Last updated:
1/19/2024
Years published: 2024
NORD gratefully acknowledges Crystal Yu, BSc, Graduate Student in Medical Genetics, University of British Columbia and William T. Gibson, MD, PhD, Senior Clinician Scientist, UBC and British Columbia Children’s Hospital Research Institute, for the preparation of this report.
Summary
Imagawa-Matsumoto syndrome (IMMAS), also known as SUZ12-related overgrowth disorder, is a rare disease caused by changes (variants or mutations) in the SUZ12 gene. It is often caused by newly arisen changes (de novo mutations) but some patients inherit the changed gene from an affected or mildly affected parent (See Causes). Children with IMMAS often have delays in motor and developmental skills and may also have signs such as tall stature, intellectual and learning disabilities and some facial features that are different than expected based on their family background. Genital and urinary tract abnormalities may be other signs. There is no cure for IMMAS. Treatment is focused on the individual signs and symptoms in each patient and includes educational support and physical therapy.
Introduction
IMMAS was first identified in a female patient with a change in the SUZ12 gene in 2017 by Dr. Eri Imagawa and Dr. Naomichi Matsumoto from Yokohama City University Graduate School of Medicine in Yokohama, Japan. More patients were identified and reported by Dr. Sharri Cyrus and Dr. William T. Gibson at the BC Children’s Hospital Research Institute in Vancouver, Canada. The disease continues to be studied by both groups to better understand how to help patients with IMMAS (See Clinical Trials and Studies).
IMMAS is sometimes known as a “Weaver-like” syndrome because patients may have symptoms like individuals with Weaver syndrome and other similar syndromes such as Cohen-Gibson syndrome (See Disorders with Similar Symptoms below). The reason for the clinical similarities between these disorders is that the SUZ12 protein (which is the product of the SUZ12 gene) works together with the gene products affected in Weaver syndrome and Cohen-Gibson syndrome to form a protein partnership called the polycomb repressive complex 2 (“PRC2 complex”). Changes to the PRC2 complex can affect many of the regular processes that happen in the body, which is why patients with IMMAS can have a wide range of signs and symptoms. Management of these signs and symptoms is important for treating patients with IMMAS.
IMMAS is characterized by rapid growth in childhood and early bone maturation, leading to features such as increased height (tall stature), enlarged head circumference and hands and feet that are large for age. Children with IMMAS may have bent fingers or toes (camptodactyly/clinodactyly) that do not completely straighten. It may also be difficult for affected individuals to extend their knees and elbows. Some patients have very flexible limbs (hypermobility of joints) and some may also develop a curved spine (scoliosis).
People with IMMAS typically have an increased head size (macrocephaly) broad or tall forehead and flattening of the back of the head (flattened occiput). Individuals who have a more triangular face with a small lower jaw (micrognathia) and a narrow head above the eyebrows (bitemporal narrowing) have also been reported. They may also have a generally round face and a more prominent chin. Some individuals may have a large space between the eyes (hypertelorism) and/or down-slanting outside corners of the eyes. A longer or more prominent space between the nose and upper lip (philtrum) may be present. Some people with IMMAS do not have all these facial differences.
Individuals with IMMAS may also have excessive loose skin and develop moles (pigmented nevi). In some individuals, increased hair growth (hypertrichosis) has been reported. Additional signs and symptoms of IMMAS include urinary and genital abnormalities.
Children with IMMAS frequently have developmental delays in acquiring motor and speech skills, and later in life may have learning and/or intellectual disabilities. They may also have autism spectrum disorder (ASD).
IMMAS is caused by changes (variants) in the SUZ12 gene. These changes can result in the production of a SUZ12 protein that does not function normally.
IMMAS is inherited in an autosomal dominant pattern, meaning that only one of the two copies of the gene needs to be changed to cause the disease. These changes usually occur for the first time in the child (de novo) but can also be inherited from a parent. The risk of passing the changed gene from an affected parent to a child is 50% for each pregnancy. The risk is the same for males and females. Some people with IMMAS may be mildly affected.
Two siblings have been reported who have two disease-causing variants in the SUZ12 gene. Their features are similar to patients with IMMAS. It is not yet clear if this is a separate medical condition.
IMMAS is an extremely rare disorder. As of 2024, there are between 15 and 17 patients reported in the medical literature with IMMAS.
IMMAS may be suspected based on a combination of the characteristic clinical features outlined above (e.g., general overgrowth, macrocephaly, increased height, developmental delay, intellectual disability, etc.).
