Chromosome 4q terminal deletions such as 4q33 occur in approximately 1:100,000 individuals;  the overall incidence of all types of chromosome 4q deletions is estimated to be 1:10,000.

The syndrome is caused by a de novo (new, non-inherited) deletion of genetic material from the long arm (q) of chromosome 4 at band 3, sub-band 3..The deletion size in reported cases ranges from 18.9-22.9 Mb (million basepairs of DNA), affecting multiple genes involved in development. In some cases, gene translocations, where chromosomal segments are rearranged, can be associated with 4q33 deletion syndrome. One candidate gene, dHAND (HAND2), has been linked to heart defects for some patients. The HAND proteins are responsible for development of the right ventricle and aortic arch arteries in the heart, and their mutation or lack of expression can lead to heart defects in the individual.

The symptoms of 4q33 deletion syndrome are highly variable, even among individuals with deletions in similar regions. Specific features and their severity depend on the genes deleted. However, some common features may include:

• Craniofacial abnormalities:  Microcephaly (small head), broad nasal bridge, short nose with upturned nostrils, low-set or rotated ears, cleft palate (with or without cleft lip), small jaw (micrognathia), wide-set eyes (hypertelorism), and a long philtrum (the groove between the nose and upper lip).

• Developmental delays: Intellectual disability, ranging from mild to severe, is almost always present. Motor skills development (sitting, crawling, walking) and speech development are typically delayed.

• Digital abnormalities: Unusual fingers and toes are frequent, such as small fifth fingers with poorly developed or absent nails (clinodactyly), tapering fingers, and abnormal positioning of toes.

• Growth deficiency: Many individuals experience poor postnatal growth, resulting in short stature. Feeding difficulties in infancy can contribute to this.

• Skeletal anomalies: These can include scoliosis (sideways curvature of spine), kyphosis (forward rounding of upper spine), and other bone abnormalities.

• Cardiac defects: Congenital heart defects are present in about half of the affected individuals.

• Hypotonia: Low muscle tone is common in infancy.

• Feeding difficulties: Many infants have problems with sucking and swallowing, sometimes requiring feeding tubes.

• Other possible features: These can include hearing loss, vision problems, genitourinary malformations, behavioral issues (including autism spectrum disorder, mood swings, aggression, auditory hallucinations), and seizures.

The manifestation of the symptoms depend on the location of the deletion and how many segments are deleted. The symptoms typically manifest unilaterally, meaning one sided. Deletion between 4q31.2 to 4q35.2 manifests as craniofacial dysfunction of the left side of the face. Craniofacial dysfunction is a deformity of the head, skull, face, neck, and jaw. Other manifestations include ipsilateral ptosis (the falling of the upper eyelid of the same side of the body), developmental delays, erythroderma (the reddening of the skin), and bilateral thumb anomalies (missing, incomplete, or amputated deficiency of the thumb). Deletion at the 4q33 region is also associated with ulna deficiency, cleft lip and palate, and slow brain development.

Diagnosis is usually prompted by the presence of physical deformities, leading to genetic testing. Methods include:

• Karyotyping: A standard chromosome analysis can detect larger deletions.

• Fluorescent in situ hybridization (FISH): This technique uses fluorescent probes to identify specific DNA sequences and can help confirm and delineate the deletion.

• Chromosomal microarray analysis (CMA): This high-resolution technique can detect smaller deletions and duplications that may be missed by karyotyping. It is often the preferred method for diagnosis.

• Whole genome sequencing: May help in characterizing breakpoints or finding other genomic changes.

• Prenatal diagnosis: The deletion can sometimes be detected during pregnancy through amniocentesis or chorionic villus sampling (CVS) if there are suggestive ultrasound findings or if a parent is known to carry a relevant chromosomal rearrangement.

There is no cure for 4q33 deletion syndrome. Treatment is symptomatic and supportive, often involving a multidisciplinary team:

• Early intervention programs (speech, hearing, vision, feeding, occupational and physical therapy)

• Special education services

• Surgery to correct cardiac defects, cleft palate or limb deformities 

• Medications for pain relief, metabolic support and anti-epileptic drugs for seizure management

• Behavioral therapies for autism spectrum features.

Early intervention is crucial to maximize the child's developmental potential.

The prognosis for patients with 4q33 deletion syndrome varies with the extent of the genetic deletion, the severity of the associated health problems and the quality of medical and supportive care received. Some individuals may live into adulthood with varying degrees of independence. Most patients will experience lifelong developmental delays and require ongoing support. 

1. Strehle EM, Bantock HM. (2003). “The phenotype of patients with 4q-syndrome.” Genet Couns. 14(2):195-205. PMID: 12872814.

2. Keeling SL, Lee-Jones L, Thompson P. (2001). “Interstitial deletion 4q32-34 with ulnar deficiency: 4q33 may be the critical region in 4q terminal deletion syndrome.” Am J Med Genet. 99(2):94-8. Doi: 10.1002/1096-8628(2000)9999:999<00::aid-ajmg1134>3.0.co;2-d. PMID: 11241465.

3. Kitsiou-Tzeli S, et al. (2008). “Distal del(4) (q33) syndrome: detailed clinical presentation and molecular description with array-CGH.” Eur J Med Genet. 51(1):61-7. doi: 10.1016/j.ejmg.2007.09.004. Epub 2007 Oct 2. PMID: 17998173.

4. National Organization for Rare Disorders (NORD):  Chromosome 4q deletion.

5. HAND2 Gene.