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Last updated:
2/13/2024
Years published: 1996, 1997, 2004, 2006, 2020, 2024
NORD gratefully acknowledges Gioconda Alyea, Brazilian MD, MS, National Organization for Rare Disorders, Jacqueline Kirsh and Eve Takazawa, Editorial Interns from the University of Notre Dame, Angela M. Mabb, PhD, Assistant Professor, Center for Behavioral Neuroscience, Neuroscience Institute, Georgia State University and Arlene J. George, Graduate Fellow, Neuroscience Institute, Georgia State University, for assistance in the preparation of this report.
Summary
Turner type X-linked syndromic intellectual developmental disorder is a rare neurologic and developmental disorder with many different signs and symptoms. Affected people show developmental delay from infancy, with intellectual disability, poor or absent speech and delayed walking.
Characteristic facial differences can include an increased size of the head (macrocephaly) or a decreased size of the head (microcephaly), deep-set eyes, an abnormally decreased distance between the eyes (hypotelorism), small palpebral fissures, abnormally shaped, large, or low-set ears, long face, narrowed size of the head above the eyebrows (bitemporal narrowing), high-arched palate and a thin upper lip.
Other common signs and symptoms may include an abnormal lateral spine curvature (scoliosis) or mild skeletal anomalies in the end part of the arms or legs, such as small hands (brachydactyly) or tapered fingers.
Males tend to have a condition in which one or both testes fail to descend from the abdomen into the scrotum (cryptorchidism). Other less common features may include low muscle tone (hypotonia), seizures and delayed bone age.
This condition is caused by changes (pathogenic variants or mutations) in the HUWE1 gene. Inheritance can be X-linked recessive or X-linked dominant.
There is no cure for this condition and treatment is directed to improve the symptoms.
Introduction
This condition has been named “intellectual developmental disorder, X-linked syndromic, Turner type” or “Turner type X-linked intellectual developmental disorder” because the first variant in the HUWE1 gene was found in the large, affected family originally reported by Turner in 1994. Subsequently, HUWE1 gene variants were found in people affected with several other similar X-linked disorders, including Juberg-Marsidi syndrome and Brooks-Wisniewski-Brown syndrome, as well as nonspecific syndromic X-linked neurologic disorders with impaired intellectual development and additional features, thus indicating that all these conditions are part of the same disorder.
People affected with Turner type X-linked syndromic intellectual developmental disorder may have several signs and symptoms that are usually fully present in males only. The range and severity of symptoms vary from person to person.
Some females who carry a single copy of the disease gene (heterozygous carriers) may have milder symptoms such as low cognitive ability and/or abnormally small head (microcephaly).
Signs and symptoms that have been reported in the medical literature include:
Other problems may include:
Turner type X-linked syndromic intellectual developmental disorder is caused by variants in the HUWE1 gene which is located on the X chromosome.
The HUWE1 gene has instructions to make a protein called E3 ubiquitin-protein ligase. This protein is present in all cells in the human body meaning that any variants in the HUWE1 gene can have significant effects throughout the body.
The process called protein ubiquitination involves modifying numerous proteins to mediate a variety of cell functions. There are three main enzymes that work in protein ubiquitination, E1, E2, and E3. E3 is called ubiquitin ligase and is the final step in the process. As commented before, the HUWE1 gene makes a specific E3 ubiquitin ligase.
Variants in the HUWE1 gene may result in decreased expression of the protein and abnormal enzyme function, which could affect protein ubiquitination. Little is known about the direct relationship between specific HUWE1 variants and the physical features of the disease, but this is being studied in a mouse model.
In general, research indicates that the HUWE1 gene has a role in controlling the release of neurotransmitters and in the formation of neurons in the developing brain. It has also been associated with intellectual disability as well as a range of other conditions.
Turner type X-linked syndromic intellectual developmental disorder can be inherited in an X-linked recessive pattern or in an X-linked dominant pattern.
X-linked genetic disorders are conditions caused by a mutated gene on the X chromosome and mostly affect males. Females who have a mutated gene on one of their X chromosomes are carriers for that disorder. Carrier females usually do not have symptoms because females have two X chromosomes and only one carries the mutated gene. Males have one X chromosome that is inherited from their mother and if a male inherits an X chromosome that contains a mutated gene, he will develop the disease.
Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease and a 25% chance to have an unaffected son.
If a male with an X-linked disorder can reproduce, he will pass the mutated gene to all his daughters who will be carriers. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male children.
X-linked dominant disorders are caused by a mutated gene on the X chromosome and mostly affect females. Females are affected when they have an X chromosome with the mutated gene for the disease. Males with a mutated gene for an X-linked dominant disorder are more severely affected than females and often do not survive.
Around 100 people with this condition have been reported in the medical literature.
Turner type X-linked syndromic intellectual developmental disorder may be suspected at birth or during early infancy, but there is often delayed diagnosis due to the large variety of possible symptoms and similarities to other diseases. A thorough clinical evaluation noting the characteristic physical findings, as well as an evaluation of family history, are used to suspect this diagnosis. Diagnosis is confirmed with genetic testing which can identify a disease-causing variant in the HUWE1 gene.
Treatment
The treatment of this syndrome is directed toward the specific symptoms that are apparent in each individual and focuses on improving the symptoms. Treatment requires the coordinated efforts of a team of specialists who need to work together in a coordinated way. The team may include pediatricians, speech pathologists, nutritionists, mental health providers, specialists who assess and treat hearing problems (audiologists), eye specialists, urologists and other health care professionals.
Early intervention is important in ensuring that affected children reach their potential. Special services that may be beneficial include special remedial education and other medical, social and/or vocational services.
Genetic counseling is recommended for affected individuals and their families.
Information on current clinical trials is posted on the Internet at www.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: prpl@cc.nih.gov
Some current clinical trials also are posted on the following page on the NORD website: https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
For information about clinical trials sponsored by private sources, contact: www.centerwatch.com
For information about clinical trials conducted in Europe, contact: https://www.clinicaltrialsregister.eu/
JOURNAL ARTICLES
George AJ, Hoffiz YC, Charles AJ, Zhu Y, Mabb AM. A comprehensive atlas of E3 ubiquitin ligase mutations in neurological disorders. Front Genet. 2018;9:29. Published 2018 Feb 14. doi:10.3389/fgene.2018.00029
Moortgat S, Berland S, Aukrust I, et al. HUWE1 variants cause dominant x-linked intellectual disability: a clinical study of 21 patients. Eur J Hum Genet. 2018 Jan;26(1):64-74. doi: 10.1038/s41431-017-0038-6. Epub 2017 Nov 27.
Friez MJ, Brooks SS, Stevenson RE, et al. HUWE1 mutations in Juberg-Marsidi and Brooks syndromes: the results of an X-chromosome exome sequencing study. BMJ Open. 2016;6(4):e009537. Published 2016 Apr 29. doi:10.1136/bmjopen-2015-009537
Villard L, Geez J, Mattei JF, et al. XNP mutation in a large family with Juberg-Marsidi syndrome. Nat Genet. 1996;12:359-60.
Juberg RC, Marsidi I. A new form of X-linked mental retardation with growth retardation, deafness, and microgenitalism. Am J Hum Genet. 1980;32(5):714–722.
INTERNET
Turner-Type X-Linked Syndromic Intellectual Developmental Disorder.Online Mendelian Inheritance In Man (OMIM). The Johns Hopkins University. Entry Number 309590. Last Edit Date: 08/20/2021. Available at: https://www.omim.org/entry/309590 Accessed Feb 6, 2024.
Non-specific syndromic intellectual disability. Orphanet. https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=93972 Accessed Feb 6, 2024.
HUWE1 Welcome Guide for Newly Diagnosed Families. HUWE1Community. https://www.huwe1.org/_files/ugd/234888_a5d046960acb4c178fd5b2b65c9244f6.pdf Accessed Feb 6, 2024.
HUWE1-related intellectual disability (ID). UNIQUE. Understanding Chromosome and Gene Disorders. 2020. https://rarechromo.org/media/singlegeneinfo/Single%20Gene%20Disorder%20Guides/HUWE1%20related%20ID%20QFN.pdf Accessed Feb 6, 2024.
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