ESPE Abstracts

Background: Autosomal recessive primary microcephaly (MCPH; “small head syndrome”) is a rare, heterogeneous disease arising from the decreased production of neurons during brain development. 25 genes are implicated in causing MCPH among them the RTTN gene. Here we present the case of a boy from two unrelated parents presenting with a complex phenotype carrying a novel mutation in the RTTN gene.

Case Presentation: A child was born prematurely at 32 weeks + 3/7, weighing 1570 gr (-0.52 SD) and measuring 39 cm (-1.39SD) in length, with a head circumference of 28.5 cm (-0.95SD). Micropenis was noted at birth. Congenital adrenal hyperplasia was ruled out. Cerebral ultrasound revealed a thin corpus callosum, poorly represented sulci and gyri, and bilateral choroid plexus cysts, prompting an MRI. Motor milestones were slightly delayed, and there was language delay. Auditory brainstem response (ABR) showed mild bilateral latency delay of wave V. EEG and ophthalmological assessments were normal. At age 1, brain MRI indicated partial agenesis of the corpus callosum, altered mesial hemispheric sulcation, and sequelae of germinal matrix hemorrhage. By age 3.3, the child had severe short stature (79.3 cm, -4.25 SDS) and microcephaly (46 cm, -2.37 SD). Pubertal stage was PH1, G1 with left mono-lateral cryptorchidism. Distinctive facial features included arched eyebrows, low-set ears, sunken nasal bridge, a thin upper lip, and clinodactyly of the fifth finger. GH deficiency was ruled out.

Methods: Array-CGH and whole exome sequencing (WES) analyses were performed.

Results: Array-CGH do not showed any pathological variants. WES identified a novel homozygous missense variation in the RTTN gene (p.His935Arg), with one allele maternally inherited and the other de novo. The variant is indeed causative as fully recapitulate clinical characteristics of the patients carrying this type of mutation.

Conclusion: this study expands the phenotypic spectrum of RTTN-associated disease and ciliary dysfunction by identifying a homozygous mutation associated with post-natal progressive severe microcephaly and altered gyrification casing mild developmental delay and dwarfism. The patient also presented micropenis with cryptorchidism, a novel feature not previously reported in literature.