ESPE Abstracts

Background: Achondroplasia (ACH) is an autosomal dominant condition, resulting from pathogenic missense FGFR3 (fibroblast-growth-factor receptor-3) variants. Foramen magnum stenosis (FMS) is a severe complication, with infants and younger children being at higher risk. FMS may be asymptomatic or cause cervical-medullary compression (CMC), presenting with hydrocephalus, hypotonia or hypertonia, central sleep apnea and sudden death. The scope of the study is to describe the incidence of FMS in a series of children with ACH and make associations with neurological sequelae, and cardiorespiratory sleep studies (CRS).

Patients & Methods: We retrospectively reviewed medical records and imaging of children with ACH attending the Division of Endocrinology. Craniovertebral junction (CVJ) abnormalities, were graded as AFMS0-4, according to the Achondroplasia Foramen Magnum Score (AFMS), using Magnetic Resonance Imaging (MRI). Sleep-disordered breathing was assessed with CRS (nocturnal desaturation, and/or sleeping polysomnography).

Results: During the study, 10 ACH patients were assessed (7 males, 3 females). The age range at their first appointment was 40 days-14^6/12 years. In 80% of individuals ACH was caused by a de novo FGFR3 p.Gly380Arg (c.1138G>A) gain-of-function variant, whereas the remaining 20% were two siblings who inherited the variant from their affected mother. In all patients the disease was suspected antenatally, due to features detected on fetal ultrasound. First brain and cervical spine MRI was performed at mean age 3.319±2.65 years. Interestingly, most of the older patients had not undergone surveillance MRI before attending the Bone Clinic. Mean age of FMS presence was 4.66±3.31 years. AFMS3 with cord compression was assigned to 3 patients (mean age 2.53±0.8 years). One patient was diagnosed with AFMS4, at the age of 14^7/12 years, and was referred to neurosurgeon, as he exhibited tingling of extremities. Snoring or sleep apnoea were subjectively reported in six patients, whereas CRS screening revealed abnormal sleeping breathing in four patients. AFMS0 was associated with normal CRS results, although one infant at the age of 7 months exhibited mild apnoea-hypopnea (1.7 episodes/hour). AFMS3 was associated with mild apnoea-hypopnea, with 2.2-3.3 episodes/hour. Abnormal speech and gross motor developmental milestones were associated with AFMS3/4 and/or significant ventriculomegaly. AFMS0/1 was not strongly associated with developmental milestones, and neurological examination.

Conclusion: In agreement with previous publications the severity of FMS clinical manifestations (neurological sequelae, sleep-disordered breathing patterns) do not necessarily correlate with AFMS. Thus, early and routine surveillance with MRIs should be incorporated in ACH follow-up, as patients could benefit from early intervention.