Clinical characteristics.

Primrose syndrome is characterized by macrocephaly, hypotonia, developmental delay, intellectual disability with expressive speech delay, behavioral issues, a recognizable facial phenotype, radiographic features, and altered glucose metabolism. Additional features seen in adults: sparse body hair, distal muscle wasting, and contractures. Characteristic craniofacial features include brachycephaly, high anterior hairline, deeply set eyes, ptosis, downslanted palpebral fissures, high palate with torus palatinus, broad jaw, and large ears with small or absent lobes. Radiographic features include calcification of the external ear cartilage, multiple wormian bones, platybasia, bathrocephaly, slender bones with exaggerated metaphyseal flaring, mild epiphyseal dysplasia, and spondylar dysplasia. Additional features include hearing impairment, ocular anomalies, cryptorchidism, and nonspecific findings on brain MRI.

Diagnosis/testing.

The diagnosis of Primrose syndrome is established in a proband with characteristic features and a heterozygous pathogenic variant in ZBTB20 identified on molecular genetic testing.

Management.

Treatment: Individualized educational program, speech therapy, physical therapy, and occupational therapy as indicated; treatment of behavioral concerns; applied behavioral analysis for autism; standard treatment for seizures, musculoskeletal issues, hearing loss, and thyroid dysfunction; oral hypoglycemics or insulin as needed for diabetes.

Surveillance: Monitor growth and development every six months; speech and developmental assessment every six months; assess for behavioral issues, seizures, and musculoskeletal complications at each visit; brain stem evoked response audiometry annually; annual fasting and postprandial blood glucose, hemoglobin A1c, and assessment for signs and symptoms of thyroid dysfunction.

Genetic counseling.

Primrose syndrome is an autosomal dominant disorder. All probands reported to date with Primrose syndrome whose parents have undergone molecular genetic testing have the disorder as a result of a de novo ZBTB20 pathogenic variant. If a parent of the proband is known to have the ZBTB20 pathogenic variant identified in the proband, the risk to the sibs of inheriting the variant is 50%. Once the ZBTB20 pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.

Suggestive Findings

Primrose syndrome should be suspected in individuals with the following clinical, laboratory, and imaging findings.

Clinical findings

• Developmental delay with speech delay
• Intellectual disability
• Behavioral issues (e.g., autism spectrum disorder, attention-deficit/hyperactivity disorder)
• Typically postnatal-onset macrocephaly (macrocephaly at birth in <50%)
• Characteristic craniofacial features (brachycephaly, high anterior hairline, sparse eyebrows, deeply set eyes, downslanted palpebral fissures, ptosis, high palate, torus palatinus, broad jaw, and large ears with small or absent lobes; see Figure 1)
• Hearing loss
• Ocular anomalies (e.g., cataracts, strabismus, glaucoma)
• Cryptorchidism
• Distal muscle atrophy and contractures
• Sparse body hair

Figure 1.

Male age two years with Primrose syndrome Note macrocephaly, high anterior hairline, sparse eyebrows, deeply set eyes, large prominent ears, and genu valgum.

Laboratory findings

• Abnormal plasma acylcarnitine profile (increased levels of C2, C4OH, C5OH, C6OH, C14, and C14:2).
• Abnormal urine organic acids (mildly elevated dicarboxylic acids (adipic, sebacic, and/or suberic acid); elevated ethylmalonic acid and glutaric acid)
• Abnormal glucose metabolic profile (e.g., elevated fasting glucose, hemoglobin A1c, and glucose levels on oral glucose tolerance testing)
• Increased serum alphafeto protein levels

Imaging findings

• Calcification of the external ear cartilage on head CT; cerebral calcification (mainly of the basal ganglia) may also occur.
• Radiographs show unique skeletal manifestations: multiple wormian bones, platybasia, bathrocephaly, bitemporal bossing, slender bones with exaggerated metaphyseal flaring, mild epiphyseal dysplasia, and spondylar dysplasia.
• Brain MRI may show agenesis/dysgenesis of the corpus callosum, mild cerebral atrophy, and delayed myelination.

Establishing the Diagnosis

The diagnosis of Primrose syndrome is established in a proband with suggestive findings and a heterozygous pathogenic (or likely pathogenic) variant in ZBTB20 identified by molecular genetic testing (see Table 1).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants. (2) Identification of a heterozygous ZBTB20 variant of uncertain significance does not establish or rule out the diagnosis.

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in suggestive findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those with a phenotype indistinguishable from many other inherited disorders with developmental delay and/or macrocephaly are more likely to be diagnosed using genomic testing (see Option 2).

Clinical Description

Primrose syndrome is a rare disorder characterized by macrocephaly with developmental delay, intellectual disability, behavioral issues, a recognizable facial phenotype, altered glucose metabolism, hearing loss, ocular anomalies, cryptorchidism, and unique imaging findings including calcification of the ear cartilage [Arora et al 2020, Melis et al 2020].

