A boy with developmental regression

CASE PRESENTATION

A 2.4 kg baby boy was born at 36-weeks’ gestation after an uncomplicated pregnancy and delivery. Shortly after birth, the baby presented as mildly hypotonic, without noticeable feeding difficulties or growing issues. In the first year of life, he met all expected developmental milestones. He walked at 17 months. By age 2 years his gait was still slightly unsteady, but he could stand upright and run without falling. He had average receptive language and understood two-step commands. However, his expressive language was delayed at this point and he had only four words. Nevertheless, this child was socially engaged, and would often imitate his siblings and frequently establish joint attention.

By age 2.5 years, developmental and medical challenges appeared. Parents noticed that he had lost interest in toys and would now spend hours just chewing on a special piece of cloth. His expressive and receptive language declined, losing his few previously spoken words and gestures. As a result, he began to have significant difficulty communicating. Socially, he no longer engaged with his siblings and became withdrawn. Due to these social-communication and behaviour deficits, autism spectrum disorder was diagnosed.

From 2.5 to 7 years of age, the patient received treatment and assistance through early intervention programs and extra school supports. His developmental profile remained unchanged. Then at age 7 years, a significant decline in his motor function became apparent. He developed a stooped posture, often tripping over his feet and needing assistance on a regular basis. Difficulties initiating movements were observed, showing clinically significant hypotonia. Further regression in fine motor function was documented through family videos. For instance, he could no longer point, hold a crayon, or bang two blocks together. In addition, generalized drop seizures developed that were refractory to medical intervention.

His weight, height and head circumference by age 8 years fell below the third percentile. Eating became very difficult. This child would frequently bring his hands to midline to clench, bite and wring them. He had severe bruxism, causing significant damage to his teeth requiring Botox (onabotulinumtoxinA). Breath-holding spells became increasingly frequent and significant sleep disturbances emerged. Furthermore, he often laughed randomly out of context. Magnetic resonance imaging revealed a Chiari malformation type I, without other brain malformations. Genetics and Metabolics became involved leading to confirmation of the suspected diagnosis.

CASE DISCUSSION

Clinically, our patient presented phenotypically consistent with Rett syndrome (RTT). Based on the 2010 criteria, all four major criteria, none of the exclusion criteria and 7 of 11 supportive criteria were met. On review of family history, there were no other family members with a similar phenotype. His karyotype was normal; however, the comparative genomic hybridization detected XY sex chromosomes and a 172 kb deletion at Yp11.2; this deletion was paternally inherited and was therefore not likely to contribute to the patient’s phenotypic presentation. Analysis of the MECP2 gene detected a heterozygous pathogenic mutation involving the initiation codon of exon 1; this was annotated as c.1A>T (p.Met1?). This finding was consistent with a somatic mosaic loss of function mutation of the MECP2 gene and was likely responsible for our patient’s clinical presentation.

RTT is a neurological disease primarily seen in females, as males with germline mutations typically do not survive to term (1). It is characterized by developmental regression, loss of communication skills, loss of hand skills, gait abnormalities and stereotypic hand movements, followed by stabilization (2). Other associated clinical findings include breathing irregularities, bruxism, abnormal gait, sleep disturbances, laughing/screaming spells and intense eye contact/eye pointing (2). RTT has been genetically linked to mutations in the MECP2 gene, which is found on the X chromosome. However, despite genetic evidence, it remains a clinical diagnosis because MECP2 mutations have been seen in unaffected individuals, primarily female cases (3). Interestingly, RTT was considered at age 3 years in our patient but ‘ruled-out’ because it was reported in the literature as typically lethal in males, and testing was not pursued at that time.

On review of the literature, XY males with a nonmosaic MECP2 null mutation have been identified. These males present with severe neonatal encephalopathy and developmental delays, often dying in early childhood (4). Due to the X-linked nature of the syndrome, for males to survive past the neonatal period, they are thought to require the presence of a somatic mutation with mosaicism, or another X chromosome as is the case in Kleinfelter’s syndrome (XXY). Worth mentioning, the triad of manic depressive psychosis, parkinsonism and macroorchidism (PPM-X) in XY males with X-linked intellectual disability has been linked to MECP2 gene, with mutations at A140V, indicating there are other phenotypes that can be apparent aside from RTT in males (5).

A recent comprehensive review of male patients presenting with phenotypic RTT was done in 2015 by Reichow (6). Among 57 cases of Rett’s in males, 56% (32) were associated with mutations to MECP2, with no cases of complete deletion of the gene, and no cases of abnormal start codon as was identified in our patient. Previous case studies identifying other males with an XY karyotype and a mosaic MECP2 mutation, showed regression around 2 to 3 years of age, whereas females with the complete mutation regressed earlier (1).

In summary, we feel the most likely explanation is somatic mosaicism for his mutation involving the start codon of MECP2b, p.M1. This mutation has been reported in females with classic RTT, but not in males. Currently, our patient is 11 years old and presents with severe intellectual disability and associated extremely low adaptive functioning. He still lives at home, attends a specialized school program and requires 24-hour care for all activities of daily living. Due to fatigue and muscle weakness, he uses a wheelchair. Refractory seizures remain a significant issue. Ketogenic diet (via g-tube), seizure medications (rufinamide and clobazam) as well as vitamin D, multivitamin, fish oil and acetyl L-carnitine are presently used. Lastly, other complementary and alternative therapies have been attempted with limited success.

CLINICAL PEARLS

• ‐ Developmental regression is an ominous sign for a genetic or metabolic disorder and should be investigated thoroughly.

• ‐ Rett (RTT) syndrome should be considered in males with developmental regression and MECP2 mutation testing should be performed.

• ‐ Contrary to female early presentation, males with a somatic mosaic MECP2 mutation typically show developmental regression around 2 to 3 years.