Ring chromosome 14 syndrome (r(14) syndrome) is a rare genetic disease with an unknown prevalence. It affects both males and females. Signs of the condition often appear in infancy. R(14) syndrome arises because of alterations to chromosome 14 during the early stages of development, resulting in the formation of an unstable ring chromosome. It is unclear whether this occurs before or after conception [1]. There are numerous ring chromosome syndromes recorded in the literature. A mosaic form of r(14) syndrome has been reported, which exhibits fewer clinical symptoms than the non-mosaic form [2].

One of the main features of r(14) syndrome is early onset epilepsy that is drug resistant and, in some cases, severe [3]. Epilepsy is a feature that has been reported in all affected individuals, and seizures may occur in any form, including generalized, partial, tonic-clonic, myoclonic, or focal [4]. Some patients proceed to status epilepticus. There is now evidence suggesting that the seizures experienced are focal seizures that may or may not progress to generalized convulsions [5]. Often, seizures are hypnagogic, hypnopompic, or occur during sleep. The frequency of the seizures changes as the disease progresses, and some patients may respond partially to drugs.

The R(14) syndrome is also typified by intellectual impairment and developmental delay, including speech delay [6]. Epilepsy that is more severe, or begins at an earlier age, is associated with a higher degree of intellectual impairment in affected individuals [7].

Typical physical manifestations of the disease include hypotonia, microcephaly, flat occiput, flat nasal bridge, anteverted nostrils, high arched palate, prominent epicanthal folds, and low set ears. Short neck or short stature may also be present. The skin and eyes (particularly the retina) may be affected by various pigmentation disorders, which may be observed as discoloration of skin, and retinopathy. There are numerous possible ocular abnormalities, such as strabismus, myopia and, less commonly, microphthalmia and colobomas [6] [8].

Other possible signs and symptoms of the condition include scoliosis, bone diseases and gastrointestinal complaints. Children with r(14) syndrome are at a higher risk of acquiring infections, particularly respiratory infections [9]; these vary in severity, and may require hospitalization.

• Recurrent Respiratory Infections

  Typically, children with this syndrome have distinct facial features, development delay, microcephaly, seizures, ocular abnormalities, and recurrent respiratory infections. [ncbi.nlm.nih.gov]

• Increased Susceptibility to Infections

  Other signs and symptoms may include a small head size (microcephaly), low muscle tone (hypotonia), scoliosis, and increased susceptibility to infections. [malacards.org]

• Painter

  Painter in 1922 was not certain whether the diploid of humans was 46 or 48, at first favouring 46, but revised his opinion from 46 to 48, considering the techniques of the time, these results were remarkable. [wikivisually.com]

• Inflammation

  The adaptive system is composed of more advanced lymphatic cells that are programmed to recognise self substances, the reaction to foreign substances is etymologically described as inflammation, meaning to set on fire. [wikivisually.com]

• Exposure to Benzene

  The frequency of Trisomy 21 has been determined to be a function of Advanced maternal age, in particular, risk of aneuploidy is increased by tobacco smoking, and occupational exposure to benzene and perfluorinated compounds. [wikivisually.com]

• Failure to Thrive

  They showed a phenotype consistent with the “ring syndrome” with failure to thrive, minor dysmporphic features and no major anomalies. [tp.amegroups.com]

• Miosis

  الصفحة 358 - Ocular signs of cerebral involvement include the following: nystagmus, unilateral mydriasis, bilateral miosis with slow response to light, paralysis of accommodation, convergence, and 3rd, 4th, and 6th cranial nerve involvement. ‏ [books.google.com]

• Neonate-Onset

  Brunner, Boris Keren, Julien Thevenon, Laurence Faivre, Gary Thomas and Christel Thauvin-Robinet, A Recurrent De Novo PACS2 Heterozygous Missense Variant Causes Neonatal-Onset Developmental Epileptic Encephalopathy, Facial Dysmorphism, and Cerebellar [doi.org]

• Cognitive Impairment

  Epilepsy is the most common and serious neurological symptom in ring chromosome 14 syndrome, also characterised by mild dysmorphisms, acquired microcephaly, cognitive impairment, hypotonia and ocular abnormalities. [ncbi.nlm.nih.gov]

  This syndrome is also characterized by behavioral problems, mild cognitive impairment and learning disabilities. Tell me more Seizures usually are the first and major clinical symptom of this syndrome& and usually do not respond to medications. [epilepsy.com]

  A recognizable pattern of anomalies characterized by growth retardation, no major malformations except for a few minor anomalies, mild cognitive impairment has been observed in patients with an autosomal ring. [tp.amegroups.com]

• Cranial Nerve Involvement

  الصفحة 358 - Ocular signs of cerebral involvement include the following: nystagmus, unilateral mydriasis, bilateral miosis with slow response to light, paralysis of accommodation, convergence, and 3rd, 4th, and 6th cranial nerve involvement. ‏ [books.google.com]

• Aura

  Moeschler, Aura Janze, Jeanne Meck, Sarah T. South and Erica F. [doi.org]

Definitive diagnosis of ring chromosome 14 syndrome can only be made via genetic testing, such as karyotyping [10]. Although the identification of r(14) syndrome may be challenging, as none of its characteristic features are exclusive to the syndrome, clinicians may begin to suspect and test for it in cases of refractory epilepsy with the occurrence of neurological or psychological symptoms [11]. The recommended cytogenetic test is an array CGH (comparative genomic hybridization) analysis.

Routine labs such as a complete blood count, liver function test, urea and electrolytes, thyroid function tests, are recommended. Radiological examination may involve magnetic resonance imaging (MRI). Neurological, ophthalmologic and psychological examination are also important initial investigations. EEG (electroencephalography) is required, and may reveal slow wave activity with intermittent spiking [4] [5].

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11. Redin C, Gérard B, Lauer J, et al. Efficient strategy for the molecular diagnosis of intellectual disability using targeted high-throughput sequencing. J Med Genet. 2014;51(11):724-736.