Acknowledgment
NORD gratefully acknowledges Abbey Roth, BS, Alissa Bandalene, BS and Rebecca Schapiro, BS, Stanford University MS Program in Human Genetics and Genetic Counseling, MaryAnn Campion, EdD, MS, CGC, Professor, Department of Genetics, Stanford University School of Medicine, and Juan P. Ramos, DO, MS., Pediatric-Medical Genetics Resident, Department of Pediatrics, Division of Medical Genetics, Stanford University, for the preparation of this report.
Disease Overview
Primrose syndrome is a rare genetic condition characterized by intellectual disability, developmental delay, behavioral problems and a distinctive calcification of the outer ear, as well as a large head (macrocephaly), low muscle tone (hypotonia), recognizable facial features, X-ray (radiographic) features and altered glucose metabolism such as diabetes mellitus. Additional features may include sparse body hair, neurologic concerns, muscle wasting in adulthood, hearing loss and eye concerns.
Primrose syndrome is caused by a change (variant) in the ZBTB20 gene. Inheritance is autosomal dominant. In all affected people diagnosed so far, the variant is new (de novo) in the affected person and not inherited from a parent.
There is no cure yet. Management is typically tailored to what each individual needs and may include various therapies such as speech therapy, physical therapy, occupational therapy, behavioral therapy, as well as assessments such as endocrine assessments, developmental assessments, neurological assessments, hearing assessments, vision tests and skeletal surveys and assessments. Follow-up care, treatment and surveillance may be required based on these assessments.
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Synonyms
- ossified ear cartilages with mental deficiency, muscle wasting and bony changes
- intellectual disability-cataracts-calcified pinnae-myopathy syndrome
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Signs & Symptoms
Primrose syndrome is a rare genetic condition that affects each person differently. The following signs and symptoms have been reported in people affected with this syndrome.
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Characteristic facial features which are often noticeable early in life
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Intellectual disability (in all patients) that can vary in severity, with or without delays in expressive speech
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Many patients have better understanding than speaking abilities, so sign language or pictograms can be very helpful.
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Behavioral anomalies such as ADHD, autism spectrum disorder, self-injurious behavior and sleep disturbances
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Head and face differences which may include:
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Large head (macrocephaly)
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High anterior hairline
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Deeply set eyes with drooping upper eyelids (ptosis) and down-slanted palpebral fissures
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High roof of the mouth with a bony growth (high palate with torus palatinus)
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Broad jaw and large ears with small or absent lobes
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Fusion of the eyebrows in the midline (synophrys)
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Flattened midface (midface retrusion)
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Variations in head shape like short head length (brachycephaly), flattening of the skull base (platybasia), outward bulge at the bottom of the skull (bathrocephaly) and asymmetric head shape (plagiocephaly)
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Neurological and motor development problems including:
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Neurosensorial hearing loss (mild to moderate)
- Seizures
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Low muscle tone (hypotonia)
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Flexion contractures
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Difficulties controlling movements (ataxia)
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Muscle wasting
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Muscle weakness
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Delayed motor development, but most children achieve independent walking by age two or three
Brain imaging findings that may include:
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Absence or malformation of the corpus callosum, the brain structure that joins the two brain halves
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Mild cerebral wasting (atrophy)
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Delayed production of myelin (myelination) which insulates the axons (the “cables” of the brain cells that transmit the electric impulses from neurons) This results in a decreased speed of signals transmitted between neurons (known as action potentials).