To date, 52 individuals have been identified with a pathogenic variant in ZBTB20 [Arora et al 2020, Melis et al 2020]. The following description of the phenotypic features associated with this condition is based on these reports.

Growth. Although historically described as an overgrowth syndrome, length at birth >+2SD was only reported in 1/22 newborns, height was >+2SD in 3/25 children (12%), and height was >+2SD in 0/9 adults [Melis et al 2020].

The majority of affected individuals have macrocephaly. Head circumference >+2SD at birth was seen in 9/22 newborns, 21/26 children (81%), and 8/12 adults (67%).

Characteristic craniofacial features become evident in early childhood and include brachycephaly, high anterior hairline, deeply set eyes, ptosis, downslanted palpebral fissures, high palate with torus palatinus, broad jaw, and large ears with small or absent lobes.

Motor development is impaired by childhood hypotonia, but almost all individuals achieve independent walking by age two to three years. Delayed motor development is found in almost all individuals [Cleaver et al 2019].

Cognitive development. Intellectual disability (ID) has been reported in all individuals. Most individuals have moderate-to-severe ID, while approximately 15% have mild ID. Severe expressive speech delay is common with minimal development of expressive speech in most individuals. Most individuals have better receptive language development; thus, sign language or use of pictograms is of value to many affected individuals [Battisti et al 2002, Carvalho & Speck-Martins 2011, Melis et al 2020].

Behavior abnormalities include attention-deficit/hyperactivity disorder, temper tantrums, self-injurious behavior, sleep disturbances, and autism spectrum disorder [Stellacci et al 2018, Melis et al 2020].

Seizures have been identified in 22% of individuals. Focal seizures were clinically described in two individuals and were controlled with anti-seizure medication. In the remaining individuals with seizures, the type of seizure was not reported.

Progressive musculoskeletal and motor involvement. Distal muscle wasting is a common feature with lower limbs more affected than the upper limbs. Flexion contractures are seen in the knees and the elbows. Genu valgum and/or genu varum have been reported. Dysplastic hips were also reported by Melis et al [2020]. This results in difficultly walking and eventually wheelchair dependence. Progressive ataxia is rare and is associated with spasticity.

Hearing loss is common (21/27 children and 12/13 adults) and is prelingual. Hearing loss is generally mild to moderate sensorineural hearing loss, although a mixed type of hearing loss was reported in one individual who had recurrent ear infections.

Brain imaging findings include agenesis/dysgenesis of the corpus callosum, mild cerebral atrophy, delayed myelination, and cerebral calcification (mainly involving the basal ganglia).

Endocrine manifestations

• Individuals with Primrose syndrome have disrupted glucose metabolism and may develop diabetes mellitus requiring oral hypoglycemics and/or insulin therapy in adulthood.
• Rarely, congenital hypothyroidism has been reported [Mattioli et al 2016]. Three instances of childhood-onset hypothyroidism have also been reported.
• Growth hormone deficiency (2 individuals)
• Delayed puberty (average onset of puberty: age 16 years)
• Sparse body hair is present in both males and females

Cryptorchidism also has been reported in half of all affected males [Melis et al 2020].

Ocular anomalies. Cataracts may be congenital or may appear later in adulthood; strabismus and glaucoma are also seen. Microphthalmia was reported in two individuals.

Other

• Pulmonary artery stenosis was described in an adult [Melis et al 2020].
• IgG2 deficiency with recurrent otitis media and testicular cancer was diagnosed at age 27 years in one individual [Yamamoto-Shimojima et al 2020].

Life expectancy. Longitudinal data are insufficient to determine life expectancy; the oldest reported individual is age 53 years [Dalal et al 2010].

Genotype-Phenotype Correlations

No genotype-phenotype correlations have been identified.

Penetrance

The penetrance is 100%.

Nomenclature

The authors of this GeneReview suggest the term "intellectual disability-cataracts-calcified pinnae-macrocephaly syndrome" as an alternative name for Primrose syndrome.

Prevalence

To date, approximately 52 individuals with Primrose syndrome have been identified.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with Primrose syndrome, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

Surveillance

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Mode of Inheritance

Primrose syndrome is an autosomal dominant disorder.

Risk to Family Members

Parents of a proband

• All probands reported to date with Primrose syndrome whose parents have undergone molecular genetic testing have the disorder as a result of a de novo ZBTB20 pathogenic variant.
• Molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling.
• If the pathogenic variant identified in the proband is not identified in either parent, the following possibilities should be considered:
  • The proband has a de novo pathogenic variant. Note: A pathogenic variant is reported as "de novo" if: (1) the pathogenic variant found in the proband is not detected in parental DNA; and (2) parental identity testing has confirmed biological maternity and paternity. If parental identity testing is not performed, the variant is reported as "assumed de novo" [Richards et al 2015].
  • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.

