Strømme syndrome is a very rare autosomal recessive genetic condition characterised by intestinal atresia (in which part of the intestine is missing), eye abnormalities and microcephaly. The intestinal atresia is of the "apple-peel" type, in which the remaining intestine is twisted around its main artery. The front third of the eye is typically underdeveloped, and there is usually moderate developmental delay. Less common features include an atrial septal defect, increased muscle tone or skeletal abnormalities. Physical features may include short stature, large, low-set ears, a small jaw, a large mouth, epicanthic folds, or fine, sparse hair. The syndrome is caused by mutations in both copies of the CENPF gene, which codes for centromere protein F. This protein is involved in cell division, in which it forms part of a disc-shaped protein complex known as a kinetochore. CENPF also has a role in orienting long, cylindrical structures called microtubules to form thin cell protrusions called cilia, which send and receive signals to trigger cell division, migration or differentiation. Mutations in the gene result in slower cell division and some embryonic developmental processes being disrupted or not completed, and the syndrome can be classified as a ciliopathy. The syndrome is typically diagnosed based on the symptoms, but genetic testing provides a full confirmation. Treatment centres around the symptoms. The intestinal atresia is usually surgically correctable in infancy with anastomosis. The prognosis is not yet certain. Those who have survived birth and infancy (the majority) have continued to live through childhood and adolescence, but a large minority with the most severe cases have died before or shortly after birth. The prevalence is not yet known. As of 2017, around 13 individuals had been diagnosed. The syndrome was first identified based on symptoms in two siblings by Norwegian paediatrician Petter Strømme and his associates in 1993. It was named after him in a 2008 study describing another patient. In 2015, mutations in CENPF were first identified as pathogenic, and a 2016 genetic analysis of Strømme's original two siblings found that both had mutations in both of their copies of CENPF, establishing it as the cause of the syndrome.
Signs and symptoms The most common symptoms of Strømme syndrome are intestinal atresia, eye abnormalities and microcephaly. However, the syndrome has a wide range of severity that generally runs in the family it presents in, ranging from only mild learning disability and microcephaly with no other features in some families to death in utero with severe kidney, heart, eye, skeletal, brain and intestinal malformations in others. The variable severity is usually due to the presence or absence in each family of mutations in other genes with similar functions to CENPF.
Intestinal Individuals with Strømme syndrome are typically born with intestinal atresia, in which parts of the intestine are narrow or missing, leading to neonatal bowel obstruction that must be operated on. The intestinal atresia is of the "apple-peel" type, an uncommon type in which the remaining portion of the intestine is found twisted around its main artery, and this usually affects the jejunum. Often, much of the bowel is missing in this form of atresia. There can sometimes also be intestinal malrotation. At least two individuals with the syndrome in literature have avoided intestinal atresia, one of which had a sibling with the same mutations who did not. In two siblings who did not survive to term, the intestinal atresia (which also included duodenal atresia) and malrotation were more severe.
Eyes The eyes are often smaller and underdeveloped, usually more severely in one eye than the other. This can manifest as a coloboma (hole) in the iris, cataracts, opacity of the cornea (leukoma), sclerocornea (in which the white of the eye blends into the cornea), a small cornea (microcornea) and synechia (in which the iris adheres to the cornea or lens). This underdevelopment of the front of the eye, known as anterior segment dysgenesis (which includes Peters' anomaly), can lead to an increased risk of glaucoma from high intraocular pressure, due to impaired eye fluid drainage, though this hadn't been reported in any of the affected individuals as of 2017. There may also be crossing of the eyes (esotropia), and less commonly there may be twisted retinal blood vessels or optic nerve hypoplasia. The eye anomalies can result in an inability to focus (astigmatism) as well as amblyopia, in which the brain begins to fail to process input from the weaker eye during childhood.
Neurological Those affected with the syndrome usually have microcephaly. A large minority also have pachygyria (fewer ridges in the brain) or lissencephaly (shallower ridges). Developmental delay is usually present. It has usually been moderate-to-severe, but in some cases it has been mild. A few of those affected have had increased muscle tone. One individual had cortical heterotopia, which is a sign of impaired neuronal cell migration during neural development. Agenesis or hypoplasia of the corpus callosum and cerebellum have been found in at least one living affected individual and several who did not survive to term. Hydrocephalus occurred in one living individual 9 months after birth and in four who did not survive to term. Hydrocephalus was also observed in zebrafish whose CENPF genes were experimentally knocked out. Cerebellar hypoplasia in association with hydrocephalus can constitute Dandy–Walker malformation, which is found in a number of other ciliopathies, sometimes together with agenesis of the corpus callosum.
Physical features Physical features are variable but usually include short stature, large, low-set ears, a high nasal bridge, a small jaw and a large mouth. Some of those affected have had epicanthal folds or fine, sparse hair. One individual was reported to have been born with a skin tag on the left cheek. Four affected individuals who did not survive to term had cleft palate.
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