Stromme Syndrome

A number sign (#) is used with this entry because of evidence that Stromme syndrome (STROMS) is caused by compound heterozygous mutation in the CENPF gene (600236) on chromosome 1q41.

Description

Stromme syndrome is an autosomal recessive congenital disorder affecting multiple systems with features of a ciliopathy. Affected individuals typically have some type of intestinal atresia, variable ocular abnormalities, microcephaly, and sometimes involvement of other systems, including renal and cardiac. In some cases, the condition is lethal in early life, whereas other patients show normal survival with or without mild cognitive impairment (summary by Filges et al., 2016).

Clinical Features

Stromme et al. (1993) reported 2 sisters, the offspring of healthy, unrelated parents, who had apple peel jejunal atresia (see 243600), severe microcephaly, and ocular abnormalities. Both had normal karyotypes, and neither had evidence of mental retardation. Filges et al. (2016) reported follow-up of the sisters reported by Stromme et al. (1993) when they were in their early twenties. Both had mild cognitive impairment noted during the preschool years (IQ of 70 and 83, respectively), but attended regular school and were meaningfully employed. Both experienced small intestinal dysfunction with clinical signs of malabsorption with lipid-laden feces and failure to gain weight. Both had ocular problems more severe in 1 eye, including microcornea, sclerocornea with superior and temporal iris coloboma, optic nerve hypoplasia, and microcornea with corneal anterior synechia that induced corneal astigmatism, and tortuous retinal blood vessels. Each woman had one eye with good vision.

Bellini et al. (2002) reported a case with this association and cited 2 others from the literature (Slee and Goldblatt, 1996; Stromme and Andersen, 1997). Their patient, a male infant born at term to unrelated parents, was noted at birth to have microcephaly and micrognathia. High jejunal atresia with 'apple peel' deformity and colonic malrotation was surgically identified. Bilateral corneal leukomas were present, but ultrasound examination showed normal retina and optic nerves. An MRI of the brain at 2 months of age showed a microcephalic brain with normal myelination and without malformations or hydrocephalus. Head CT did not show cranial calcifications. High resolution karyotype and renal and cardiac ultrasound examinations were normal. TORCH studies were negative. At 4 months of age, his neurologic exam was normal except for slightly increased tone.

Keegan et al. (2004) described a patient with microcephaly, jejunal atresia, aberrant right tracheobronchial tree, mild left blepharoptosis, and corectopia, left sectoral iris stromal hypoplasia and peripheral anterior synechia, and 46,XY sex reversal. The patient represented a multiple anomaly disorder similar to intestinal atresia/ocular anomalies/microcephaly syndrome but incorporating 46,XY sex reversal with testicular tissue as an additional feature.

Van Bever et al. (2008) reported a 1-year-old girl, born to nonconsanguineous parents, who had 'apple peel' jejunal atresia, microcephaly, microphthalmia, and anterior eye chamber abnormalities. Her parents were unaffected and she had a healthy younger sister. Chromosome analysis showed a 46,XX karyotype; no mutations were found in the candidate genes PITX2 (601542), FOXC1 (601090), PAX6 (607108), and MYCN (164840). The authors reviewed the phenotypic findings in the 7 patients reported to date, and suggested that this entity be referred to as Stromme syndrome.

Waters et al. (2015) reported a Caucasian family in which 4 fetuses had an embryonic lethal phenotype reminiscent of a ciliopathy. The fetuses died in midgestation, and autopsy showed hydrocephalus, cerebellar hypoplasia, agenesis of the corpus callosum, duodenal atresia, gastrointestinal malrotation, and renal hypodysplasia. Abnormal craniofacial features included microcephaly, cleft palate, micrognathia, hypertelorism, low-set ears, prominent nose, broad nasal root, and high nasal bridge.

