorithm will help increase molecular diagnosis to well above 30%, the currently reported proportion of patients who receive a molecular diagnosis.
Not So Rare Anomaly
But the number of babies identified with ambiguous genitalia may actually be higher than previously reported. In a prospective study, Aydin and her team examined 14,177 newborns, all examined at birth; data on weeks of gestation, birth weight, and length were collected. “A structured questionnaire was used for data collection. Quigley and Prader scales were used for phenotypic grading. Clinical and genetic investigations were performed,” the authors write.
Eighteen babies with ambiguous genitalia were found among 14,177 newborns – or 1.3 in 1,000, far more than the previously reported one in 4,500. Aydin says that the reason for this is that past studies were mostly done retrospectively or using registries with a possibly lower capture rate.
But Aydin is careful here, pointing to the study’s limitations, such as the fact that it was held in tertiary hospitals, to which complicated pregnancies are referred, causing a selection bias. “Additionally, in Turkey, the consanguineous marriage rate is high, causing a higher incidence of autosomal recessive diseases,” Aydin says.
And again, the genetic approach is important, uncovering a possible connection between the mother’s health and a diagnosis of DSD in her baby. Fifteen newborns were diagnosed with 46,XY DSD, which occurs in male infants when the body can’t use testosterone properly or the testicles do not develop properly. Birth weight was lower in babies with 46, XY DSD than healthy babies, and preeclampsia was a common condition in those pregnancies. “It is believed that early placental dysfunction creates immune alteration and vascular disorder and causes preeclampsia,” Aydin says. “In addition to our results, a Danish Nationwide Cohort Study reported that boys of mothers with preeclampsia had the highest occurrence of cryptorchidism and hypospadias, increasing with preeclampsia severity.”
“Education is key to ease parent’s anxiety and to delay surgery. Still, we don’t know the long-term impact of atypical genitalia on the psychological state of the child.” – Vincent Harley, PhD, Hudson Institute of Medical Research, Clayton, Victoria, Australia
Aydin says that the Danish researchers posited that preeclampsia and genital anomalies share common etiologic factors and that placental dysfunction and androgen deficiency in early pregnancy are important in the etiology of male genital anomalies. “There are also other studies suggesting similar conclusions; readers can find some of which in our discussion section,” she says.
Multidisciplinary Treatment Team
DSDs are highly heterogeneous, clinically and genetically unique. In every case it is crucial to consider the needs, wishes, and concerns of the patients and their families. In babies born with ambiguous genitalia, the parents and, in the future, the patients, need psychological support and comprehensible information. “The heterogeneity of these conditions makes it difficult for parents to get specific advice from reliable sources online,” Harley says. “The DSD multidisciplinary team [specialists in surgery, urology, endocrinology, psychology, psychiatry, radiology, nursing, and clinical genetics] needs to review each case individually for the optimal medical management. Psychosocial assessment is also required to strengthen the parent’s and patient’s ability to cope with the condition.”
Harley goes on to say that non-reversible surgeries continue in children without their consent when conditions are non-life threatening as a result of pressure from parents, cultural norms, and/or societal pressures to normalize the genital appearance. “Education is key to ease parent’s anxiety and to delay surgery,” Harley says. “Still, we don’t know the long-term impact of atypical genitalia on the psychological state of the child.”
Aydin and her team plan to do more comprehensive genetic analyses in patients still coming in for follow-up, and she says she sees a near future in which whole genome sequencing will be used as one of the first-line tests for diagnosis of DSD, although some challenges to that remain, including long turnaround times, high costs, a lack of national healthcare system coverage, and difficulties in the interpretation of the results. For now, she says, “It would be good to see the frequency of ambiguous genitalia in other populations with new prospective studies.”
— Bagley is the senior editor of Endocrine News. He wrote about testosterone treatment in men with obesity and hypogonadism in the June issue.