The following description of the EBF3-related HADDS clinical spectrum is based primarily on the Chao et al. (2017); Harms et al. (2017) and Sleven et al. (2017) publications available at the American Journal of Human Genetics.
Growth parameters
The majority of children with EBF3-related HADDS have normal growth parameters. Short stature is proportionate. Head circumference is within normal ranges.
Neurological features
Individuals with EBF3-related HADDS have hypotonia, delayed development, ataxia, and variable cognitive impairments. Mild to moderate cognitive impairment, low normal IQ, and normal IQ have been described. In general, the level of psychomotor delay is moderate and expressive language development is particularly affected compared with receptive language or motor skills.
Neonatal hypotonia is one key feature of HADDS. It may result in feeding difficulties and gastroesophageal reflux in the neonatal period, but typically hospitalization and/or nasogastric tube feeding is not required. Hypotonia persists lifelong but later in development hypertonia in the extremities can also develop.
Febrile seizures, unprovoked seizures and abnormal electroencephalogram findings have been reported in a few individuals. The seizures are typically infrequent and respond well to monotherapy.
About half of the reported cases have structural anomalies of the central nervous system primarily resulting in underdevelopment of the cerebellar vermis or hemisphere.
Spinal cord anomalies have not been described in these cases.
Neuropsychological features
In general, individuals with EBF3-related HADDS are sociable. Their affect may be deceptively flat due to the hypomimia and facial hypotonia. Behavioral problems can be seen in individuals with HADDs including autism, autistic-like behaviors, ADHD (attention deficit and hyperactivity), anxiety, phobias, impulsivity, stereotyped behaviors, compulsive behaviors, and emotional lability.
Facial dysmorphisms
Individuals with EBF3-related HADDS have characteristic facial features including long forehead, a “myopathic” appearance, posteriorly rotated ears, deep-set eyes, variable synophrys, hypertelorism, and downturned corners of the mouth. Other non-facial dysmorphic features include smaller hands and feet.
Visual impairments
Strabismus is a common feature in EBF3-related HADDS.
Renal and urogenital anomalies
Cryptorchidism, micropenis, and hypospadias has been seen in males with EBF3-related HADDS. Mild underdevelopment of the external genitalia has been described in females. Bi-cornuate uterus was reported in one individual with EBF3-related HADDS. Other important anomalies of the renal and urogenital tract include vesicoureteral reflux, hydronephrosis, horseshoe kidney, partial duplication of the renal system, and abnormal ureteral placement. Not all individuals will have renal or urogenital anomalies.
Miscellaneous
Recurrent urinary tract infections have been seen in association with renal and urogenital anomalies in EBF3-related HADDS. However, in general there is no evidence of an increased susceptibility to infections.