What Medical Problems Can Patients with Turner Syndrome Have?

Patient Presentation
A 6-year-old female with known Turner Syndrome (TS) came to clinic for her health maintenance examination. She had just finished kindergarten which she enjoyed. Her parents’ main concern was about attentional issues as her teacher had noted that she seemed more distracted in the classroom. The teacher was able to help redirect her and at this time did not have any concerns about her learning. Her parents noted that she did need more redirection and they had to do more physical redirection or verbally pointing out social cues to her at home. Currently, these issues generally did not cause any problems in the family or for the child. She was well-liked by teachers, peers and her family. The past medical history revealed that she was diagnosed around birth because of growth retardation, lymphedema, webbed neck, shield chest, and shorted metacarpal bones. She had been comprehensively managed by specialists at the local children’s hospital. She had no cardiac defects, hearing loss or hypothyroidism. She had multiple episodes of otitis media which required 2 sets of pressure equalizing tubes. She also had 1 urinary tract infection and was known to have a duplicated renal collecting system. The review of systems was normal.

The pertinent physical exam showed a smiley school-age female with normal vital signs. Her weight was 10% (on a normal growth chart). Her height was 102 centimeters (5% on normal growth charts and 50% for height on TS growth chart) and was consistent with previous measurements. She had wide-spaced nipples, webbing of her neck, short 4th metacarpal bones bilaterally, and an increased carrying angle to her arms. She had otosclerosis bilaterally. Her thyroid was not enlarged and her cardiac examination had no murmurs. She was Tanner 1 for pubertal development. The rest of her examination was unremarkable.

The diagnosis of a healthy child with TS was made. In addition to reviewing that she was properly following up with her multiple specialists at the children’s hospital, the pediatrician made sure that she had a dental home and her immunizations were complete. “I know that people with Turner Syndrome can have more problems with learning and also with attention problems. At this time you and the teachers seem to be meeting her social and school needs and she isn’t have problems, but I can refer you to a psychologist who could do an initial evaluation for her attention plus give us more insights if she has other learning needs. We can also wait a few months and monitor her closely and then refer her. I don’t want to overlook the things her teacher and you are seeing,” he said. After some discussion, the parents decided to make the psychology appointment so they could continue to understand their daughter’s needs and try to meet them.

Discussion
Turner Syndrome (TS) is one of the most common genetic disorders in females. It was first described by Dr. Henry H. Turner in 1938. It affects 1 in 2000-2500 births and ~70,000 girls and women have TS in the United States. It is caused by the absence of all or part of the second X chromosome. The most common variation is 45X which affects about 50% of TS patients and usually has the most complications, but there are other variations. Phenotypes vary and therefore the age of diagnosis varies. Mean age of diagnosis unfortunately is 15 years. Diagnosis is made by chromosomal analysis. Haploinsufficiency of the SHOX gene is associated with short stature in Turner syndrome.

Patient presentations depend on age and phenotype. Most (almost all) TS patients have short stature and primary ovarian failure, but patients can have a variety of medical problems. Patients need comprehensive management from a variety of specialists to address their medical and psychosocial needs throughout their lifetime. Recommendations for comprehensive management can be found in the To Learn More section below.

Learning Point
Medical problems that patients with Turner Syndrome can have include:

