George Anadiotis
It is not uncommon in medicine to discover a child presenting with one problem that leads to a variety of other concerns and eventually to the underlying etiology. The importance of tying together the physical findings with the history for the patient cannot be overestimated and is essential to achieving a diagnosis and an effective follow-up treatment plan. Identifying the child who is apparently well but short and then moving forward to the issue of a genetic cause with a host of other potential health problems is not an easy step for the healthcare provider, family, and child. However, the outcomes can be very satisfying when the child is on a path towards a more healthy future.
Educational Objectives
1. Identify possible causes of short stature in young girls.
2. Discuss the types of treatment options available.
3. Understand appropriate referral patterns for further treatment.
4. Clarify the role of the primary care provider caring for a child with a genetic condition.
Case Presentation and Discussion
Jane Murphy is a 10-year-old girl who is brought to you by her mother because of concern regarding her height. Upon evaluation, you note that her height is 120 centimeters (48 inches; < fifth percentile) with a weight of 30 kilograms (68.2 pounds; < fifth percentile) and a head circumference of 51 centimeters (20 inches; within normal limits for age 10 years). You talk with Jane’s mother about her concerns.
Further discussion with Mrs. Murphy reveals that Jane has occasional visits to a urologist because she was born with a horseshoe kidney, and that she has a heart murmur that was described as innocent. She states that Jane does well in school although she has some social issues including difficulty interacting with other children her age; Jane prefers to play with younger children.
When you ask Jane how she feels regarding her height, she becomes somewhat tearful and tells you that she is the shortest girl in her class and the other girls are growing very rapidly. She often gets teased for being so small. Sometimes when she is out with her friends, other individuals think that she is a younger sister of her friends. At this point, Jane’s mother adds that this has become a more pressing concern for Jane; she has been voicing more frequently how much it bothers her to be small.
Her physical examination reveals a child who appears to be in good health. She has some soft physical findings such as some minimal swelling in her hands and feet, which Mrs. Murphy states has been there since infancy. She has a small chin with a low posterior hairline and posteriorly rotated ears. The rest of her examination does not reveal any health problems. You hear a grade I/VI heart murmur today. You did the head circumference because you were interested in whether she was in proportion or had either macro-cephaly or microcephaly. Her head circumference was within normal limits. Head circumference tables are available for older children as well as infants.
What questions are going through your mind at this point? 
Within this very brief visit, you should have a variety of questions arising for you as the primary care provider. Questions to consider regarding Jane’s findings include:
• How long has Jane been below the fifth percentile on the growth curve?
• Although we know Jane appears to have some social interaction issues, has she ever been assessed for any type of learning disorder?
• Has Jane ever been evaluated by cardiology regarding her murmur?
• Has Jane shown any evidence of starting puberty?
• Has anyone in the family been evaluated for late growth spurts or short stature?
• Have the renal issues been fully evaluated, and can the urologist provide any other information that may be useful?
• Are there any options available for this 10-year-old to increase her growth velocity and final height?
Short Stature
The history and physical examination of this child appear to be consistent with a genetic syndrome, most likely Turner syndrome. The combination of the physical findings such as rotated ears, low posterior hairline, micrognathia, renal abnormalities, and short stature are classic for Turner syndrome. However, there are other genetic causes of short stature that can present somewhat similarly, and they must be ruled out.
The differential of short stature can be quite large. The most common causes are 1) familial short stature in which individuals have normal growth below the fifth percentile with no skeletal delay and normal onset of puberty, and 2) constitutional short stature with normal growth velocity but delayed skeletal maturity. An in-depth family history as well as radiologic studies are necessary to diagnose these types. Other causes include a variety of endocrine abnormalities such as growth hormone deficiency. Chromosomal anomalies such as Turner or Noonan syndrome must also be considered. In this case, the physical features suggest a syndromic cause.
Turner Syndrome
Pathophysiology
Due to the loss of one X chromosome, approximately 50% of individuals with Turner syndrome will show a 45, X karyotype in a phenotypic female. However, this classic chromosomal finding is not the only karyotype that can result in the physical features of Turner syndrome. Mosaicism is fairly common in Turner syndrome. This term indicates the presence of two cell lines in a single individual. Individuals with mosaic cell lines such as 45, X with 46, XX or 46, XY or 47, XXX can all be placed under the Turner syndrome category. Mosaicism with a 46, XX usually results in individuals with a much milder phenotype of Turner features than the classic 45, X individuals.
