Macrocephaly, Dysmorphic Facies, And Psychomotor Retardation

A number sign (#) is used with this entry because of evidence that macrocephaly, dysmorphic facies, and psychomotor retardation (MDFPMR) is caused by homozygous or compound heterozygous mutations in the HERC1 gene (605109) on chromosome 15q22.

Description

Macrocephaly, dysmorphic facies, and psychomotor retardation (MDFPMR) is an autosomal recessive neurodevelopmental disorder characterized by large head and somatic overgrowth apparent at birth followed by global developmental delay. Affected individuals have characteristic dysmorphic facial features and persistently large head, but increased birth weight normalizes with age. Additional neurologic features, including seizures, hypotonia, and gait ataxia, may also occur. Patients show severe intellectual impairment (summary by Ortega-Recalde et al., 2015).

Clinical Features

Ortega-Recalde et al. (2015) reported a brother and sister, born of unrelated Colombian parents, with overgrowth and intellectual disability since infancy. Both patients presented at birth with macrocephaly and increased birth length and weight. They had delayed psychomotor development and hypotonia. The brother had seizures during infancy. Physical examination of the patients in their twenties showed dysmorphic features, including tall stature and asthenic habitus with long limbs (dolichostenomelia), frontal bossing, triangular long face, sparse eyebrows, hypertelorism, downslanting palpebral fissures, malar hypoplasia, prominent nasal bridge, high-arched palate, moderate to severe prognathism, macrotia, and long neck. Other features included asymmetric thorax, severe kyphoscoliosis, lumbar hyperlordosis, joint laxity, flat feet, and large hands with arachnodactyly. Bone age and genitalia were normal. Both sibs had severe expressive language delay and ataxic gait. Brain imaging was normal in the boy, whereas brain imaging in the girl showed communicating hydrocephalus, megalencephaly with cortical atrophy, and ventriculomegaly without cerebellar abnormalities.

Nguyen et al. (2016) reported an 18-year-old man, born of consanguineous Moroccan parents, with megalencephaly and severe intellectual disability. He showed increased birth weight and length, which normalized as he matured. However, his head circumference remained above average (+3 SD); bone age was normal. He had severe developmental delay with absent speech, difficulty walking, joint limitation, and limited social interaction. He developed generalized epilepsy at age 4 years, which was controlled by medication. Dysmorphic features included hypotonic long face with high forehead, prognathism, and long thin feet and hands. He also had severe myopia. Brain imaging showed megalencephaly, thick corpus callosum, enlarged white matter, and small cerebellum.

Aggarwal et al. (2016) reported a brother and sister, born of consanguineous Indian parents, who presented at ages 7 and 3, respectively, with syndromic global developmental delay. Both had mild to moderate macrocephaly, but other growth parameters were not consistently increased, and anthropomorphic measurements at birth were not available. Dysmorphic features included tall forehead, long face, proptosis, hypertelorism, upslanting palpebral fissures, sparse eyebrows, and low-set, posteriorly rotated, large ears. The patients had hypotonia, joint laxity, kyphoscoliosis, and long fingers. Neither patient had seizures, and bone age was normal. Brain imaging, performed only in the boy, was normal except for metopic synostosis.

Inheritance

The transmission pattern of MDFPMR in the family reported by Ortega-Recalde et al. (2015) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 2 sibs, born of unrelated Colombian parents, with MDFPMR, Ortega-Recalde et al. (2015) identified compound heterozygous mutations in the HERC1 gene (W875X, 605109.0001 and G4520E, 605109.0002). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Functional studies of the variants and studies of patient cells were not performed.

In an 18-year-old boy, born of consanguineous Moroccan parents, with MDFPMR, Nguyen et al. (2016) identified a homozygous truncating mutation in the HERC1 gene (R3250X; 605109.0003). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Patient fibroblasts showed decreased mutant transcript and complete absence of the protein, suggesting that the mutation results in nonsense-mediated mRNA decay. Patient fibroblasts did not show changes in either TSC2 (191092) or mTORC1 (see MTOR; 601231) compared to controls; HERC2 (605837) levels were also unchanged. Nguyen et al. (2016) postulated that alterations in the mTOR pathway resulting from loss of HERC1 could be tissue-specific.

In 2 sibs, born of consanguineous Indian parents, with MDFPMR, Aggarwal et al. (2016) identified a homozygous splice site mutation in the HECT1 gene (605109.0004). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Aggarwal et al. (2016) suggested that loss of the HECT domain, which would occur in these patients, is likely of pathogenic significance as that domain interacts with TSC2 and decreases its stability by ubiquitinization and targeted degradation, which could disrupt regulation of the mTOR pathway. The mutation could also disrupt intracellular trafficking.

Animal Model

Mashimo et al. (2009) described a mouse mutant, 'tambaleante' (tbl, meaning 'staggering' in Spanish), characterized by severe ataxia, abnormal hindlimb posture, and tremor associated with progressive degeneration of Purkinje cells in the cerebellum beginning at 2 months of age. Mutant mice also had reduced growth and lifespan compared to wildtype. Positional cloning identified a homozygous missense mutation (G483E) in the Herc1 domain as responsible for the phenotype. The mutation occurred at a highly conserved residue in the N-terminal RLD1 domain. Mutant tissue showed an increase of the mutant protein, a decrease in mTOR activity, and an increase in autophagy in the cerebellum.

By electrophysiologic analysis of motor function of tbl mice, Bachiller et al. (2015) found that Herc1 malfunction produces motor defects at about 30 days of age, prior to the onset of ataxia and cerebellar cell loss. Examination of the skeletal muscle showed that mutant mice had morphologic and functional defects at the neuromuscular junction, including smaller postsynaptic regions and impaired synaptic vesicle release, compared to controls. These changes were evident as early as 2 weeks of age. Overall, the findings suggested that HERC1 is essential for proper development, maintenance, and function of the neuromuscular junction.

Ruiz et al. (2016) performed electron microscopic analysis of various regions of the central nervous system in homozygous tbl mutant mice. Features of autophagy, including autophagosomes, lysosomes, altered mitochondria, and some chromatin alteration, were present in Purkinje cells in the cerebellum, as well as in neocortical and hippocampal pyramidal cells and spinal cord motor neurons. The neuronal loss was more dramatic in the cerebellum. Autophagy signs were not found in interneurons or neuroglia cells. These findings suggested that affected neurons are projection neurons that have a high degree of neuronal activity, and that regions other than the cerebellum may be affected.