  • *Short stature/growth retardation – almost 100% of patients
    • Short stature occurs in almost all patients with an average of 8 in (20 cm) shorter than predicted mid-parental height. Final adult height has been dramatically improved with growth hormone treatment. Short stature or growth failure are reasons to consider TS in females at any age as this can be the only sign of TS. Special growth charts are available for monitoring TS patients.
  • Endocrine – almost 100% of patients
    • *Primary ovarian failure
      • Patients have a hypoplastic sometimes “streaked” ovary with few or no follicles. Estrogen is inadequately produced and patients often have delayed puberty.
    • *Delayed puberty or pubertal arrest
    • *Infertility
      • Infertility is common. Having TS may be a relative contraindication to pregnancy because of higher risk of maternal complications.
    • Diabetes
    • *Thyroid disorders
  • Lymphatic
    • *Nuchal lucency on prenatal ultrasound
    • Cystic hygroma
    • *Lymphedema
    • Webbed neck with or without lower hairline
  • *Cardiac anomalies – 30-50% of patients
    • Mainly left sided anomalies and is the most common reason for premature mortality
    • Bicuspid aortic valve
    • Aortic coarctation
    • Aorta, dilated
  • Cognition/Educational/Psychological
    • Patients have normal intelligence but may have other problems
    • Attention deficit/hyperactivity disorder
    • Mathematics problems
    • Mental health issues – anxiety, decreased self-esteem, social isolation
    • Non verbal impairments – visual-spatial, problem-solving, social cognition and other executive function problems
  • Gastrointestinal
    • Celiac disease
    • Liver disease
    • Obesity
  • Renal
    • *Collecting duct anomalies
    • Horseshoe kidney
    • Hypertension
  • Skeletal
    • Shield chest with inverted/wide-spaced nipples
    • Nail hypoplasia
    • Short 4th metacarpal/metatarsal
    • Cubitus valgus (increased carrying angle)
    • Madelung deformity of the wrist
    • High arched palate
    • Micrognathia/retrognathia
    • Dental malocclusions
    • Hip dislocation
    • Scoliosis/kyphosis
    • Pes planus
    • Osteoporosis
  • Ophthalmology
    • Hyperopia
    • Strabismus
  • Otolaryngology
    • *Hearing loss – sensorineural and conductive
    • Abnormal ear position – low set or rotated
    • Otitis media

* some of the most common medical problems

Questions for Further Discussion
1. How are Turner Syndrome and Kleinfelter syndrome similar?
2. What is the role of the primary care provider in the care of patients with multiple medical problems?

Related Cases

To Learn More
To view pediatric review articles on this topic from the past year check PubMed.

Evidence-based medicine information on this topic can be found at SearchingPediatrics.com, the National Guideline Clearinghouse and the Cochrane Database of Systematic Reviews.

Information prescriptions for patients can be found at MedlinePlus for this topic: Turner Syndrome

To view current news articles on this topic check Google News.

To view images related to this topic check Google Images.

To view videos related to this topic check YouTube Videos.

Turner Syndrome Society of the United States. Available from the Internet at http://www.turnersyndrome.org.

Bondy CA, Turner Syndrome Study Group. Care of girls and women with Turner syndrome: a guideline of the Turner Syndrome Study Group. J Clin Endocrinol Metab. 2007 Jan;92(1):10-25.
http://media.wix.com/ugd/8fb9de_e000a4b246f44f2cbd4e5cd026576d74.pdf.

Milbrandt T, Thomas E. Turner syndrome. Pediatr Rev. 2013 Sep;34(9):420-1.

Lee MC, Conway GS. Turner’s syndrome: challenges of late diagnosis. Lancet Diabetes Endocrinol. 2014 Apr;2(4):333-8.

Kingery SE, Wintergerst KA. Turner Syndrome and Klinefelter Syndrome. Adolesc Med State Art Rev. 2015 Aug;26(2):411-27.

Author
Donna M. D’Alessandro, MD
Professor of Pediatrics, University of Iowa Children’s Hospital

When Is the Clinical Nadir for Guillain-Barré Syndrome?

Patient Presentation
A 6-year-old female came to clinic with a 3 day history of abnormal gait. Her mother said she seemed to be walking funny and was having more problems going up stairs.
She said she felt a little unbalanced but denied any vertigo. She also denied any pain, fever, chills, nausea, emesis, diarrhea, cough, rhinorrhea, rashes, vision changes or breathing problems. The mother said she was able to do other things but seemed a little more tired. The past medical history showed she was treated as an outpatient for community acquired pneumonia 1 month previously. She was otherwise well and was completely immunized. The family history showed no neurological diseases but there was thyroid disease and diabetes on both sides of the family. The review of systems was otherwise normal. There was no travel history and no known tick bites.