Filges et al. (2016) reported 2 sibs, born of unrelated parents of northern European descent with a severe form of Stromme syndrome. The first affected child, a girl, died 12 days after birth due to multiorgan failure. Prenatal ultrasound showed duodenal obstruction and difference in the right and left orbital diameters. She had microcephaly, large dysplastic ears, deep-set eyes with short palpebral fissures, and broad nasal root and tip. She had multiple intestinal atresias, as well as an accessory spleen, hydronephrosis, persistent foramen ovale, Peters anomaly of the eyes, congenital defects of the anterior chamber of the eye, cataract, and atrophy of the iris villi. Prenatal ultrasound of a subsequent pregnancy showed intestinal atresia and hyperrotation, hypoplastic kidneys, persistent foramen ovale, and left preaxial polydactyly, suggesting recurrence of the condition. The pregnancy was terminated at 22 weeks' gestation. Histologic examination of the heart of the fetus showed myopathic changes, including hypoplastic musculature, small cardiomyocytes with little cytoplasm, and increased binucleated cells.

Ozkinay et al. (2017) reported a 24-month-old girl, born to consanguineous parents, with Stromme syndrome. Craniofacial features included microcephaly, sloped forehead, metopic suture synostosis, large ears, skin tag on the left cheek, long philtrum, micrognathia, and large mouth. Ophthalmologic examination revealed bilateral microphthalmia, corneal clouding, and sclerocornea. Other findings included a secundum atrial septal defect and mild developmental delay. Brain MRI showed lissencephaly. She had no gastrointestinal features. The family history was remarkable for a male sib with similar findings who had died in the neonatal period following surgery for 'apple peel' jejunal atresia.

Clinical Variability

Waters et al. (2015) reported a patient with microcephaly and mild to moderate learning disabilities who was compound heterozygous for 2 truncating mutations in the CENPF gene (600236.0001 and 600236.0003). Other body systems were unaffected and overall growth was normal.

Inheritance

The transmission pattern of Stromme syndrome in the families reported by Waters et al. (2015) and Filges et al. (2016) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 4 affected fetuses from a nonconsanguineous Caucasian family with Stromme syndrome, Waters et al. (2015) identified compound heterozygous mutations in the CENPF gene (600236.0001 and 600236.0002). The mutations were found by whole-exome sequencing. Exome sequencing of the CENPF gene in 1,000 patients with microcephaly further identified 1 patient who was compound heterozygous for 2 truncating mutations (600236.0001 and 600236.0003). Renal epithelial cells from the fetuses from the first family showed that the cilia were shortened compared to controls, consistent with defective ciliogenesis.

In 2 sets of sibs from 2 unrelated and nonconsanguineous families of European descent with Stromme syndrome, Filges et al. (2016) identified compound heterozygous truncating mutations in the CENPF gene (600236.0001; 600236.0004-600236.0006). The mutations were found by whole-exome sequencing. One of the families had previously been reported by Stromme et al. (1993). The phenotype was highly variable: the 2 sisters reported by Stromme et al. (1993) were alive in their early twenties with minimal impairment, whereas the 2 sibs in the second family had multiple organ involvement and died early in life or were severely affected in utero necessitating termination of the pregnancy. All mutations were predicted to result in complete loss of function, but functional studies of the variants and studies of patient cells were not performed. The findings indicated that Stromme syndrome can be considered a ciliopathy.

In 2 sibs, born to consanguineous parents, with Stromme syndrome, Ozkinay et al. (2017) identified a homozygous frameshift mutation in the CENPF gene (600236.0007). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the phenotype in the family. Ozkinay et al. (2017) proposed that variability in clinical features in the 2 sibs with the same mutation suggested that other modifying factors may be at play, rather than the phenotype being dependent on the amount of protein produced.

Animal Model

Waters et al. (2015) found that morpholino knockdown of cenpf in zebrafish embryos resulted in decreased survival and a ciliopathy phenotype, including axis curvature defects, abnormal heart looping, hydrocephalus, and pronephric cysts. Mutant zebrafish also showed left-right patterning defects and shortened Kupffer vesicle cilia compared to controls.