Primrose Syndrome

A number sign (#) is used with this entry because of evidence that Primrose syndrome (PRIMS) is caused by heterozygous mutation in the ZBTB20 gene (606025) on chromosome 3q13.

Description

Primrose syndrome consists of recognizable facial features, macrocephaly, mental retardation, enlarged and calcified external ears, sparse body hair, and distal muscle wasting (summary by Carvalho and Speck-Martins, 2011).

Patients with a deletion syndrome involving 3q13.31 (615433) exhibit features overlapping those of Primrose syndrome.

Clinical Features

Primrose (1982) described the single case of a 33-year-old male with mental retardation who had been institutionalized from the age of 12 years. The parents were not related. He showed progressive wasting of the distal muscles of the legs and later of the small muscles of the hands. The cartilage of each pinna was extensively ossified, and photographs showing a fracture were presented. Cystic changes were observed in the head of the humerus and of the femurs, with deformity or destruction of the articular surfaces. Bilateral circumscribed, whitish, paracentral posterior polar cataracts were also described. He had had recurrent attacks of bilateral otitis media and was somewhat deaf. There was a 'hard mass filling in the cavity of the hard palate' which was not radioopaque. The same condition may have been described by Collacott et al. (1986). Their patient had large, calcified pinnae, and the buccal cavity was reduced by a large, soft-tissue mass extending over the inferior surface of the hard palate. Both lower limbs were wasted distally, and the hands were small and wasted. He had had recurrent attacks of otitis media and was profoundly deaf; he had dense bilateral cataracts.

Lindor et al. (1996) described a third affected male who also had schizophrenia.

Mathijssen et al. (2006) described a mentally retarded adult man who had joint contractures, sparse body hair, hearing loss, dysmorphic facial features, and, as cardinal features suggesting Primrose syndrome, large calcified pinnae and a huge torus palatinus. In addition, he developed a germ cell tumor of his right testicle at age 27 years. It was uncertain whether an increased risk of malignancy forms part of this syndrome or is only a consequence of cryptorchidism in the patient reported.

Dalal et al. (2010) reported a 43-year-old woman with all the clinical elements of Primrose syndrome who remained undiagnosed for over 4 decades. She was born with congenital heart disease, hip dysplasia, and agenesis of the corpus callosum. In childhood, she was noted to have hearing impairment, cataracts, neoplasm of the bone in the palate, ossification of cartilage, cystic bone changes, diabetes mellitus, and hypothyroidism. She walked at age 6 years and was severely mentally retarded. She slowly lost the ability to walk, had distal muscle wasting, and needed a wheelchair by age 40. She had dysmorphic facial features, including micrognathia, anteverted nares, prominent ears and nasal root, ptosis, and microphthalmia. She also had spastic paraparesis, areflexia, motor tics, hand stereotypies, and self-flagellating behaviors. Brain MRI showed partial calcification of the basal ganglia, and laboratory studies showed increase serum calcitonin. Microarray analysis detected a small 225.5-kb deletion on chromosome 11p between rs12275693 and rs1442927 encompassing the BBOX1 gene (603312). Dalal et al. (2010) postulated an abnormality in calcium homeostasis.

Carvalho and Speck-Martins (2011) described a 23-year-old Brazilian man, born of nonconsanguineous parents, who had mental retardation and developmental delay, macrocephaly, wide forehead, broad face, deeply set eyes, downslanting palpebral fissures with mild ptosis, large ears, high nasal bridge, large jaw, and apparently small mouth. The ears were unusually firm and immobile. He had thoracic kyphosis but no scoliosis, and genu valgum with distal muscle wasting of the lower extremities was apparent. Ankles and elbows had mild reduction of mobility. He also displayed sparse body hair and thin, dystrophic fingernails and toenails. There was scaly, thickened skin over extensor joint surfaces, and a great number of pigmented nevi as well as some striae were present. Examination at 23 years of age showed poor coordination and mild bradykinesia, but follow-up over 2 decades did not reveal progressive neurologic involvement. Hearing loss was not clinically noticeable, but audiometric evaluation detected a bilateral moderate mixed hearing loss. Skeletal x-rays showed calcification of the ear cartilages, thoracic kyphosis, and sloping ribs; osteopenia was not noted. CT of the head revealed uniform and extensive calcification of both pinnae and part of the external ear canals, with no brain calcification. Echocardiography showed signs of concentric left ventricular remodeling. Carvalho and Speck-Martins (2011) reviewed the key features of the 7 reported patients with Primrose syndrome, noting that all cases had been sporadic, with no familial occurrence or consanguinity.

Posmyk et al. (2011) reported a 27-year-old man with Primrose syndrome who had only mild mental retardation. He also exhibited hypergonadotropic hypogonadism and low bone density due to progressive osteoporosis. Posmyk et al. (2011) stated that their findings confirmed that Primrose syndrome is a progressive neurodegenerative disorder with late-onset neurologic signs.