The pertinent physical exam showed a well-appearing child. Her vital signs were normal without tachycardia, blood pressure changes or fever. Her growth parameters were normal. Heart and lungs were normal. Her neurological examination showed normal mentation. Cranial nerves III-XII were normal. She had normal strength and deep tendon reflexes in her upper extremities. In her lower extremities she was able to lift her legs against gravity but not against pressure. Ankle reflexes could not be obtained and knee reflexes were decreased bilaterally. She said her legs felt a little funny but there was no discernable level where she had changed sensation in her legs. She was able to sit without support. She had a slightly halting gait and a positive Gower sign. No skin changes were noted. She had good peripheral pulses. The laboratory evaluation in the clinic showed a normal respiratory peak flow.

The diagnosis of an acute onset of lower extremity weakness and areflexia was made. Guillian-Barré syndrome was considered the most likely cause as the patient was afebrile and had recent community acquired pneumonia. After discussion with a pediatric neurologist, the patient was transferred to a regional children’s hospital where her clinical course showed she underwent several tests including neuroimaging which showed no spinal cord anomalies and a lumbar puncture that had increased protein and 8 lymphocytes. The patient had ascending paralysis of the lower extremities over the next 2 days up to her hips and was treated with intravenous gamma globulin. The patient improved slowly and was monitored closely and never had any respiratory compromise. She was discharged on day 10 to a local relative’s home and she was monitored daily for the next few days. Her symptoms continued to improve and by 6 weeks the family denied any problems and her examination was normal.

Discussion
Guillian-Barré syndrome (GBS) is an acquired, acute, inflammatory, demyelinating polyneuropathy. It is the most common cause of acute and subacute flaccid paralysis in children.
GBS causes about 0.4-1.3 cases per 100,000 persons/year in children. It can occur in any age group and the incidence increases among all age groups until a peak in the 50s. Both genders are affected and there may be a slight increase in males.

GBS usually occurs 2-4 weeks after a prodromonal gastroenteritis or respiratory illness. It is most often associated with Campylobacter jejunae, Haemophilus infuenza, Mycoplasma pneumoniae, cytomegalovirus, Epstein-Barr virus, and herpes simplex virus. There are some possible associations with GBS and influenza A vaccination but it has not been associated with other vaccines. GBS causes autoantibody production against Schwann cells of the neuron and the axon itself. There is an increase in anti-ganglioside antibodies which can be specifically identified in about 50% of children. Surgery may also trigger antibody production.

Classically GBS is a symmetric, progressive ascending muscle weakness and/or paralysis usually first occurring in the legs and then ascending to the upper extremities usually over days to weeks. Areflexia or diminished deep tendon reflexes are early signs (usually first week) if the patient comes to attention. Reflexes can be preserved in some patients though. Sensory changes including pain or paraesthesia can be a first sign in up to 50% of children. The pain can be poorly localized or vocalized because of the children’s age and development. Patients can appear to be ataxic but with further examination this is due to muscle weakness and sensory changes, not actual ataxia. Patients are afebrile.

There are a number of variations of GBS. The classic form is acute inflammatory demyelinating polyneuropathy (ADIP) and ADIP is about 75% of cases especially in the US and Europe. Acute motor axonal neuropathy (AMAN) is similar but has no sensory defects and has more fulminant motor defects. Miller-Fisher syndrome is another variant that has ataxia, ophthalmoplegia and areflexia without peripheral weakness. The other variations have different sensory deficit profiles.

The differential diagnosis of paralysis is large, but important ones for GBS as they are treatable include botulism (which is a descending paralysis), acute spinal cord problems such as cord compression or transverse myelitis (usually has a spinal cord level on examination), and tick paralysis (which improves after the tick is removed). Diagnosis is clinical but elevated cerebrospinal fluid protein without an elevated cell count, usually < 10 cells/mm3 and all or most are lymphocytes, is the most common profile.