Clinical Findings
Although Turner syndrome can be diagnosed prenatally or in infancy— especially if a child is born with features such as lymphedema, webbed neck, or cardiac and renal anomalies—many individuals with Turner syndrome are diagnosed later in childhood when they present with short stature but without the other classical physical findings. Common clinical findings are found in Table 34-1. Intelligence in these individuals is normal, but a variety of issues are related to learning disabilities, particularly with mathematics, memory, spatial perception, or visual motor integration as well as issues associated with immaturity, hyperactivity, anxiety, low self-esteem, or even depression (Bondy, 2007; McCauley, Ross, Kushner, & Cutler, 1995; Tyler & Edman, 2004). The psychosocial concerns raised by both Jane and her mother are often the driving factors bringing these children in. They are concerned about being the smallest in the class, especially when other children begin to make fun of them.
As adults, women with Turner syndrome can have health problems such as obesity, and autoimmune issues such as diabetes, hypothyroidism, and inflammatory bowel disease. High-frequency hearing loss occurs in about 25% to 66% of individuals (see Table 34-1).
Epidemiology
Turner syndrome occurs in approximately 1 in 2,000 to 3,000 live female infant births (Frias, Davenport, Committee on Genetics, & Section on Endocrinology, 2003; Nielsen & Wohlert, 1991). It is thought to occur in about 1–2% of all conceptuses; however, the majority of these are spontaneously lost in the first trimester of pregnancy. The retained X chromosome can come from either parent (Tsezou et al., 1999).
Differential Diagnoses
Although Turner syndrome is classically the most common syndrome associated with young women with short stature, it should be noted that Noonan syndrome also presents with similar findings, including poor growth, congenital heart malformations, short stature, renal problems, learning problems, pectus excavatum, impaired blood clotting, webbed neck, low hairline, low-set ears, and scoliosis. This syndrome may occur in males or females. It is caused by genetic mutations of chromosome 12q24.1, including genes PTPN11, KRAS, and RAF1. The karyotype is different from that of Turner syndrome.
Table 34–1 Common Clinical Findings in Turner Syndrome
Making the Diagnosis
What test will you order to make the diagnosis of Turner syndrome or another chromosomal condition? 
Diagnostic Testing
The diagnosis of Turner syndrome is confirmed by obtaining high-resolution chromosome studies.
You discuss the possibility of a genetic cause for Jane’s short stature and kidney problem with Jane and her mother. They agree to testing and you send them off for high resolution chromosome studies. The results shows a 45, X karyotype as you suspected. You might choose to call a geneticist and consult with him or her regarding testing at this point or make a referral and then let that person decide what studies are necessary. In this case, you are fairly confident about the diagnosis and a karyotype is a basic genetics test. Other diagnoses might require considerably more studies including metabolic assays and others. In that case, given the expense, it would probably be better to send the child off and let appropriate studies be ordered from there.
Management
How will you begin management of this child with the genetic condition of Turner syndrome?
Because genetic conditions do not occur very often in your daily primary care practice, you go online to see if there are guidelines for care of these children prepared by experts from across the country. The National Institutes of Health and the American Academy of Pediatrics are good places to start. Online, you quickly find that guidelines have been developed by the National Institutes of Health, National Institute of Child Health and Human Development, and Turner Syndrome Consensus Study Group (Bondy, 2007). Earlier guidelines were published in 2003 by the American Academy of Pediatrics (Frias et al., 2003). You feel prepared now for the Murphys’ return visit.
Jane and her mother return to the clinic to learn the results of the chromosome studies. You tell them what the syndrome is and explain that the condition was not the fault of either parent. Turner syndrome is caused by a loss of an X chromosome, so the underlying chromosomal defect cannot be repaired. However, there are a variety of treatments that can positively affect the symptoms of the genetic disorder, including help with her short stature.
Management of Turner Syndrome
Your management plan generally follows the national guidelines. Here is the information you learned from your study before seeing the family.
Short Stature
Short stature is one of the most common findings associated with Turner syndrome, affecting almost all of the girls with this diagnosis. The mean final height in untreated women is 143 cm, or only 4’ 9” (57 inches). Growth hormone has been approved for the treatment of short stature and is considered the standard of care for a child with Turner syndrome. The best time for it to be started would be when the child’s height falls below the fifth percentile. For approximately 50% of girls, that would occur between 2 and 3 years of age. Starting children on growth hormone at an early age is important, because gains of 8 to 10 centimeters (about 3 to 4 inches) have been noted if individuals receive at least 6 years of growth hormone (Bondy, 2007; Tsezou et al., 1999).
Starting Jane on growth hormone at age 10 years will not give her as much additional height as it would had she been started at age 2 or 3 years, but some increase in growth velocity and final height can be anticipated.
Cardiovascular Issues
Jane requires a cardiovascular evaluation, although her murmur sounds innocent. Even if there is no evidence of a murmur, all children with the diagnosis of Turner syndrome should be evaluated by a cardiologist and have an echocardiogram, an ECG, and other studies as necessary. Cardiovascular anomalies are thought to occur in 20% to 40% of affected individuals or more, and many of these congenital heart problems can be repaired through intervention. Hypertension occurs in about 25% of girls and is an important risk factor for dissecting aneurysms, another health problem for Turner syndrome patients (Bondy, 2007).
