Because of its generally mild symptoms and physical signs, the genetic condition Klinefelter Syndrome (KS) continues to be underdiagnosed, explained Ilene Fennoy, MD, MPH, Professor of Pediatrics, NewYork-Presbyterian/Morgan Stanley Children’s Hospital at Columbia University Medical Center.

However, with the advent of a new diagnostic tool—devised by Sharron Close, PhD, a former nursing student at Columbia University School of Nursing, in collaboration with Dr. Fennoy and others—pediatricians should soon have an easier time identifying the condition and getting patients much-needed intervention for its related cognitive and psychological problems.

KS, caused by the presence of an extra X chromosome in the male karyotype, is marked by physical signs such as small testes and androgen deficiency; in children it also is associated with learning disabilities and other developmental issues. About one in 600 male newborns has the condition, Dr. Fennoy said. Although it occurs relatively frequently, less than 25% of cases are ever diagnosed, and less than 10% of cases are diagnosed during childhood.

A Diagnostic Challenge

“The problem with KS is the difficulty in recognizing it and making the diagnosis,” she said. “Parents run around from provider to provider with no one able to develop appropriate interventions because they don’t know what the problem is. They try things that may or may not work because they think the patient has some other problem.

“We wanted to create a tool to try and facilitate the ability to recognize that the patient is likely to have KS so providers can do something about it.”

The diagnostic tool, which is still in development, is called the KS Phenotype Index Scale (KSphI). It measures 13 physical traits associated with the condition, including tall stature, wide arm span, large waist circumference, small testes, short phallus, breast tissue development and skeletal abnormalities, assigning one point for each feature, for a total score of 0 to 13.

A recent study by Drs. Close, Fennoy and colleagues, published in The Journal of Pediatrics (2015;167:650-657), suggests that the tool could be used to identify boys with KS who are suffering an impaired quality of life. For the study—the first to look at the relationship between physical features of the syndrome and psychosocial characteristics—the investigators enrolled 43 boys with KS, aged 8 to 18 years. Participants underwent physical examination and hormone analyses, and completed four questionnaires assessing quality of life, self-esteem, self-concept and risk for depression. The KSphI and other tools were used to assess physical characteristics.

A majority of the boys reported learning disabilities (70%), speech and language problems (67%), and social interaction issues (63%), with more than one-third (37%) reporting attention-deficit disorder. Almost 50% of the boys had received testosterone either as an infant or therapeutically during puberty, but testosterone level was not associated with measures of psychosocial health. The mean KSphI score was 5.1; scores were significantly lower for the prepubertal group compared with the pubertal group (4.2 vs. 5.6; P=0.01). Milder KSphI phenotype was observed in boys diagnosed prenatally (mean, 4.5) versus postnatally (mean, 6.2).

Quality of Life Affected

Overall, two-thirds of participants (67%) showed lower quality of life, and regression models demonstrated an inverse relationship between KSphI and total quality of life. Thirty-eight percent of the boys had low self-esteem, 26% had low self-concept and 16% revealed a risk for depression. Two respondents agreed with the statement, “I want to kill myself,” and were referred for more comprehensive screening and consultation with a mental health professional.

“The study demonstrated that children had more problems with quality of life than we had anticipated, and that these problems were associated with the number of features that they had,” Dr. Fennoy said. Although it needs to be validated in additional studies, “We are hoping that this tool we’ve developed to help recognize KS will facilitate our ability to get these children the services that they need.”

Typically, parents wait until children are having difficulty in school to find resources, she added. “We strongly recommend that children get evaluated in infancy by early intervention services, that children who have issues are allowed to receive services during early childhood school programs and that ongoing resources are provided as they go through school, not waiting for school failure as the index for doing this.”

The study was supported by the Pediatric Endocrinology Nursing Society, National Association of Pediatric Nurse Practitioners, Alpha Zeta Chapter of Sigma Theta Tau, Yale School of Nursing and The National Center for Advancing Translational Sciences at the National Institutes of Health.