Abstract
A twelve years-old girl was admitted at the pediatric emergency unit for a severe pleuro-pneumopathy. She had a long history of recurrent infections in a complex neurological context. Since birth, she had suffered from an epileptic encephalopathy with West syndrome, severe microcephaly and spastic tetraplegia. Her neurological development was extremely impaired: she was not able to neither hold her head nor develop any voluntary hand use. Moreover, she had a precocious puberty and a progressive worsening of her neurological status. She is bedridden, has very poor visual contact and does not speak.
Brain magnetic resonance imaging (MRI) examination has evidenced a severe microcephaly, without gyral anomalies, cerebral atrophy predominating in the frontal lobes, hypoplasia of the corpus callosum and dysmyelination.
Her older sister and parents are healthy and there is no history of consanguinity in the family.
During the infection mentioned above, the only anomaly at complete blood count (CBC) was an excess of monocytes. Yet, and although the CBC instrument had not indicated any alarm for neutrophils, abnormal granules were observed microscopically in polymorphonuclears on the blood smear (fig. 1). The coarse and purplish granules were toluidine-negative, myeloperoxidase-positive and only present in the polymorphonuclear lineage. The large vacuoles in these cells, also seen in monocytes, are related to the infectious condition of the patient in this context of pleuro-pneumopathy. There was no anomaly of the lymphocytes, and specifically no image recalling storage disease.
Although previous CBC had not led to the identification of these granules, they were systematically investigated for, at high magnification, afterwards, always observed but seemed to increase during each infectious episode. Their appearance suggests a coalescence of smaller granules during infection.
A bone marrow aspiration was performed as the patient underwent surgery for severe scoliosis, at distance from any infectious episode. Abnormal granules were present at all stages of neutrophil maturation (fig. 2).
Nobody in the family presents these abnormal granules. Yet, investigations were performed in search of a congenital syndrome or storage disease: metabolic balance, amino acids chromatography in blood and urine, functional analyses of polymorphonuclears, karyotype, CGH array. No anomaly was disclosed. A skin biopsy looking for inclusions allowed to exclude lipofuscinose. Several other investigations were performed which excluded a lysosomal storage disease.
A whole exome analysis was then decided for the child, parents and sister after obtaining informed consent from the parents. This allowed to discover mutations on both alleles ofthe WDR81 gene in the propositus: a deletion leading to a frame shift in exon 3 and a substitution generating a missense in exon 9 (c.3820_3835del p.Pro1274Thrfs*56 and c.5453G>T p.Gly1818Val respectively). The c.3820_3835del deletion was inherited by the father and the c.5453G>T mutation was inherited by the mother.
The mutations were confirmed by Sanger sequencing and segregated with the expected pattern of autosomal-recessive inheritance in all available family members.
This gene has previously been shown to be associated with cerebral ataxia, intellectual disability and quadrupedal locomotion in patients with homozygous mutations in consanguineous families. Moreover, a murine model with mutation of this gene showed tremor and ataxic gait. Expression of WDR81 was found in neuron of central nervous system included Purkinje cells, photoreceptor cells. All these aspects are consistent with the clinical features of the patient, the severity of her disease being possibly related to the fact that both alleles of the WDR81 gene carry a different mutation.
This also suggests that the double genetic defect observed in the WDR81 in this child is responsible for the peculiar granules appearing early during myeloid maturation. Interestingly, the WDR81 gene contains a BEACH domain on its N terminal portion. This domain was described in the BEIGE protein and the highly homologous CHS protein which are involved in Chediak-Higashi syndromes. Although the patient has none of the phenotypic nor immune characteristics of a Chediak-Higashi syndrome, it is highly likely that involvement of the WDR81 gene is responsible for the formation of such pseudo Chediak abnormal granules.
No relevant conflicts of interest to declare.
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