Endocrinology
An endocrine evaluation is extremely useful because gonadal dysgenesis is common (90%) in Turner syndrome (Doswell et al., 2006). Many girls will require sex hormone replacement in order to begin puberty. It should be noted that a variety of issues are associated with sex hormone replacement. It can be initiated early in some individuals, whereas other individuals who are still working on gaining height may have their estrogen therapy delayed until as late as 15 years of age to allow them to achieve their maximum height potential. Although secondary sexual characteristics can develop in individuals with mosaicism, even those individuals should have their endocrine system evaluated because they may also require estrogen therapy.
In the majority of cases, individuals with Turner syndrome are not able to bear children. It is the responsibility of the primary care provider to discuss reproductive options such as adoption or medically assisted reproduction with individuals who have this diagnosis when they are at an age for comprehension. Occasionally, a rare individual may have sufficient ovarian function to ovulate and may become pregnant; however, there is an increased risk of fetal chromosomal abnormalities or miscarriages in such women so genetic counseling is important. Pregnancy with a donated egg is more commonly achieved (Doswell et al., 2006).
Neurocognitive Issues
Many individuals with Turner syndrome have a specific set of cognitive functioning differences in the areas of decreased visual-spatial organization, social cognition, nonverbal problem-solving, right-left sequencing, executive function, attention, and self-esteem (Bondy, 2007; Doswell et al., 2006; McCauley et al., 1995; Romans, Stefanatus, Roeltgen, Kushner, & Ross, 1998; Ross, Zinn, & McCauley, 2000).
Psychosocial Support
It is important for the primary care provider to assess the psychological support that is available to the child and family. Involvement with local Turner syndrome support groups or the Turner Syndrome Society of the United States (http://www.turnersyndrome.org) is a way of allowing individuals to interact with other families who have similar problems. Literature should be supplied to the family about Turner syndrome, and other resources should be available including therapy resources if they are needed. The American Academy for Pediatrics provides information for medical providers.
Genetics Issues
Genetic conditions, as do other chronic conditions, affect families for many years, influencing decisions about childbearing, health care, social relationships, finances for health insurance, and many other aspects of life. Consultation with a genetics clinic or geneticist can be very helpful in answering a family’s questions.
Other Healthcare Needs
A variety of other abnormalities are associated with Turner syndrome, including hearing loss, strabismus, obesity, glucose intolerance, hypertension, thyroid dysfunction, orthopedic issues, and urinary tract abnormalities, among others. Each of these systems needs to be evaluated in a child with Turner syndrome, and appropriate referrals will need to be made (Bondy, 2007; Donaldson, Gault, Tan, & Dunger, 2006; Doswell et al., 2006; Tyler & Edman, 2004).
Given the national guidelines for treatment of girls with Turner syndrome (Bondy, 2007), you talk with the family to describe the plan and rationale for each step. You arrange for her:
Referrals for care:
- A pediatric endocrinologist for growth hormone and estrogen therapy to increase her height and then to induce puberty at the appropriate time
- A pediatric cardiologist for evaluation and monitoring of her cardiac status
- A pediatric genetics clinic for further discussion of Turner syndrome and its influences on Jane and the family
Evaluations to assess needs for care:
- By an audiologist for hearing loss
- By an ophthalmologist
- By an orthodontist
- An educational evaluation by her school’s personnel
You also describe the current national guidelines for them and begin the screening and on-going monitoring protocol for Turner syndrome (Bondy, 2007). Thus, you also order T4 and thyroid stimulating hormone (TSH) tests for thyroid function, celiac screen (TTG-Ab), liver function tests, fasting blood sugar, lipids, CBC, and creatinine and BUN for kidney functioning.
You also give the family the Web site for the Turner Syndrome Society of the United States with the suggestion that meeting other girls who also have Turner syndrome might be very helpful to Jane, and meeting their parents would be helpful to Mr. and Mrs. Murphy.
You consider whether Jane would benefit from some counseling regarding her self-esteem and feelings about being teased due to her size. You decide to wait on this given the number of other evaluations scheduled. Perhaps with more information, the initiation of growth hormone therapy, and meeting some other girls with the condition, Jane will begin to feel better about herself, but you note that this issue needs monitoring both short-term and long-term.
When do you want to see this family back again?
You schedule the family to return to the clinic after the evaluations have occurred to review Jane’s overall health status and to see how various therapy programs are evolving.
