Clinical Characteristics

Growth parameters
Intrauterine growth retardation (IUGR) and postnatal growth retardation can be present, but most children with ZFHX4 abnormalities have normal growth parameters. Fetal macrosomia has been reported in some cases.

Neurological features
Individuals with ZFHX4 abnormalities have developmental delay and intellectual disability (ID). In general, the level of ID is within the mild to moderate range, but also low normal intelligence has been described. Motor skills and speech seems to be particularly affected. Imbalance is described in some individuals. Muscular hypotonia is a frequent finding. Feeding difficulties in the neonatal period can be present. Seizures are present in some cases.

Morphological abnormalities of the central nervous system can be present including aplasia or hypoplasia of the corpus callosum, abnormal gyration, widened subarachnoid space and dilated ventricles. Cerebral cystic malformation has been described in some individuals.

Neuropsychological features
Behavioral problems can be present in some individuals including stereotyped behavior, sleep disturbance, overfriendliness and autism/autistic traits.

Facial dysmorphisms
Most individuals with ZFHX4-associated syndrome have some characteristic facial features such as a broad face, prominent forehead, biparietal narrowing, laterally sparse eyebrows, short palpebral fissures, eyelid ptosis (frequently unilateral), periorbital fullness, epicanthal folds, low set ears, posteriorly rotated ears, abnormally prominent ear helix, wide nasal bridge, narrow nasal tip, flared nostrils, enlarge naris, underdeveloped nasal alae, and abnormality of the upper lip vermillion. Microphthalmia, cleft lip and/or palate, long maxillary central incisors and a large anterior fontanelle are reported in some cases.

Other non-facial dysmorphic features that have been described include abnormalities of digits, such as camptodactyly, clinodactyly, broad toes, overlapping toe, syndactyly, broad phalanx, short metacarpals and proximal placement of thumb.

Musculoskeletal anomalies
Musculoskeletal anomalies described in our series include hip dysplasia, joint hypermobility, shortening of the Achilles tendon, abnormality of the shoulder, short neck, hyperlordosis, scoliosis, and pectus excavatum.

Visual and hearing impairments
Most common visual problems include abnormal anterior eye segment morphology such as Peter’s anomaly, sclerocornea, microcornea, cataracts and astigmatism. Strabismus is also a frequent finding. Abnormalities of refraction have been described in some cases, including hypermetropia, myopia, nystagmus, amblyopia, Duane anomaly, diplopia and cerebral visual impairment. Hearing impairment can be present in some cases.

Cardiovascular defects
Congenital heart anomalies are not frequent in our series; however, some individuals presented with atrial septal defect (ASD) or ventricular septal defect (VSD) and pulmonary stenosis.

Renal and urogenital anomalies
Cryptorchidism is present in some males with ZFHX4-associated syndrome. Other anomalies of the renal and urogenital tract that have been reported include hypogenitalism, hydronephrosis, pyelectasia, and abnormality of the scrotum.

The clinical spectrum of ZFHX4-associated syndrome is broad and some features may be present in only a few individuals. In our cohort we have observed the presence of Peter’s anomaly, microphtalmia, cleft lip or palate, a large anterior fontanelle as well as abdominal wall defects that include diastasis recti and a prominent umbilicus in a few individuals. These features may be part of the spectrum of characteristics associated with ZFHX4. Recurrent infections have also been described in some cases.

Systematic collection of clinical data from new cases will help us to understand the breadth of characteristics associated with alterations in the ZFHX4 gene.