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Hydrocephalus, abnormal buildup of cerebrospinal fluid (LCR) within the cavities of the brain (ventricles) deep within the brain
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Cerebral calcification, mainly involving the brain structure known as basal ganglia
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Calcification of the external ear cartilage, a distinctive sign of this syndrome
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Other bones abnormalities such as:
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Multiple Wormian bones, the small bones sometimes found between the cranial sutures
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Slender bones with exaggerated flaring of the metaphysis, the neck portion of a long bone that contains the growth cartilage
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Abnormal vertebral bodies and endplates
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Mild changes in the epiphysis, the large ends of the long bones and spondylar dysplasia and in the spine (spondylar)
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Abnormal lateral curvature of the spine (scoliosis)
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Forward rounding of the upper back (kyphosis)
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Osteolysis (bone resorption or loss of calcium)
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Posterior scalloping of vertebral bodies of the spine
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Abnormal palate morphology
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Narrow wing of the hip bone (narrow iliac wing)
Hormonal problems that may include:
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Problems with glucose metabolism or diabetes mellitus
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Sparse body hair
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Low levels of the thyroid hormone (hypothyroidism)
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Growth hormone deficiency
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Delayed puberty and hypogonadism (low or absent sex hormones)
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Breast overdevelopment (gynecomastia)
Eye problems such as:
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Misalignment of the eyes (strabismus)
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Cloudy lenses (cataracts)
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Vision loss due to nerve damage caused by a high pressure inside the eye (glaucoma)
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Small eyes (microphthalmia)
Additional Features may include:
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Anemia
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Missing fingernails and toenails (anonychia)
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Narrow or sunken chest (pectus excavatum)
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Short stature
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Tumors (described in a few patients
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Causes
Primrose syndrome is caused by a change (variant) in the ZBTB20 gene. Genes provide instructions for creating proteins that play a role in many functions of the body. When a disease-causing variant in the gene occurs, the protein may not be able to perform its normal function. The ZBTB20 gene creates a protein that is a transcription factor. This protein is involved in growth, brain development and glucose metabolism. Primrose syndrome can be caused by a change in the spelling or a loss of a small piece of the ZBTB20 gene.
In all known cases of Primrose syndrome, the variant in ZBTB20 is new in the affected individual (de novo), meaning that the change occurred during the creation of the egg or sperm before conception of the child and that was not inherited from a parent. There is a low chance of other family members being affected. To date, all individuals with disease-causing variants in ZBTB20 show signs of Primrose syndrome, meaning that the penetrance is 100%.
There have been no known instances of someone with Primrose syndrome having children; however, if they did have children, the condition would be inherited in an autosomal dominant manner. Dominant genetic disorders occur when only a single copy of a disease-causing gene variant is necessary to cause the disease. The risk of passing the gene variant from an affected parent to a child is 50% for each pregnancy. The risk is the same for males and females.
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Affected populations
Primrose syndrome affects both males and females and can affect individuals of any ethnic or racial background. The exact incidence of the disorder is unknown. Approximately 57 affected individuals have been identified worldwide.
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Disorders with Similar Symptoms
The typical findings in Primrose syndrome are intellectual disability, hearing loss and hypotonia and these are seen in many genetic conditions. The most distinguishing findings include calcification of the external ear cartilage, sparse body hair and bone differences. Muscle loss is seen as a patient enters adolescence and young adulthood and are more specific findings associated with this condition.
Symptoms of the following disorders can be similar to those of Primrose syndrome.
7q11.23 duplication syndrome is a chromosome abnormality characterized by speech and language delay; behavior differences including anxiety disorders, attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD); neurologic differences including low muscle tone (hypotonia), differences in walking and standing, seizures; an increased head circumference (macrocephaly); distinctive facial features; and heart defects, such as enlargement of the blood vessel that carries blood from the heart to the rest of the body (aortic dilation). This condition is caused by a small amount of extra (duplicated) genetic material from chromosome 7.
3q13.31 deletion syndrome is a chromosome abnormality characterized by developmental delay, low muscle tone (hypotonia), excessive growth after birth, specific facial features and differences in male genitalia including micropenis. It is caused by a loss of genetic material on the long arm of chromosome 3 (3q13.31) that may include the ZBTB20 gene as well as other genetic material.
Fragile X syndrome is the most common cause of inherited intellectual disabilities. It can occur in both males and females, though females often have milder features than males. It is characterized by intellectual disabilities, learning and behavioral differences and/or autism spectrum disorders; delays in walking and talking; characteristic facial features which become more obvious with age and medical problems including low muscle tone (hypotonia), acid reflux (gastroesophageal reflux disease [GERD]), curving of the spine (scoliosis), flat feet (pes planus), seizures and sleep disorders. There is a wide range in the severity of symptoms. Fragile X syndrome is caused by an abnormal expansion in the CGG region in the FMR1 gene which is located on the X chromosome.
