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NORD gratefully acknowledges Emily Brown, MMSc, NORD Editorial Intern from the Emory University Genetic Counseling Training Program and Cecelia A. Bellcross, PhD, MS, CGC, Associate Professor, Director, Genetic Counseling Training Program, Emory University School of Medicine, for assistance in the preparation of this report.
Seckel syndrome is rare genetic condition with slow growth before birth (intrauterine growth restriction) resulting in low birth weight. Slow growth continues after birth (postnatal), causing short height (dwarfism). Some features of Seckel syndrome are a small head (microcephaly) and intellectual disability. Possible facial features are a sloping forehead and “beak-like” nose. Other features may include large eyes, a narrow face, ears of a different shape and/or a small jaw (micrognathia). In addition, some affected infants may have curving of the pinkie finger (clinodactyly) or unusual development of the hips (hip dysplasia). They may also have dislocation of a bone in the forearm (radial dislocation) and/or other physical features.
Seckel syndrome presents with slow growth during fetal development (intrauterine growth restriction). This results in low birth weight. Slow growth (growth retardation and delayed bone maturation) continues after birth (postnatal). This can lead to short height (dwarfism) with arms and legs that are proportionate to height. (This is different than short height with small arms and legs). Moderate to severe intellectual disability may
also be present at birth, but may not be obvious until the child is older. Some individuals with Seckel syndrome have kidneys in the wrong place (ectopic kidneys).
In addition, infants with Seckel syndrome have differences of the head and face (craniofacial). Most affected infants have small heads (microcepahly) for their age, sex, and body size. Individuals can also have a forehead that slopes backward (receding) and a small jaw (micrognathia) that is farther back than usual (retrognathia). They may also have a curved, triangular “beak-like” nose. Due to these differences, the middle portion of the face may appear to stick out more. In some children, spaces between the bones of the skull (cranial sutures) may close earlier than they should (craniosynostosis). As a result, the head may look long or shortened, depending on which part of the skull is affected.
Some infants with Seckel syndrome have other features including large eyes with downward slanting eyelid folds (palpebral fissures). They may have crossed eyes (strabismus). They can also have low-set, differently shaped (dysplastic) ears without ear lobes, and/or a high-arched roof of the mouth (palate) that may be not be formed completely (cleft palate). In some patients, one side of the face may look larger than the other (facial asymmetry). Some affected infants and children may have weak tooth enamel, and differences in the number, and/or positioning of the teeth.
Children with Seckel syndrome may have skeletal changes like the lower end of the bone on the thumb side of the hand being out of place (radial dislocation). They may also have elbows or hips that pop out of place, and/or unusual development (dysplasia) of the hips. Some children are not able to fully extend their knees. They may also have cone-shaped ends of bones. Some affected children may develop front-to-back and/or side-to-side curvature of the spine (kyphoscoliosis). An additional skeletal feature may be permanent curving of the pinkie finger stuck in place (clinodactyly). Children can have a twisted position of the foot (clubfoot), flat feet (pes planus) and/or be missing a pair of ribs (11 pairs instead of 12).
Males with Seckel syndrome may have testes that do not lower properly (cryptorchidism). Affected females may have a large clitoris (clitoromegaly). In addition, affected children may have increased body hair (hirsutism). Another possible feature is a single, deep crease across the palms of the hands (single palmar crease).
Some people with Seckel syndrome may have blood (hematological) problems. These include a reduced amount of all parts of bone marrow including red blood cells, white blood cells, and platelets (pancytopenia). A low level of red blood cells is known as anemia.
Seckel syndrome is rare genetic disorder that is inherited in an autosomal recessive pattern. There are multiple types of Seckel syndrome caused by harmful changes in genes (mutations) on multiple chromosomes. The types and gene names are:
· Seckel syndrome 1: ataxia-telangiectasia and Rad3-related protein (ATR) gene
· Seckel syndrome 2: RB binding protein 8 (RBBP8) gene
· Seckel syndrome 4: centromere protein J (CENPJ) gene
· Seckel syndrome 5: centrosomal protein 152 (CEP152) gene
· Seckel syndrome 6: centrosomal protein 63 (CEP63) gene
· Seckel syndrome 7: ninein (NIN) gene
· Seckel syndrome 8: DNA 2 protein (DNA2) gene
· Seckel syndrome 9: ATR interacting protein (ATRIP) gene
· Seckel syndrome 10: SMC5-SMC6 complex SUMO ligase (NSMCE2) gene
Chromosomes are present in every human cell. Human cells have 23 pairs of chromosomes for a total of 46. One of each pair comes from the father and the other of the pair from the mother. The chromosomes carry our genetic information (genes).
The genes provide instructions to make the proteins used by the body. If there is a harmful change (mutation) in the gene, then the protein may not work correctly, or be made in the wrong amount. These changes affect how the body develops and functions.
Recessive genetic disorders occur when an individual inherits two non-working genes for the same trait, one from each parent. If an individual receives one working gene and one non-working gene, the person will be a carrier for the disease, but will usually not show symptoms. The risk for two carrier parents to both pass on the non-working gene and have an affected child is 25% with each pregnancy. The risk to have 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 and be genetically normal for that particular trait is 25%. The risk is the same for males and females.