Sibs of a proband. The risk to the sibs of the proband depends on the genetic status of the proband's parents:

• If a parent of the proband is known to have the ZBTB20 pathogenic variant identified in the proband, the risk to the sibs of inheriting the variant is 50%.
• If the ZBTB20 pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [Rahbari et al 2016].

Offspring of a proband. Individuals with Primrose syndrome are not known to reproduce; however, many are not yet of reproductive age.

Other family members. Given that all probands with Primrose syndrome reported to date have the disorder as a result of a de novo ZBTB20 pathogenic variant, the risk to other family members is presumed to be low.

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals.

Prenatal Testing and Preimplantation Genetic Testing

Once the ZBTB20 pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

Primrose syndrome is caused by functional dysregulation of ZBTB20, a transcriptional repressor controlling energetic metabolism and developmental programs. ZBTB20 is a transcriptional repressor involved in the control of brain development and glucose metabolism [Sutherland et al 2009]. This protein belongs to the Broad-complex, Tramtrack, and Bric-a-brac zinc finger (BTB-ZF) family of transcription factors [Zhang et al 2015]. The N-terminal BTB domain participates in protein-protein interaction, whereas five C2H2 zinc fingers at the C terminus mediate binding to promoters of target genes.

Mechanism of disease causation. A dominant-negative mechanism has been proposed [Stellacci et al 2018].

Author Notes

Dr Veronica Arora, Associate consultant, Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital, New Delhi, India

Dr Carlos R Ferreira, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA

Dr Ratna Dua Puri, Chairperson and Senior consultant, Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital, New Delhi, India

Dr Ishwar Chander Verma, Advisor, Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital, New Delhi, India

Revision History

• 17 June 2021 (ma) Revision: modifications to Suggestive Findings; Clinical Description (Table 2)
• 6 May 2021 (sw) Review posted live
• 1 February 2021 (crf) Original submission

