Autistic symptoms in Greig cephalopolysyndactyly syndrome: a family case report

A 7-year-old Italian white boy affected by GCPS and ASD was referred to our Child Psychiatry Unit for a neuropsychiatric assessment.

The child, born of non-consanguineous white parents, was born at 40 weeks of gestation by vaginal delivery. A previous spontaneous miscarriage was reported. His birth weight was 3070 g (15–50th centile), length 49 cm (15–50th centile), head circumference 34 cm (15–50th centile), and APGAR Index 9–10. He was born with postaxial polysyndactyly of his hands (right hand had two extra fingers, partial syndactyly of finger 5–6; left hand had one extra finger) and of his right foot (one extra toe), surgically corrected at 6 months of age. In the early perinatal period, due to the observed dysmorphic features, the child underwent brain ultrasound (referred as normal) and genetic counseling without specific indication for subsequent genetic screening.

Motor developmental milestones were normally achieved. A history of language delay was reported: first words at 18 months with a following regression of the verbal development. At around 30 months of age, restricted and repetitive behaviors (RRBs), social withdrawal, lack of pretending game together with poor communicative skills were the main parental worries. Based on these clinical features, at 3 years of age a diagnosis of ASD was made and for this reason he started applied behavior analysis (ABA) behavioral therapy (12 hours per week).

The diagnosis of GCPS was clinically suspected in both the child and his father respectively at 3 and 42 years of age, and later molecularly confirmed through direct sequencing and multiplex ligation-dependent probe amplification (MLPA): “heterozygous for the single nucleotide deletion c.3677del, point mutation paternally transmitted, not previously described, localized in gene’s region associated with GCPS, resulting in a truncated GLI3 protein caused by the frameshift mutation and the insertion of a premature stop codon (Pro1226Glnfs4)” (see Fig. 1 for the chromatogram).

Asymmetry of the ventricular supratentorial system (right major representation) and lateral deviation of a septum pellucidum were present on brain magnetic resonance imaging performed at 6 years of age; whereas a routine and sleep-induced electroencephalogram recorded diffused paroxysmal abnormal activity during the falling asleep phase and decreasing during sleep.

No history of clinical seizures was reported. Sleep/wake cycle was regular. Food selectivity was reported since 30 months of age.

On our clinical examination at 7 years and 5 months of age, he weighed 26 kg (50–85th centile), his height was 126 cm (50–85th centile), and his head circumference around was 54.3 cm (98th centile); frontal bossing, a prominent forehead, hypertelorism, a flat nasal bridge, and low-set ears were present. A neurological examination showed normal cranial nerves, and regular muscular tropism and tone. No sensory or autonomic involvement was observed. Deep tendon reflexes of superior and lower limbs were present and normal. The Finger-to-Nose test, performed with open eyes, due to lack of collaboration, showed mild hesitation. A widespread ligament lassitude and a mild deficiency of superior limbs’ strength were observed.

We performed a neuropsychiatric assessment of cognitive, adaptive, socio-communicative, and behavioral skills through standardized tools (see Table 1); in detail, the Leiter International Performance Scale, Third Edition (Leiter-3) [10] and the Coloured Progressive Matrices (CPM) [11] were administered revealing a non-verbal intellectual quotient (IQ) of 71 and inclusion between 10 and 25th centile (range 75–85).

The Adaptive Behavior Assessment System, Second Edition (ABAS-II) [12], a questionnaire filled in by the caregivers evaluating ten adaptive areas organized in four main domains (General Adaptive, Conceptual, Social, Practical), showed adaptive skills below the average in all the fields evaluated (see Table 1).

The previous diagnosis of ASD was confirmed through clinical observation and the administration of the Autism Diagnostic Observation Schedule, Second Edition (ADOS-2), which is the gold standard instrument for the evaluation and diagnosis of autism [13]. We performed Module 1, which is suitable for children beyond 30 months of age with a verbal language composed of single words. The diagnostic algorithm is organized in two main areas: social affect (SA) and RRB. The total score obtained (SA 16 + RRB 7 = 23) exceeded the cut-off (16) for the diagnosis of autism. Finally, a moderate level of ASD symptom severity was measured through the Calibrated Severity Score (ADOS-CSS).

A Social Responsiveness Scale (SRS) [14], a questionnaire filled in by the parents, showed a moderate deficiency of the child’s social relationship, which compromised his general functioning.

Finally, no significant problematic behavior emerged from the caregiver report, Child Behavior Checklist (CBCL) [15], except for a borderline score in the area investigating anxiety problems (see Table 1).

He was born of Italian non-consanguineous white parents with postaxial polydactyly of the hands and of the right foot and congenital clubfoot, which were surgically operated on after birth. No genetic counseling and screening were performed in the perinatal and postnatal period. Developmental milestones were referred as normal. No academic difficulties were reported and he graduated with success. No family history of neuropsychiatric diseases emerged.

Concurrently with the child’s evaluation, we performed a neuropsychological assessment of the 45-year-old father. Until our clinical examination, he had never undergone a psychiatric evaluation. In particular, a cognitive assessment and a specific evaluation of autistic symptoms were performed (see Table 2). His non-verbal IQ, measured by Standard Progressive Matrices (SPM) [16], turned out to be above average (IQ 128). Autistic symptoms were measured with the ADOS-2 [13]. We performed Module 4, which is suitable for adults with fluent speech. The diagnostic algorithm was composed of two main domains: Communication domain (C domain) and Social Relationship domain (SR domain); the algorithm revealed a total score of 5 (C domain 2 + SR domain 3) which does not exceed the general cut-off for the “spectrum” (7) or for “autism” (10). The partial score of the C domain, however, reached the cut-off for the “spectrum” (2).