ESPE Abstracts

Background and Aims: Coats plus syndrome (MIM # 612199) is a highly pleiotropic disorder particularly affecting brain, eye, bone and gastrointestinal tract. We describe the phenotype of a patient with severe growth failure where whole exome sequencing (WES) revealed compound heterozygosity for two mutations in the CTC1 gene.

Patient and Methods: The patient, the fourth child of healthy non-consanguineous parents, was born SGA (length -5.0 SDS, weight -2.7 SDS) with thumb malformations and bilateral narrowing of external auditory canals. Two siblings are healthy; one malformed sib died in utero. Postnatal growth was poor, IQ 65 and she had suffered five fractures. At 23 yrs she presented with a height of 117.7 cm (-7.0 SDS), progeroid appearance, elevated upper/lower segment ratio (1.2), BMI -2.3 SDS, head circumference -2.0 SDS, breast stage 2, thin skin and hair, microdontia/oligodontia, high palate, right thumb agenesis, left thumb hypoplasia and arthrogryposis. Further investigations showed hypergonadotropic hypogonadism (FSH 118, LH 49 IU/L, estradiol <1 pg/mL); IGF-I 193 ng/mL (ref 18-172); normal GH peak (22.5 ng/mL); bilateral radiohumeral luxofractures; agenesis of right thumb-metacarpal-scaphoid; hypoplasia of left thumb-metacarpal; bicuspid aortic valve; borderline bone mineral density (T-score -1.8 SDS); anemia (11.2 g/dL); uterine size of 34x10x13 cm (no endometrial lining); left ovary 17x9x13 mm (right ovary not visualized); large bilateral calcifications in basal ganglia on brain CT scan. Ophthalmological investigation was normal. Sequencing data of WES of patient and parents were analysed with a stringent post-sequencing annotation pipeline including de novo, X-linked recessive and recessive modes of inheritance filters.

Results: The recessive inheritance filter revealed a paternally (c.1617+5G>T) and maternally (c.724_727del, p.(Lys242Leufs*41)) inherited pathogenic variant in the CTC1 gene. Mutations in this gene are known to cause Cerebroretinal Microangiopathy with Calcifications and Cysts 1 (CRMCC1; Coats plus syndrome). The c.724_727del p.(Lys242Leufs*41) variant has been described in various patients; the c.1617+5G>T variant has not been reported. Splice predict software predicts the loss of the splice donor site which probably results in an in frame skip of exon 10.

Conclusion: Multiple characteristics (progeroid appearance, cerebral calcifications of the basal ganglia, osteopenia, bone anomalies, fractures, growth failure, anemia) are consistent with of Coats plus syndrome, but this patient is the first to present with complete hypogonadism and thumb anomalies. Retinal and gastrointestinal features are absent, confirming the large phenotypic variability of the syndrome. This case also illustrates the importance of WES in the diagnosis of children with extreme short stature.