All individuals carry a few non-working genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same harmful gene change, which increases the risk to have children with a recessive genetic disorder.
Seckel syndrome is a rare genetic disorder that affects males and females in equal numbers. About 1 in 10,000 individuals have Seckel syndrome.
Seckel syndrome may be diagnosed before birth (prenatally). Ultrasound can be done to create an image of the developing fetus. Seckel syndrome may be suspected if a fetus has a small head (microcephaly), slow growth or features of the head and face (craniofacial) associated with Seckel syndrome. Sometimes, a diagnosis of Seckel syndrome may not be confirmed until an affected child gets older. More features may be seen with age like intellectual disability or short height.
Genetic testing can be done to confirm the diagnosis, either prior to birth or after. If Seckel syndrome is suspected, all of the genes associates with the syndrome should be tested at once (gene panel).
Short height associated with Seckel syndrome involves proportional growth of the arms and legs. This allows for differential diagnosis from syndromes that involve short stature and small arms and legs (short-limbed dwarfism).
Treatment
Medical treatment for Seckel syndrome is based on the specific problems that are present in the affected child. The child should be treated for the range of features associated with Seckel syndrome, including tooth crowding or position issues, bone dislocations, genital differences and anemia.
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:
Toll-free: (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/news-patient-recruitment/
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/
(Please note that some of these organizations may provide information concerning certain conditions potentially associated with this disorder [e.g., short stature, mental retardation, etc.].)
TEXTBOOKS
Gorlin RJ, Cohen MMJr, Hennekam RCM. Eds. Syndromes of the Head and Neck. 4th ed. Oxford University Press, New York, NY; 2001:387-90.
Jones KL. Ed. Smith’s Recognizable Patterns of Human Malformation. 7th ed. Saunders Co., Philadelphia, PA; 2013:146-148.
JOURNAL ARTICLES
Ouattara ABI, Barro M, Nacro SF, et al. The Seckel syndrome: A case observed in the pediatric department of the University Hospital Center Sourou Sanou (Burkina Faso). Pediatric Reports. 2020;12(1).
Marakhonov AV, Konovalov FA, Makaov AK, et al. Primary microcephaly case from the Karachay-Cherkess Republic poses an additional support for microcephaly and Seckel syndrome spectrum disorders. BMC Medical Genomics. 2018;11(S1).
Dinçer T, Yorgancıoğlu-Budak G, Ölmez A, et al. Analysis of centrosome and DNA damage response in PLK4 associated Seckel syndrome. European Journal of Human Genetics. 2017;25(10):1118-1125.
Khetarpal P, Das S, Panigrahi I, Munshi A. Primordial dwarfism: overview of clinical and
genetic aspects. Molecular Genetics and Genomics. 2016;291(1):1-15.
Vascone C, Di Meglio F, Di Meglio L, et al. Antenatal diagnosis of Seckel Syndrome: a rare case report. J Prenat Med. 2014;8(3-4):70-72.
Al-Dosari MS, Shaheen, R., Colak, D., Alkuraya, F. S. Novel CENPJ mutation causes Seckel syndrome. J Med Genet. 2010;47: 411-414.
Denz K, Kontas O, Akcakus M. Neonatal hepatitis in 2 siblings with Seckel syndrome. Pediatr Dev Pathol. 2006;9:81-85.
Alderton GK, Joenje H, Varon R, Borglum AD, Jeggo PA, O’Driscoll M. Seckel syndrome exhibits cellular features demonstrating defects in the ATR-signalling pathway. Hum Mol Genet. 2004;13:3127-34.
Murthy J, Seshadri KG, Ramanan PV, Rajamani A, Hussain A. A case of cleft lip and palate associated with Seckel syndrome. Cleft Palate Craniofac J. 2004;41:202-05.
Bobabilla-Morales L, Corona-Rivera A, Corona-Rivera JR, et al. Chromosomal instability induced in vitro with Mitomycin C in five Seckel syndrome patients. Am J Med Genet A. 2003;123:148-52.
INTERNET
McKusick VA, ed. Online Mendelian Inheritance In Man (OMIM). The Johns Hopkins University. Seckel Syndrome 1. Entry Number: 210600. Last Edit Date:9/20/21. https://omim.org/entry/210600?search=210600&highlight=210600 Accessed Nov 17, 2021.
McKusick VA, ed. Online Mendelian Inheritance In Man (OMIM). The Johns Hopkins University. Seckel Syndrome 2; SCKL2. Entry Number: 606744. Last Edit Date; 5/24/2019. https://omim.org/entry/606744?search=606744&highlight=606744 Accessed Nov 17, 2021.
McKusick VA, ed. Online Mendelian Inheritance In Man (OMIM). The Johns Hopkins University. Microcephalic Primordial Dwarfism, Montreal Type. Entry Number: 210700. Last Edit Date: 3/29/2012. https://omim.org/entry/210700 Accessed Nov 17, 2021.
Seckel Syndrome. Orphanet. Updated 2005. https://www.orpha.net/consor/cgi-bin/OC_Exp.php?Lng=GB&Expert=808 Accessed Nov 17, 2021.
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