References

• Arora V, Leon E, Diaz J, Hove HB, Carvalho DR, Kurosawa K, Nishimura N, Nishimura G, Saxena R, Ferreira C, Puri RD, Verma IC. Unique skeletal manifestations in patients with Primrose syndrome. Eur J Med Genet. 2020;63:103967. [PMC free article: PMC9445699] [PubMed: 32473227]
• Battisti C, Dotti MT, Cerase A, Rufa A, Sicurelli F, Scarpini C, Federico A. The Primrose syndrome with progressive neurological involvement and cerebral calcification. J Neurol. 2002;249:1466–8. [PubMed: 12532939]
• Carvalho DR, Speck-Martins CE. Additional features of unique Primrose syndrome phenotype. Am J Med Genet. 2011;155A:1379–83. [PubMed: 21567911]
• Cleaver R, Berg J, Craft E, Foster A, Gibbons RJ, Hobson E, Lachlan K, Naik S, Sampson JR, Sharif S, Smithson S, Parker MJ, Tatton-Brown K, 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;179:344–9. [PubMed: 30637921]
• Dalal P, Leslie ND, Lindor NM, Giulbert DL, Espay AJ. Motor tics, stereotypies, and self-flagellation in Primrose syndrome. Neurology. 2010;75:284–6. [PMC free article: PMC3463006] [PubMed: 20644156]
• Juven A, Nambot S, Piton A, Jean-Marçais N, Masurel A, Callier P, Marle N, Mosca-Boidron AL, Kuentz P, Philippe C, Chevarin M, Duffourd Y, Gautier E, Munnich A, Rio M, Rondeau S, El Chehadeh S, Schaefer É, Gérard B, Bouquillon S, Delorme CV, Francannet C, Laffargue F, Gouas L, Isidor B, Vincent M, Blesson S, Giuliano F, Pichon O, Le Caignec C, Journel H, Perrin-Sabourin L, Fabre-Teste J, Martin D, Vieville G, Dieterich K, Lacombe D, Denommé-Pichon AS, Thauvin-Robinet C, Faivre L. Primrose syndrome: a phenotypic comparison of patients with a ZBTB20 missense variant versus a 3q13.31 microdeletion including ZBTB20. Eur J Hum Genet. 2020;28:1044–55. [PMC free article: PMC7382504] [PubMed: 32071410]
• Mattioli F, Piton A, Gérard B, Superti-Furga A, Mandel JL, Unger S. Novel de novo mutations in ZBTB20 in Primrose syndrome with congenital hypothyroidism. Am J Med Genet A. 2016;170:1626–9. [PubMed: 27061120]
• Melis D, Carvalho D, Barbaro-Dieber T, Espay AJ, Gambello MJ, Gener B, Gerkes E, Hitzert MM, Hove HB, Jansen S, Jira PE, Lachlan K, Menke LA, Narayanan V, Ortiz D, Overwater E, Posmyk R, Ramsey K, Rossi A, Sandoval RL, Stumpel C, Stuurman KE, Cordeddu V, Turnpenny P, Strisciuglio P, Tartaglia M, Unger S, Waters T, Turnbull C, Hennekam RC. Primrose syndrome: characterization of the phenotype in 42 patients. Clin Genet. 2020;97:890–901. [PMC free article: PMC7384157] [PubMed: 32266967]
• Rahbari R, Wuster A, Lindsay SJ, Hardwick RJ, Alexandrov LB, Turki SA, Dominiczak A, Morris A, Porteous D, Smith B, Stratton MR, Hurles ME, et al. Timing, rates, and spectra of human germline mutation. Nat Genet. 2016;48:126–33. [PMC free article: PMC4731925] [PubMed: 26656846]
• Rasmussen MB, Nielsen JV, Lourenço CM, Melo JB, Halgren C, Geraldi CV, Marques W Jr, Rodrigues GR, Thomassen M, Bak M, Hansen C, Ferreira SI, Venâncio M, Henriksen KF, Lind-Thomsen A, Carreira IM, Jensen NA, Tommerup N. Neurodevelopmental disorders associated with dosage imbalance of ZBTB20 correlate with the morbidity spectrum of ZBTB20 candidate target genes. J Med Genet. 2014;51:605–13. [PubMed: 25062845]
• Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405–24. [PMC free article: PMC4544753] [PubMed: 25741868]
• Shuvarikov A, Campbell IM, Dittwald P, Neill NJ, Bialer MG, Moore C, Wheeler PG, Wallace SE, Hannibal MC, Murray MF, Giovanni MA, Terespolsky D, Sodhi S, Cassina M, Viskochil D, Moghaddam B, Herman K, Brown CW, Beck CR, Gambin A, Cheung SW, Patel A, Lamb AN, Shaffer LG, Ellison JW, Ravnan JB, Stankiewicz P, Rosenfeld JA. Recurrent HERV-H-mediated 3q13.2-q13.31 deletions cause a syndrome of hypotonia and motor, language, and cognitive delays. Hum Mutat. 2013;34:1415–23. [PMC free article: PMC4599348] [PubMed: 23878096]
• Stellacci E, Steindl K, Joset P, Mercurio L, Anselmi M, Cecchetti S, Gogoll L, Zweier M, Hackenberg A, Bocchinfuso G, Stella L, Tartaglia M, Rauch A. Clinical and functional characterization of two novel ZBTB20 mutations causing Primrose syndrome. Hum Mutat. 2018;39:959–64. [PubMed: 29737001]
• Stenson PD, Mort M, Ball EV, Chapman M, Evans K, Azevedo L, Hayden M, Heywood S, Millar DS, Phillips AD, Cooper DN. The Human Gene Mutation Database (HGMD®): optimizing its use in a clinical diagnostic or research setting. Hum Genet. 2020;139:1197–207. [PMC free article: PMC7497289] [PubMed: 32596782]
• Sutherland AP, Zhang H, Zhang Y, Michaud M, Xie Z, Patti ME, Grusby MJ, Zhang WJ. Zinc finger protein Zbtb20 is essential for postnatal survival and glucose homeostasis. Mol Cell Biol. 2009;29:2804–15. [PMC free article: PMC2682054] [PubMed: 19273596]
• Wiśniowiecka-Kowalnik B, Kastory-Bronowska M, Bartnik M, Derwińska K, Dymczak-Domini W, Szumbarska D, Ziemka E, Szczałuba K, Sykulski M, Gambin T, Gambin A, Shaw CA, Mazurczak T, Obersztyn E, Bocian E, Stankiewicz P. Application of custom-designed oligonucleotide array CGH in 145 patients with autistic spectrum disorders. Eur J Hum Genet. 2013;21:620–5. [PMC free article: PMC3658201] [PubMed: 23032108]
• Yamamoto-Shimojima K, Imaizumi T, Akagawa H, Kanno H, Yamamoto T. Primrose syndrome associated with unclassified immunodeficiency and a novel ZBTB20 mutation. Am J Med Genet A. 2020;182:521–6. [PubMed: 31821719]
• Zhang H, Cao D, Zhou L, Zhang Y, Guo X, Li H, Chen Y, Spear BT, Wu JW, Xie Z, Zhang WJ. ZBTB20 is a sequence-specific transcriptional repressor of alpha-fetoprotein gene. Sci Rep. 2015;5:11979. [PMC free article: PMC4648434] [PubMed: 26173901]