Clinical, developmental and serotonemia phenotyping of a sample of 70 Italian patients with Phelan-McDermid Syndrome

Abstract

Background: Phelan-McDermid syndrome (PMS) is caused by monoallelic loss or inactivation at the SHANK3 gene, located in human chr 22q13.33, and is often associated with Autism Spectrum Disorder (ASD).

Objectives: To assess the clinical and developmental phenotype in a novel sample of PMS patients, including for the first time auxometric trajectories and serotonin blood levels.

Methods: 70 Italian PMS patients were clinically characterized by parental report, direct medical observation, and a thorough medical and psychodiagnostic protocol. Serotonin levels were measured in platelet-rich plasma by HPLC.

Results: Our sample includes 59 (84.3%) cases with chr. 22q13 terminal deletion, 5 (7.1%) disruptive SHANK3 mutations, and 6 (8.6%) ring chromosome 22. Intellectual disability was present in 69 (98.6%) cases, motor coordination disorder in 65 (92.9%), ASD in 20 (28.6%), and lifetime bipolar disorder in 12 (17.1%). Prenatal and postnatal complications were frequent (22.9%-48.6%). Expressive and receptive language were absent in 49 (70.0%) and 19 (27.1%) cases, respectively. Decreased pain sensitivity was reported in 56 (80.0%), hyperactivity in 49 (80.3%), abnormal sleep in 45 (64.3%), congenital dysmorphisms in 35 (58.3%), chronic stool abnormalities and especially constipation in 29 (41.4%). Parents reported noticing behavioral abnormalities during early childhood immediately after an infective episode in 34 (48.6%) patients. Brain MRI anomalies were observed in 53 (79.1%), EEG abnormalities in 16 (23.5%), kidney and upper urinary tract malformations in 18 (28.1%). Two novel phenotypes emerged: (a) a subgroup of 12/44 (27.3%) PMS patients displays smaller head size at enrollment (mean age 11.8 yrs) compared to their first year of neonatal life, documenting a deceleration of head growth (p < 0.001); (b) serotonin blood levels are significantly lower in 21 PMS patients compared to their 21 unaffected siblings (P < 0.05), and to 432 idiopathic ASD cases (p < 0.001).

Conclusions: We replicate and extend the description of many phenotypic characteristics present in PMS, and report two novel features: (1) growth trajectories are variable and head growth appears to slow down during childhood in some PMS patients; (2) serotonin blood levels are decreased in PMS, and not increased as frequently occurs in ASD. Further investigations of these novel features are under way.

Keywords: SHANK3; 22q13 deletion syndrome; Autism spectrum disorder; Hyperserotonemia; Intellectual disability; Macrocephaly; Neuroinflammation; Phelan-McDermid syndrome; Phenotype; Serotonin.

Fig. 1

Problem behaviors measured using the Aberrant Behavior Checklist (ABC) (n = 51). Data reported as mean ± SEM score for each ABC subscale (N = 51)

Fig. 2

Percentage of patients above the borderline cut-off for each Child Behavior Checklist (CBCL) subscale: (a) Children up to 5 years of age (n = 15); (b) Children and adolescents 6–18 years old (n = 29)

Fig. 3

Percentile distributions of (A) head circumference, (B) height, and (C) weight, measured at the time of enrollment in our study (black columns) and during the first year of postnatal life (gray columns)

Fig. 4

Structural brain abnormalities observed at the MRI in 67 PMS patients. Data are presented as % of patients (length of each bar referred to the X-axis), whereas numbers at the end of each bar represent patient counts

Fig. 5

A Serotonin levels (ng/ml) measured in platelet-rich plasma of 21 intrafamilial PMS affected-unaffected sibling pairs; B Mean (± SD) serotonin levels measured in 53 PMS patients, 20 PMS unaffected siblings, 432 iASD patients, and 115 unaffected siblings of individuals with iASD. **p < 0.01, ***p < 0.001 after Bonferroni correction