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Last updated: 8/10/2023
Years published: 2004, 2018, 2023
NORD gratefully acknowledges Hannah Sur, Editorial Intern from the Keck Graduate Institute, Alexandra Oxford, MD Candidate, University of Utah School of Medicine and Julia Thom Oxford, PhD, Distinguished Professor, Department of Biological Sciences, Biomolecular Research Center, Boise State University, for assistance in the preparation of this report.
Summary
Stuve Wiedemann syndrome (STWS) is a rare genetic disorder that has been diagnosed in very few patients. It is characterized by short stature, bowing of the long bones of the arms and legs (campomelia) and fingers or toes that are permanently flexed (camptodactyly) outward away from the thumb (ulnar deviation). Affected infants are often unable to survive past one year due to life-threatening complications, including respiratory distress and episodes during which there is a sudden rise in body temperature (hyperthermia). Those who do survive will develop severe spinal deformities, spontaneous bone fractures, temperature instability (from dysautonomia) and some general developmental delays, though no intellectual deficits have been found. STWS is inherited in an autosomal recessive pattern.
In the past, STWS was thought to be a lethal condition in all affected individuals. Today, survival past the first year of life is increasingly common thanks to early diagnosis and proper medical monitoring.
The symptoms of STWS vary from person to person. Most infants develop characteristic skeletal abnormalities including permanent flexion of fingers or toes (camptodactyly) outward away from the thumb (ulnar deviation) and bowing of the long bones of the arms and legs (camptomelia), which results in short stature. Affected infants may also have underdeveloped muscle tone (hypotonia) and/or an elbow that is permanently fixed in a bent or flexed position (elbow contracture). Some children with STWS have distinctive facial features, including a small chin (micrognathia), pursed mouth, and underdeveloped upper jaw, cheekbones, and eye sockets (midface hypoplasia) that sometimes results in protruding eyes.
Some infants with STWS may develop episodes where they repeatedly stop breathing during sleep (sleep apnea). Feeding and swallowing difficulties may also occur. In some children, life-threatening complications may develop early during infancy including respiratory distress and repeated episodes where there is a sudden rise in body temperature (hyperthermia).
Other symptoms include decreased bone density (osteopenia) and autonomic nervous system dysfunction (dysautonomia) that includes difficulty regulating temperature, smooth tongue and absent corneal (blinking) and patellar reflexes. The absence of a corneal reflex may put children at risk of physical damage to the eye resulting in vision loss. Affected children will also have general developmental delays, though there have been no reports of any intellectual deficits.
The specific clinical picture of STWS is unclear due to the small number of cases reported in the medical literature. Some affected individuals develop symptoms similar to those associated with dysautonomia. (For more information on dysautonomia, see the Related Disorders section below). These symptoms may include diminished sensitivity to pain, absence of the knob-like projections that cover the tongue (fungiform papillae), excessive sweating at low temperatures, absent corneal reflexes, multiple fractures and spinal abnormalities.
Additional findings have been reported in some children with STWS including high blood pressure of the main artery of the lungs (pulmonary hypertension), liver (hepatic) failure, and a form of clubfoot in which the heel is turned outward away from the midline of the leg (talipes valgus). It is not known whether these are characteristic findings of STWS or coincidental findings. As STWS becomes better recognized, more cases will be identified allowing for a clearer clinical picture to emerge.
STWS is caused by changes (variants or mutations) in the leukemia inhibitory factor receptor (LIFR) gene. Variants in this gene may cause the complete absence of the LIFR protein or the production of a non-functional LIFR protein. LIFR gene variants ultimately affect the JAK/STAT 3 signaling pathway. This pathway is one of the many signaling pathways involved in human development, involving many different cytokines and growth factors. Of note, not all reported individuals have a LIFR gene variant, indicating that not all of the STWS-causing genes have been identified.
STWS is inherited in an autosomal recessive pattern. Recessive genetic disorders occur when an individual inherits a mutated gene from each parent. If an individual receives one normal gene and one mutated gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the mutated gene and have an affected child is 25% with each pregnancy. The risk of having a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.
Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.
STWS has a very low prevalence of <1 out of 1,000,000. However, the disease is relatively common in the United Arab Emirates with a prevalence of 1 out of 20,000 births. STWS affects males and females in equal numbers. Patients with STWS often go unrecognized, making it difficult to determine the true frequency of the disorder in the general population. STWS was first described in the medical literature in 1971.
STWS is usually diagnosed based on clinical and radiological findings after birth. A detailed patient history is taken into account. Radiological images show the telltale congenital contractures, bowed long bones, decreased bone density and other abnormal patterns. Genetic testing for variants in the LIFR gene can confirm a STWS diagnosis. At least one child with STWS was diagnosed before birth (antenatally) by fetal ultrasound during the late second or third trimester. In fetal ultrasound, sound waves are used to create an image of the developing fetus.
Treatment
The treatment of STWS currently involves treatment of the symptoms of each patient. This might include prevention of choking while eating via a tube that connects the nose to the stomach for feeding (nasogastric tube), prevention of inhaling food on accident (lung aspiration) or physiotherapy and/or surgery to correct bone malformations. However, it should be noted that due to the tendency of affected individuals to have episodes of hyperthermia, use of anesthesia for procedures should be treated with extreme caution. Other treatment considerations include eye protection to prevent vision loss in the absence of a corneal reflex.
Genetic counseling is recommended for affected individuals and their families. Other treatment is symptomatic and supportive.
Information on current clinical trials is posted on the Internet at https://clinicaltrials.gov/ All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/for-patients-and-families/information-resources/info-clinical-trials-and-research-studies/
For information about clinical trials sponsored by private sources, contact:
https://www.centerwatch.com/
For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
Please note that some of these organizations may provide information concerning certain conditions potentially associated with this disorder.
Stuve-Wiedemann Syndrome. Genetic and Rare Diseases Information Center. Last updated: 5/4/2016. https://rarediseases.info.nih.gov/diseases/5045/stuve-wiedemann-syndrome Accessed August 9, 2023.
Stuve-Wiedemann Syndrome. Orphanet. Last update: March 2016. https://www.orpha.net/consor/cgi-bin/Disease_Search.php?lng=EN&data_id=3233&Disease_Disease_Search_diseaseGroup=Stuve-Wiedemann-syndrome&Disease_Disease_Search_diseaseType=Pat&Disease(s)/group%20of%20diseases=Stuve-Wiedemann-syndrome&title=St%FCve-Wiedemann%20syndrome&search=Disease_Search_Simple Accessed August 9, 2023.
Mikelonis D, Jorcyk CL, Tawara K and Oxford, JT. Stรผve-Wiedemann syndrome: LIFR and associated cytokines in clinical course and etiology. Orphanet Journal of Rare Diseases. 2014;9:34. https://doi.org/10.1186/1750-1172-9-34 Accessed August 9, 2023.
Rawlings JS, Rosler KM, Harrison DA. The JAK/STAT signaling pathway. Journal of Cell Science 2004;117:1281-1283; doi: 10.1242/jcs.00963 https://jcs.biologists.org/content/117/8/1281 Accessed August 9, 2023.
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