The family returns in 3 months, having been to the endocrinologist, cardiologist, urologist, ophthalmologist, audiologist, genetics clinic, and orthodontist. She also has an educational evaluation scheduled in the next few weeks. The endocrinologist has started her on growth hormone treatment, which has been accepted positively by Jane. The cardiologist identified a bicuspid aortic valve but does not want to do anything at this time to repair it. Her blood pressure is normal. The urologist was surprised to learn that Jane has Turner syndrome and will follow her regularly, but did not find significant urological problems at this time. Her hearing and vision are normal so she will return for annual evaluations. The geneticist provided them with more information about Turner syndrome, its inheritability, and the health issues they need to monitor.
Jane reports that when kids tease her, she tells them that she has Turner syndrome and is hoping that she will grow a bit faster now that she is getting treatment. Her friends are supportive. Her mother and father are beginning to accept the fact that their daughter has a genetic condition with many health issues to face as she matures, but are hopeful that with good care she can avoid significant problems. They have not yet made contact with the Turner Syndrome Society but know when the next meeting in their area is to be held and plan to attend with Jane.
You congratulate them on their progress navigating all the healthcare evaluations and assure them that you will be available at any time and will continue to oversee the various specialties’ plans to help Jane. You also alert them that positive mental health and strong self-esteem are important for Jane and suggest that they return any time they see Jane becoming stressed so appropriate mental health interventions can be instituted.
What are some other issues you need to address with the family in the future?
You will need to address the following with the Murphys:
• Obesity is a common problem for individuals with Turner syndrome. Jane needs a healthy diet and plenty of exercise. You will monitor her weight carefully as she moves into adolescence.
• Finding a sport that Jane can be successful in, such as dance, gymnastics, or swimming.
• The probability that Jane will not have children or will achieve pregnancy with difficulty.
• The long-term health problems such as diabetes and autoimmune diseases that Jane needs to be monitored for.
• Scoliosis may emerge as an issue when she is growing more rapidly.
• Many girls with Turner syndrome have neurocognitive problems such as visual-spatial deficits, poorer nonverbal memory, problems perceiving social situations appropriately, and attention deficits, which may yet emerge in Jane. They will need to monitor her progress in school and socially because educational help can be provided to keep her functioning at age level if such problems arise.
Not all of these can be addressed at once, but these will need to be priorities for discussion over the next several years.
Key Points from the Case
1. Young females with short stature require a variety of evaluations including a genetic evaluation for the possibility of Turner syndrome.
2. An individual diagnosed with Turner syndrome can have a variety of organs affected, and a thorough work-up is required once a diagnosis is made.
3. Future issues such as growth, reproduction, obesity, diabetes, vision, hearing, cardiovascular system, autoimmune disorders, learning, psychological, and other issues will also need to be monitored by the primary care provider.
REFERENCES
Bondy, C., for the Turner Syndrome Consensus Study Group. (2007). Care of girls and women with Turner syndrome: a guideline of the Turner Syndrome Study Group. Journal of Clinical Endocrinology and Metabolism, 92(1), 10–25.
Donaldson, M. D. C., Gault, E. J., Tan, K. W., & Dunger, D. B. (2006). Optimizing management in Turner syndrome: from infancy to adult transfer. Archives of Diseases in Children, 91, 513–520.
Doswell, B., Visootsak, V., Brady, A., & Graham, J. M. (2006). Turner syndrome: an update and review for the primary care pediatrician. Clinical Pediatrics, 45, 301–313.
Frias, J. L., Davenport, M. L., Committee on Genetics, & Section on Endocrinology. (2003). Health supervision for children with Turner syndrome. Pediatrics, 111(3), 692–702.
McCauley, E., Ross, J. L., Kushner, H., & Cutler Jr., G. (1995). Self-esteem and behavior in girls with Turner syndrome. Journal of Developmental and Behavioral Pediatrics, 16, 82–88.
Nielsen, J., & Wolhert, M. (1991). Chromosome abnormalities found among 34,910 newborn children: results from a 13-year incidence study in Arhus, Denmark. Human Genetics, 87, 81–83.
Romans, S., Stefanatus, G., Roeltgen, D., Kushner, H., & Ross, J. L. (1998). Transition to young adulthood in Ullrich-Turner syndrome: neurodevelopmental changes. American Journal of Medical Genetics, 79, 140–147.
Ross, J., Zinn, A., & McCauley, E. (2000). Neurodevelopment and psychosocial aspects of Turner syndrome. Mental Retardation and Developmental Disabilities Research Reviews, 6, 135–141.
Tsezou, A., Hadyiathanasiou, C., Gourgiotis, D., Galla, A., Kavazarakis, E., Pasparaki, A., et al. (1999). Molecular genetics of Turner syndrome: correlation to clinical phenotype and response to growth hormone. Clinical Genetics, 56, 441–446.
Tyler, C., & Edman, J. C. (2004). Down syndrome, Turner syndrome and Klinefelter syndrome: primary care throughout the lifespan. Primary Care Clinics in Office Practice, 31, 627–648.