Cordeddu et al. (2014) studied 8 individuals with Primrose syndrome, 5 of whom had previously been described in detail (Battisti et al., 2002; Mathijssen et al., 2006; Dalal et al., 2010; Carvalho and Speck-Martins, 2011; Posmyk et al., 2011), and all of whom had mutations in the ZBTB20 gene. Mutation-positive patients exhibited a consistent phenotype characterized by increased growth, variable intellectual disability, autistic traits and other behavioral problems, hypotonia, and distinctive facial features overlapping with the phenotype of the 3q13.31 deletion syndrome (615433). However, the phenotype in the Primrose syndrome patients was more severe, including disturbances of glucose metabolism with insulin-resistant diabetes occurring in adulthood, distal muscle wasting resulting in contractures in adulthood, and hearing loss and ectopic calcification of the ears and brain during puberty or early adulthood.

Battisti et al. (2002) reported a 49-year-old woman who exhibited the classic features of Primrose syndrome, associated with late-onset progressive gait ataxia, pyramidal signs, and cerebral calcification. Neurologic examination revealed severe mental retardation, frequent confabulation, severely impaired spastic-ataxic gait, positive Romberg sign, slight hypertonia, mild muscular atrophy of the limbs, upper limb areflexia, brisk tendon reflexes in the legs, bilateral ankle clonus, and Babinski sign. Brain CT showed areas of dense calcification in both heads of the caudate nuclei, with less dense calcification in both globi pallidi and in the anterior limb of the left internal capsule; dense calcification of both external ears was also evident. Muscle biopsy was suggestive of neurogenic atrophy. The authors noted that this was the first reported case of a female patient with Primrose syndrome, and suggested that the diagnosis should be considered in patients with syndromic mental retardation plus progressive neurologic involvement, including cerebral calcification, ataxia, and peripheral neuropathy.

Mattioli et al. (2016) studied a 4-year-old boy, ascertained from a cohort of patients with developmental delay, in whom targeted sequencing of candidate genes revealed mutations in the ZBTB20 gene. Reverse phenotyping showed that the patient presented the classic features of Primrose syndrome, including dysmorphic facies, macrocephaly, hearing loss, hypotonia, and hypoplasia of the corpus callosum. His ears were large, but were supple to palpation with no evidence of calcification; the authors noted that calcified pinnae had only been observed in adult cases. In addition, the proband had congenital hypothyroidism, and thyroid scan showed a large volume thyroid gland with homogeneous uptake suggesting a problem in thyroid hormone synthesis. Mattioli et al. (2016) noted that 1 other patient with Primrose syndrome had been reported to have hypothyroidism (Dalal et al., 2010).

Grimsdottir et al. (2019) reported a 14-year old boy with many features of Primrose syndrome, including macrocephaly, intellectual disability, agenesis of the corpus callosum, hearing impairment, and characteristic facial dysmorphology, and a mutation in the ZBTB20 gene. Facial features included downslanting palpebral fissures, low-set ears, flat hypoplastic midface with maxillary retrognathia, relative mandibular prognathism, and a narrow and tapered lower face and chin. The patient also had short stature and did not respond sufficiently to growth hormone therapy. Craniofacial and dental findings not previously reported in Primrose syndrome included large paranasal sinuses, narrow cranial base, decreased cranial base angle, maxillary hypoplasia, a supernumerary tooth, and retention of 2 mandibular premolars.

Inheritance

All reported cases of Primrose syndrome have been sporadic (Lindor et al., 1996).

Molecular Genetics

In 4 unrelated patients with Primrose syndrome, including the patients reported by Mathijssen et al. (2006), Dalal et al. (2010), and Carvalho and Speck-Martins (2011), Cordeddu et al. (2014) performed whole-exome sequencing and identified heterozygosity for de novo missense variants in the ZBTB20 gene (see, e.g., 606025.0001 and 606025.0002); subsequent mutation analysis in 4 more affected individuals, including the patients reported by Battisti et al. (2002) and Posmyk et al. (2011), revealed a heterozygous ZBTB20 missense mutation in each (see, e.g., 606025.0003 and 606025.0004). Functional analysis showed strongly reduced DNA binding for all mutants compared to wildtype, and results were consistent with the mutations having a dominant-negative impact on the wildtype allele. The authors noted that the more severe phenotype seen in Primrose syndrome patients compared to that of patients with 3q13.31 deletion syndrome, who exhibit overlapping but milder features, was in line with a dominant-negative effect of the ZBTB20 mutations compared to the haploinsufficiency that likely underlies the 3q13.31 deletion syndrome.

By targeted exome sequencing of 275 genes known to be or potentially associated with intellectual disability in a cohort of individuals with mild to severe developmental delay, who were negative for pathogenic CNV by array-CGH, Mattioli et al. (2016) identified a 4-year-old boy with Primrose syndrome who was heterozygous for 2 de novo missense mutations on the same allele of the ZBTB20 gene (606025.0005).

In a 14-year-old boy with Primrose syndrome, Grimsdottir et al. (2019) identified heterozygosity for a de novo missense mutation in the ZBTB20 gene (H600Q; 606025.0006). The mutation was found by exome sequencing and confirmed by Sanger sequencing.