The Eight and a Half Year Journey of Undiagnosed AD: Gene Sequencing and Funding of Advanced Genetic Testing Has Led to Hope and New Beginnings.

BACKGROUND: Activity-dependent neuroprotective protein (ADNP) is one of the most prevalent de novo mutated genes in syndromic autism spectrum disorders, driving a general interest in the gene and the syndrome. AIM: The aim of this study was to provide a detailed developmental case study of ADNP p.Tyr719* mutation toward improvements in (1) diagnostic procedures, (2) phenotypic scope, and (3) interventions. METHODS: Longitudinal clinical and parental reports. RESULTS: AD (currently 11-year-old) had several rare congenital anomalies including imperforate anus that was surgically repaired at 2 days of age. Her findings were craniofacial asymmetries, global developmental delay, autistic behaviors (loss of smile and inability to make eye contact at the age of 15 months), and slow thriving as she gradually matures. Comprehensive diagnostic procedures at 3 years resulted in no definitive diagnosis. With parental persistence, AD began walking at 3.5 years (skipping crawling). At the age of 8.5 years, AD was subjected to whole exome sequencing, compared to the parents and diagnosed as carrying an ADNP p.Tyr719* mutation, a causal recurring mutation in ADNP (currently ~17/80 worldwide). Brain magnetic resonance imaging demonstrated mild generalized cerebral volume loss with reduced posterior white matter. AD is non-verbal, communicating with signs and word approximations. She continues to make slow but forward developmental progress, and her case teaches newly diagnosed children within the ADNP Kids Research Foundation. CONCLUSION: This case study emphasizes the importance of diagnosis and describes, for the first time, early motor intervention therapies. Detailed developmental profile of selected cases leads to better treatments.

Severe cleidocranial dysplasia and hypophosphatasia in a child with microdeletion of the C-terminal region of RUNX2.

Cleidocranial dysplasia (CCD) is a rare autosomal dominant skeletal dysplasia due to mutations causing haploinsufficiency of RUNX2, an osteoblast transcription factor specific for bone and cartilage. The classic form of CCD is characterized by delayed closure of the fontanels, hypoplastic or aplastic clavicles and dental anomalies. Clinical reports suggest that a subset of patients with CCD have skeletal changes which mimic hypophosphatasia (HPP). Mutations in RUNX2 are detected in approximately 65% of cases of CCD, and microdeletions occur in 13%. We present clinical and radiological features in a 6-year-old child with severe CCD manifested by absence of the clavicles marked calvarial hypomineralization, osteoporosis and progressive kyphoscoliosis. HPP features included Bowdler spurs, severe osteopenia, and low alkaline phosphatase. Following negative mutation analysis of RUNX2, comparative genomic hybridization (CGH) microarray was performed. The result revealed a microdeletion in RUNX2, disrupting the C-terminal part of the gene.