Symptoms that raise suspicion of IMMAS include a combination of:
Diagnosis of IMMAS is confirmed with genetic testing. The most common genetic tests used to diagnose IMMAS are next-generation sequencing panels that focus on disorders with overgrowth and intellectual disability, and exome sequencing. Both of these tests look at the part of DNA that encodes proteins, and these tests will find changes in the SUZ12 gene. These changes need to be considered pathogenic (harmful) or likely pathogenic (likely harmful) variants to confirm a diagnosis of IMMAS. Not all changes in the SUZ12 gene cause IMMAS, so DNA testing of the SUZ12 gene should be interpreted by experts in the context of the patient’s medical features.
NF1-SUZ12 microdeletion syndrome is typically diagnosed using chromosomal microarray analysis (CMA) which detects the microdeletion.
Clinical Testing and Workup
Further clinical testing is required to follow up on signs and symptoms that are present or may develop over time. A variety of medical specialists may be involved in a patient’s care, depending on their symptoms. Evaluations for heart (cardiac) and lung (respiratory) disorders may be recommended for some patients. Routine testing with a physician trained in physical medicine (physiatrist) may help identify and address skeletal problems.
Patients with IMMAS are recommended to have testing for neurodevelopmental symptoms such as intellectual and learning disabilities and autism. They may also have screening for developmental delays such as delays in motor skills and speech.
There is currently no cure for IMMAS. Treatment for IMMAS is focused on the individual signs and symptoms in each patient.
Developmental assessment is recommended for patients with IMMAS to identify areas in motor skills, speech and cognition that may need to be addressed. Autism spectrum disorder assessment is also recommended. Educational support and the development of individualized education programs (IEP) may be helpful for children with intellectual disability and/or autism. Speech therapy may help to improve speech and language skills.
An orthopedic assessment is recommended to identify orthopedic concerns such as scoliosis and tight joints. Physical therapy may help improve some common musculoskeletal features of individuals with IMMAS.
Genetic counseling is recommended in addition to routine physician care to help patients and their families understand genetic testing results and provide information to help with decision-making. Genetic counselors can also provide support for the care of other family members.
Research studies dedicated to understanding IMMAS are underway globally. Current studies regarding IMMAS include a longitudinal study conducted in an Epigenetic Registry from the BC Children’s Hospital Research Institute based in Canada, as well as ongoing work at Yokohama City University Graduate School of Medicine in Japan.
As of 2024, there are no therapeutic clinical trials being conducted for IMMAS.
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
Imagawa E, Seyama R, Aoi H, et al. Imagawa-Matsumoto syndrome: SUZ12-related overgrowth disorder. Clin Genet. 2023;103(4):383-391. doi:10.1111/cge.14296
Ülker AY, Alkaya D, Çağlayan A, et al. An investigation of the etiology and follow-up findings in 35 children with overgrowth syndromes, including biallelic SUZ12 variant. Am J Med Genet A. 2023;191(6):1530-1545. Doi:10.1002/ajmg.a.63180
Hetzelt KLML, Winterholler M, Kerling F, et al. Manifestation of epilepsy in a patient with EED-related overgrowth (Cohen-Gibson syndrome). Am J Med Genet A. 2022;188(1):292-297. Doi:10.1002/ajmg.a.62496
Manor J, Lalani SR. Overgrowth Syndromes-Evaluation, Diagnosis, and Management [published correction appears in Front Pediatr. 2020 Dec 23;8:624141]. Front Pediatr. 2020;8:574857. Published 2020 Oct 30. doi:10.3389/fped.2020.574857
Cyrus SS, Cohen ASA, Agbahovbe R, et al. Rare SUZ12 variants commonly cause an overgrowth phenotype. Am J Med Genet C Semin Med Genet. 2019;181(4):532-547. doi:10.1002/ajmg.c.31748
Imagawa E, Higashimoto K, Sakai Y, et al. Mutations in genes encoding polycomb repressive complex 2 subunits cause Weaver syndrome. Hum Mutat. 2017;38(6):637-648. doi:10.1002/humu.23200
Cohen AS, Gibson WT. EED-associated overgrowth in a second male patient. J Hum Genet. 2016;61(9):831-834. doi:10.1038/jhg.2016.51
Cohen AS, Tuysuz B, Shen Y, Bhalla SK, Jones SJ, Gibson WT. A novel mutation in EED associated with overgrowth. J Hum Genet. 2015;60(6):339-342. doi:10.1038/jhg.2015.26
INTERNET
Gigantism. UCLA Health. https://www.uclahealth.org/medical-services/neurosurgery/pituitary-skull-base-tumor/conditions/pituitary-adenomas/gigantism Accessed Jan 11, 2024.
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