Developmental Delay, Intellectual Disability, Obesity, And Dysmorphism

A number sign (#) is used with this entry because of evidence that developmental delay, intellectual disability, obesity, and dysmorphism (DIDOD) is caused by heterozygous mutation in the PHIP gene (612870) on chromosome 6q14.

Description

DIDOD is a disorder characterized by global developmental delay apparent from infancy, intellectual disability or learning difficulties, behavioral abnormalities, dysmorphic features, and obesity. The severity of the phenotype and additional features are variable (summary by Jansen et al., 2018).

Clinical Features

De Ligt et al. (2012) reported a girl with moderate gross motor delay, broad-based gait, severe speech delay, and intellectual disability. She had dysmorphic features, including straight eyebrows, strabismus, blepharophimosis, ptosis, a long philtrum and full lips, tapered fingers, clinodactyly of fifth fingers, and long toes. Brain imaging was normal. Jansen et al. (2018) reported follow-up of this patient (patient 8), noting that she also had stereotypic behavior and anxiety. Jansen et al. (2018) stated that brain MRI of this patient showed slightly enlarged gyri and sulci and atypical large cavum septum pellucidum.

Webster et al. (2016) reported 2 unrelated girls with a developmental disorder characterized by global developmental delay, intellectual disability, anxiety, hypotonia, poor balance, obesity, and dysmorphic features. Both girls had normal weight at birth but became obese later in childhood, with weight and body mass index (BMI) above the 97th percentile. Patient 1 was a 14-year-old girl who also had insulin resistance and polycystic ovary syndrome, and patient 2 was an 8-year-old girl with behavioral issues, including aggression. Dysmorphic features in patient 2 included fleshy ears, small nose, deep-set eyes, short philtrum, micrognathia, round face, and upturned upper lip. Brain imaging was normal in both girls.

Jansen et al. (2018) reported 21 patients, including 2 sets of sib pairs and the patient reported by de Ligt et al. (2012) (patient 8), with DIDOD associated with point mutations in the PHIP gene. Two additional patients had gross chromosomal abnormalities, including a translocation (patient 13) and a large deletion encompassing several genes (patient 14). Three patients (patients 3, 9, and 17) carried variants of uncertain significance in another gene in addition to mutation in PHIP, although the PHIP mutations were considered to be responsible for the neurologic phenotype. The patients had global developmental delay, variable intellectual disability or learning difficulties, and behavioral problems, such as autistic features, attention deficit-hyperactivity disorder (ADHD), anxiety, aggression, poor impulse control, and mood disorders. Most had obesity and dysmorphic features, including high forehead, full eyebrows/synophrys, full fleshy ears, upturned nose with thick alae nasi, long philtrum, and thin lips. Additional features included hypotonia, easy fatigability, tapered fingers, clinodactyly, and skin syndactyly of the second and third toes. More variable features included high palate, hypertelorism, upslanting palpebral fissures, epicanthal folds, strabismus, cryptorchidism, joint hypermobility, cafe-au-lait spots, hypermetropia, and nystagmus. Most patients had normal brain imaging, but some had nonspecific mild abnormalities.

Molecular Genetics

In a girl with DIDOD, de Ligt et al. (2012) identified a de novo heterozygous nonsense mutation in the PHIP gene (Y1149X; 612870.0001). The patient was ascertained from a cohort of 100 patients with severe intellectual disability who underwent exome sequencing. Functional studies of the variant were not performed.

In 2 unrelated girls with DIDOD, Webster et al. (2016) identified different de novo heterozygous mutation in the PHIP gene (F17S, 612870.0002 and c.779delT, 612870.0003). The mutations were found by whole-exome sequencing and confirmed by Sanger sequencing. Functional studies of the variants and studies of patient cells were not performed, but Webster et al. (2016) postulated haploinsufficiency as a mechanism, since 1 of the mutations was predicted to result in a frameshift and premature termination. The patients were part of a cohort of 2,522 patients with developmental delay or intellectual disability who underwent whole-exome sequencing.

In 20 patients with DIDOD, Jansen et al. (2018) identified heterozygous point mutations in the PHIP gene (see, e.g., 612870.0004-612870.0007). Most of the mutations occurred de novo, but parental DNA was not available for all patients. There were 2 sets of affected sibs, including 2 sisters (patients 18 and 19) who inherited a mutation from their mildly affected father, and a brother and sister (patients 6 and 7) whose mother did not carry the mutation and whose father was not available for testing, suggesting either paternal inheritance or germline mosaicism. The first 5 individuals with loss-of-function point mutations in the PHIP gene were ascertained from a cohort of 3,275 patients with intellectual disability collected through international collaboration who underwent targeted resequencing of 24 candidate genes. The remaining individuals were collected from data-sharing resources. Functional studies of the variants and studies of patient cells were not performed, but Jansen et al. (2018) concluded that the mutations resulted in haploinsufficiency of PHIP as the underlying cause of the phenotype.