Treatment is supportive. The nutrition, respiratory support, rehabilitation and psychosocial needs of the patient need to be met. Patients are usually monitored in the hospital especially for the risk of respiratory failure. Immunoglobulin (IVIG) is felt to bind the autoantibiodies and downregulate antibody production. IVIG helps to improve ambulation and decrease hospital stays. Dosing is usually a total dose of 2 g/kg that is divided over 2-5 days. Plasmapheresis decreases the levels of autoantibodies that are circulating and may also decrease cytokines. It can be performed in patients > 10 kg but obviously has additional problems of being more invasive than IVIG. Both IVIG and plasmapheresis have not shown differences in long term outcomes.

Learning Point
The clinical nadir when symptoms are the worst is usually around 2 weeks after symptoms begin and most patients begin improving after that. Most have signficant improvement by 4 months and most have full recovery. Patients with classic AIDP or AMAN usually recover more quickly than other variations. Some still have problems including fatigue and sensory issues long term. It is uncommon but GBS can occur more than once.

Questions for Further Discussion
1. What are indications for referral to a neurologist?
2. What are potential radiologic imaging studies which may help with the diagnosis for GBS?
3. What causes ataxia? Click here for a differential diagnosis.
4. What causes muscle weakness with and without hypotonia Click here for a differential diagnosis.

Related Cases

To Learn More
To view pediatric review articles on this topic from the past year check PubMed.

Evidence-based medicine information on this topic can be found at SearchingPediatrics.com, the National Guideline Clearinghouse and the Cochrane Database of Systematic Reviews.

Information prescriptions for patients can be found at MedlinePlus for this topic: Guillian-Barre Syndrome

To view current news articles on this topic check Google News.

To view images related to this topic check Google Images.

To view videos related to this topic check YouTube Videos.

Rosen BA. Guillain-Barre syndrome. Pediatr Rev. 2012 Apr;33(4):164-70.

Ryan MM. Pediatric Guillain-Barre syndrome. Curr Opin Pediatr. 2013 Dec;25(6):689-93.

Roodbol J, de Wit MC, Aarsen FK, Catsman-Berrevoets CE, Jacobs BC. Long-term outcome of Guillain-Barre syndrome in children. J Peripher Nerv Syst. 2014 Jun;19(2):121-6.

Sudulagunta SR, et. al.. Guillain-Barre syndrome: clinical profile and management. Ger Med Sci. 2015 Sep 21;13:Doc16..

Author
Donna M. D’Alessandro, MD
Professor of Pediatrics, University of Iowa Children’s Hospital

What Are the Complications and Treatment for Lymphedema?

Patient Presentation
A 10-year-old female came to clinic for her health maintenance examination. She was a survivor of childhood leukemia and it was 3 years after her last chemotherapy. She was followed by her oncologist and did not have any obvious side effects of her treatment other than some mild lymphedema. It had begun about 15 months after a lymph node biopsy in her left inguinal area and was relatively mild. She was using a compression garment most days and was followed by the pediatric surgeons. She was current on all of her immunizations. The review of systems was negative.

The pertinent physical exam showed a healthy female with normal vital signs and growth parameters were 50-75%. She had no obvious lymphadenopathy, masses or hepatosplenomegaly. She had well-healed scars in her upper right chest from a port placement, and a scar in her left inguinal area. Her left foot and calf were mildly enlarged compared to her right (3 cm difference in calf size) with a symmetric outline of the anatomical structures. There was no pitting edema and pulses were strong and symmetric. The rest of her examination was normal.

The diagnosis of a healthy girl who was a cancer survivor with mild lymphedema was made. The pediatrician reiterated that it was important to continue to use the compression garments all or most of the time to help with the lymphedema. He also reminded the girl to make sure she wore shoes to protect her feet.