Simpson-Golabi-Behmel syndrome type 1 is a rare genetic condition that mostly affects males. Females may or may not show signs of the condition. It is characterized by excessive growth both before and after birth; specific facial features and intellectual disability that ranges in severity. Individuals may also have an opening in the roof of the mouth (cleft palate) or in the upper lip (cleft lip); an extra nipple; a bulge near the belly button called an umbilical hernia and risks for specific kinds of tumors. Simpson-Golabi-Behmel syndrome is caused by variants in the GPC3 gene, which is located on the X chromosome.
Sotos syndrome is a genetic disorder characterized by excessive growth before and after birth; characteristic facial features; a large, elongated (dolichocephalic) head and intelligence that ranges from normal to moderate intellectual disability. Other features include behavioral differences including autism spectrum disorder, advanced bone age and low muscle tone (hypotonia). Children usually are delayed in learning to walk and speak. In approximately 90% of patients, the condition is caused by variants in the NSD1 gene.
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Diagnosis
A diagnosis of Primrose syndrome may be suspected based on the characteristic clinical features listed above as well as laboratory tests and imaging studies.
The diagnosis is confirmed by genetic testing that identifies a disease-causing variant in the ZBTB20 gene.
Laboratory Findings
Results may show an abnormal acylcarnitine profile, abnormal organic acid levels in a urine test, elevated levels of fasting glucose and hemoglobin A1c (in people with diabetes) and increased levels of a molecule called alpha fetoprotein (AFP) in the blood that may indicate the presence of a tumor.
Imaging Findings
Imaging may be done, including a CT scan, MRI and X-rays. A CT scan may show calcification of the cartilage of the ear and cerebellar calcification. X-rays can show differences in the bones like multiple Wormian bones (where there is extra bone growth at joints in the skull), flattening of the base of the skull, bulging of the occipital bone, slender bones with flaring near the ends and spondylar dysplasia or overgrowth of the bones. An MRI of the brain may indicate agenesis or dysgenesis of the corpus callosum, mild cerebral atrophy, delayed myelination abnormal coating of the nerves in the brain (delayed myelination) and cerebral calcifications involving the basal ganglia.
Molecular Testing
A diagnosis of Primrose syndrome is confirmed with molecular genetic testing. If clinical findings are present and Primrose syndrome is suspected, single gene testing may be done to look for a disease-causing variant in the ZBTB20 gene. Alternatively, a gene panel that includes testing for many genes that cause intellectual disability including ZBTB20 may be ordered. Some patients may be diagnosed with exome sequencing that looks for variants in all genes.
Clinical Testing and Work-Up
The GeneReview provides information about evaluations that may be recommended as part of the diagnostic work-up or after a diagnosis is made.
At every visit, the doctor should check for any mental or emotional problems and for new or existing seizures. An evaluation of the patient’s mobility and self-help skills by an occupational or physical therapist is also recommended.
Every 6 months a doctor should do a clinical exam to monitor growth and assess development and educational requirements.
It is also recommended to have a hearing test called “brain stem evoked response audiometry” every year to check the hearing, as well as an evaluation with an endocrinologist who will check the glucose levels and evaluate the thyroid function.
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Standard Therapies
There is no cure yet for Primrose syndrome. Treatment is focused on managing and treating the specific symptoms and supporting educational needs to help the patient reach their maximal potential.
- Developmental delay and intellectual disability:
- For children ages 3-5 in United States, an Individualized Education Plan (IEP) can be beneficial for use in preschool or developmental preschool settings. The recommended therapies include:
- Speech therapy to help with speech delays
- Physical therapy to assist with motor skills
- Occupational therapy to support daily living skills
- For ages 5-21 it is recommended to review and update the educational needs to ensure continued support throughout the school years.
- The transition plan from childhood to adulthood care should start around age 12 and include planning for financial, employment and medical arrangements.
- For all ages, ongoing consultations with a developmental pediatrician are recommended, who can help with accessing community, state and educational support and assist with transitioning into adulthood.
- Behavioral problems such as ADHD and autism spectrum disorder (ASD):
- Developmental pediatrician consultations: Essential for developing a therapy plan
- Applied behavioral analysis (ABA) therapy: A board-certified behavior analyst can help tailor therapy plans to the child’s behavioral and social needs
- Supportive therapies: Involvement of a child development team and a child psychiatrist for additional behavioral support
- Seizure management by a neurologist; anti-seizure medications (ASMs), which may be effective even though there are no specific ASMs for this condition
- Bone problems should be addressed by an orthopedic doctor. It may be necessary to discuss surgical options for correcting some of the bone abnormalities.