Discussion
Lymphedema occurs because of abnormal development or damage to the lymphatic structures. It is a chronic often progressive swelling of tissues starting distally and advancing more proximally. Extremities are the most common sites followed by genitalia. Fluid accumulation in the interstitial, superficial spaces causes adipose deposition and fibrosis. This causes the lymphedematous tissue to then enlarge. Edema is pitting early on and later is non-pitting.

Causes of lymphedema can be primary (~1%) or secondary (~99%). Primary lymphedema has been associated with several genetic mutations. Milroy disease is a primary lower extremity lymphedema that occurs in infants with a positive family history or who have a positive mutation for VEGFR3. Familial lymphedema with onset in the adolescent age group is called Meige disease and its mutation is not known at this time.

Secondary lymphedema is most common after trauma (e.g. penetrating trauma, lymph node excision, radiation) or infectious disease (especially the round worms of Filarioidea family).

The term “lymphedema” is often generically used for causes of extremity overgrowth or misdiagnosed for other vascular anomalies. For a review of overgrowth syndromes click here. A review of lymphatic malformations can also be found here.

In addition to history and physical examination, genetic studies can be done and lymphoscintigraphy is considered the standard for lymphatic function evaluation.

Learning Point
Complications of lymphedema include an increased risk of infections, skin changes (often thickening) and potentially but rarely malignancy. Patients with lymphedema do not have skin ulceration but do have an increased risk of skin infections often with Streptococcus species.

Lymphedema can’t be cured but can be treated. Treatment is conservative if at all possible. The affected area should have good skin hygiene of washing/drying and moisturizing to help prevent infections. Protective clothing is also helpful, especially wearing long pants/sleeves and foot wear or gloves. Compression garments (usually custom made) are a main treatment modality and can help to reduce the extremity volume and help to slow the disease progression. Patients need enough garments so they can be laundered regularly and they need to be replaced when worn (usually every 6 months). Other compression treatments can be offered including using pneumatic pumps. Regular exercise to maintain conditioning and normal body mass also helps treatment. Muscle contraction is the primary way that lymph fluid is transported centrally to the body. Elevation of the extremity when non weight bearing and when convenient to the patient can also help. Specific massage techniques from a trained professional can also provide some relief but can be time consuming and expensive.

Surgical treatments are used when the lymphedema is causing significant morbidity. They include lipectomy to remove adipose tissue and skin/subcutaneous resections. Microsurgical techniques can also be used to help reconstruct or reconnect lymphatic drainage.

Questions for Further Discussion
1. How is lymphedema different than generalized edema?
2. What are complications of cancer treatment that survivors need to be monitored for?
3. What are indications for surgical consultations?

Related Cases

    Symptom/Presentation: Edema

To Learn More
To view pediatric review articles on this topic from the past year check PubMed.

Evidence-based medicine information on this topic can be found at SearchingPediatrics.com, the National Guideline Clearinghouse and the Cochrane Database of Systematic Reviews.

Information prescriptions for patients can be found at MedlinePlus for this topic: Lymphedema

To view current news articles on this topic check Google News.

To view images related to this topic check Google Images.

To view videos related to this topic check YouTube Videos.

Schook CC, Mulliken JB, Fishman SJ, Alomari AI, Grant FD, Greene AK. Differential diagnosis of lower extremity enlargement in pediatric patients referred with a diagnosis of lymphedema. Plast Reconstr Surg. 2011 Apr;127(4):1571-81.

Blatt J, Powell CM, Burkhart CN, Stavas J, Aylsworth AS. Genetics of hemangiomas, vascular malformations, and primary lymphedema. J Pediatr Hematol Oncol. 2014 Nov;36(8):587-93.

Maclellan RA, Greene AK. Lymphedema. Semin Pediatr Surg. 2014 Aug;23(4):191-7.

Author
Donna M. D’Alessandro, MD
Professor of Pediatrics, University of Iowa Children’s Hospital