- Muscle weakness may need to be addressed by a team of specialists including orthopedics, physical medicine and rehabilitation, physical therapy, and occupational therapist who can help manage muscle wasting, contractures and ataxia.
- Stretching exercises can be useful to avoid contractures and falls; Mobility and positioning devices should be used as needed.
- Hearing loss should be addressed by an otolaryngologist and hearing aids may be considered, along with community hearing services through early intervention programs or the school district.
- Hormonal problems should be addressed by an endocrinologist who can evaluate the need for insulin or oral hypoglycemic therapy and for potential thyroid dysfunction treatment.
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References
- Arora V, Ferreira CR, Dua Puri R, et al. Primrose Syndrome. 2021 May 6 [Updated 2021 Jun 17]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from: https://www.ncbi.nlm.nih.gov/books/NBK570205/ Accessed July 17, 2024.
- Arora V, Leon E, Diaz J, et al. Unique skeletal manifestations in patients with Primrose syndrome. Eur J Med Genet. 2020;63(8):103967. doi:10.1016/j.ejmg.2020.103967. https://doi.org/10.1016/j.ejmg.2020.103967.
- Cleaver R, Berg J, Craft E, et al. Refining the Primrose syndrome phenotype: A study of five patients with ZBTB20 de novo variants and a review of the literature. Am J Med Genet A. 2019;179(3):344-349. doi:10.1002/ajmg.a.61024 Cordeddu, V., Redeker, B., Stellacci, E. et al. Mutations in ZBTB20 cause Primrose syndrome. Nat Genet 46, 815–817 (2014). https://doi.org/10.1038/ng.3035
- Primrose Syndrome. Genetic and Rare Diseases Information Center (GARD) https://rarediseases.org/gard-rare-disease/primrose-syndrome/. Accessed February 19, 2024.
- 7q11.23 Duplication Syndrome. Genetic and Rare Diseases Information Center https://rarediseases.org/gard-rare-disease/7q11-23-duplication-syndrome/. Accessed February 19, 2024.
- Hunter JE, Berry-Kravis E, Hipp H, et al. FMR1 Disorders. 1998 Jun 16 [Updated 2019 Nov 21]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1384/ Accessed July 17, 2024.
- Juven A, Nambot S, Piton A, et al. Primrose syndrome: a phenotypic comparison of patients with a ZBTB20 missense variant versus a 3q13.31 microdeletion including ZBTB20. Eur J Hum Genet. 2020;28(8):1044-1055. doi:10.1038/s41431-020-0582-3 https://doi.org/10.1038/s41431-020-0582-3
- Klein SD, Nisbet AF, Hathaway ER, et al. Simpson-Golabi-Behmel Syndrome Type 1. 2006 Dec 19 [Updated 2023 Dec 7]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1219/ Accessed July 17, 2024.
- Melis D, Carvalho D, Barbaro-Dieber T, et al. Primrose syndrome: Characterization of the phenotype in 42 patients. Clin Genet. 2020; 97: 890–901. https://doi.org/10.1111/cge.13749
- Mervis CB, Morris CA, Klein-Tasman BP, et al. 7q11.23 Duplication Syndrome. 2015 Nov 25 [Updated 2021 Mar 25]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from: https://www.ncbi.nlm.nih.gov/books/NBK327268/ Accessed July 17, 2024.
- Molin AM, Andrieux J, Koolen DA, et al. A novel microdeletion syndrome at 3q13.31 characterised by developmental delay, postnatal overgrowth, hypoplastic male genitals, and characteristic facial features. J Med Genet. 2012;49(2):104-109. doi:10.1136/jmedgenet-2011-100534. https://doi.org/10.1136/jmedgenet-2011-100534
- Vuillaume ML, Delrue MA, Naudion S, et al. Expanding the clinical phenotype at the 3q13.31 locus with a new case of microdeletion and first characterization of the reciprocal duplication. Mol Genet Metab. 2013;110(1-2):90-97. doi:10.1016/j.ymgme.2013.07.013 https://doi.org/10.1016/j.ymgme.2013.07.013
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