1p36 deletion syndrome (also known as monosomy 1p36) is a congenital genetic disorder characterized by moderate to severe intellectual disability, delayed growth, hypotonia, seizures, limited speech ability, malformations, hearing and vision impairment, and distinct facial features. The symptoms may vary, depending on the exact location of the chromosomal deletion.
The condition is caused by a genetic deletion (loss of a segment of DNA) on the outermost band on the short arm (p) of chromosome 1. It is one of the most common deletion syndromes. It is estimated that the syndrome occurs in one in every 5,000 to 10,000 births. Knowledge of the disorder has increased a great deal over the last decade, mainly because more patients have been accurately diagnosed and described in international medical literature.
The facial features of 1p36 deletion syndrome have been considered to be characteristic, although few patients have been diagnosed solely on the basis of facial appearance. These features may include microcephaly, small, possibly slanted, deep-set eyes, a flat nose and nasal bridge, anomalous, low-set and small ears, a small mouth with down-turned corners and a pointed chin. Distinguishing features in another study were a large or late-closing anterior fontanelle (up to 85% of patients) and facial asymmetry.
The first cases of 1p36 deletion syndrome were described in the 1980s. However, since many of these individuals also had other chromosomal imbalances, symptoms varied widely. The reason it took so long to recognize the condition as a distinct chromosome deletion syndrome is that the deletions causing the disorder are too small to be detected in a routine chromosomal analysis. FISH (fluorescent in situ hybridization) and DNA-based technology known as MLPA (multiple ligation probe amplification) used in testing have aided in diagnosing an increasing number of cases since the 1990s.
1p36 Deletion Syndrome is a congenital genetic disorder caused by the deletion of the most distal light band of the short arm of chromosome 1. Chromosome 1 is the largest human chromosome and represents about 8 percent of the total DNA in human cells. The "p" stands for the short or 'petite' arm of the chromosome. '36' stands for the location of the deletion on the chromosome.
The breakpoints for 1p36 Deletion Syndrome have been variable and are most commonly found from 1p36.13 to 1p36.33. 40 percent of all breakpoints occur 3 to 5 million base pairs from the telomere. The size of the deletion ranges from approximately 1.5 million base pairs to greater than 10 million. Studies have suggested that the larger the deletion, the more severe the symptoms exhibited in the individual, but this has not been proven definitively.
Most deletions in chromosome 1p36 are new mutations, that occur before fertilization, during the formation of gametes (eggs or sperm). There have also been reports of patients with 1p36 deletion syndrome whose parents have a balanced or symmetrical translocation. This means a portion of one chromosome is transferred to another chromosome, so the parent has the "36" portion of chromosome 1 attached in an alternate location. When this occurs, cell division creates gametes that are missing a piece of 36.
In new mutations, the mechanism causing chromosome breakage is unknown. Deletions of paternal origin (father) are larger than the deletions deriving from the maternal (mother) chromosome. The majority of deletions are maternally derived. There do not seem to be differences in the clinical manifestations (the symptoms or observable conditions which are seen as a result of 1p36) based on whether the deletion is on the paternal or maternal chromosome.
Most young children with 1p36 deletion syndrome have delayed development. They sit up, walk and talk later than typical children. Speech is severely affected, with many patients learning only a few words. It was originally thought that the degree of the delay and the ability to acquire complex speech was somewhat dependent on deletion size. Reports of a milder learning disability in children with smaller deletions have suggested that there may be a correlation between deletion size and mental ability; however, this requires further investigation and research. Recent research by Dr Lisa Shaffer has shown however that there is no correlation between deletion size and degree of developmental delay. This suggests that the most genetically potent area of the 1P36 chromosome occurs at the terminal end of the chromosome.
Many children with 1p36 deletion syndrome have behavioral problems. Some of these include temper outbursts, banging or throwing objects, striking people, screaming episodes, and self-injurious behavior (wrist biting, head striking/banging). Autistic behavior has also been noted in some children. Also, some parents have described behaviors such as a love of water, although there have not been any studies into this yet.
Many children with 1p36 deletion syndrome have oropharyngeal dysphagia which is characterized by difficulty in initiating a swallow. Some of the other feeding issues include poor sucking and swallowing, reflux, and vomiting in infancy. Many require nasalgastric or gastric tubes to ensure they are receiving sufficient nutrition.
Brain imaging has documented cerebral atrophy, which is a loss of neurons in the brain and the connections between them. Also documented were problems with the ventricular system in the brain, such as ventricular asymmetry and ventricular enlargement. Hydrocephalus has also been noted in children with 1p36 deletion syndrome. This is basically too much fluid within the brain. Hyperreflexia, which is defined as overactive or overresponsive reflexes in the body, was also found to be common. Many children also have epilepsy which is a disorder of the brain that results in recurrent, unprovoked seizures.
Microcephaly is a disorder in which the circumference of the head is smaller than average for the person's age and gender. Most children with microcephaly also have a smaller than typical brain and intellectual disability. Some of the most common signs and symptoms associated with microcephaly are seizures, poor feeding, high pitched cry, intellectual disability, developmental delay, and increased movement of arms and legs.
Vision abnormalities in children with 1p36 have been wide-ranging, including:
- Strabismus: A condition in which the two eyes do not point in the same direction when the patient is looking at a distant object.
- Sixth nerve palsy: In an adult, new-onset sixth nerve palsy will result in double vision, but congenital sixth nerve palsy will lead to amblyopia.
- Refractive errors: Refractive errors include nearsightedness, farsightedness, astigmatism (a warping of the curvature of the cornea) and presbyopia (the inability to maintain a clear image or focus as objects are moved closer). These disorders of the eye can be corrected with glasses or contacts.
- Hypermetropia: A condition where the eye is too small and eyes have to over focus to see clearly; also called farsightedness.
- Cataracts: A cataract is an opacity or cloudiness in the natural lens of the eye.
- Nystagmus: A condition characterized by the repetitive oscillations (vibration) of the eyes. Parents of children with nystagmus often refer to this as "jerking" "or "jiggling" eyes.
- Lacrimal defects: The lacrimal glands in the eye secrete tears.
- Visual Inattentiveness: Defined as an absence of attentive visual behavior such as fixation and following movements.
Distinct facial features
Children with 1p36 deletion syndrome are all unique individuals, but do have some common distinct facial features such as:
- Large anterior fontanelle/Frontal bossing: The anterior fontanelle is the "soft spot" towards the front of the top of an infant's head between the growing skull bones. Frontal bossing simply means a prominent forehead.
- Small and pointed chin
- Flat nose and/or nasal bridge
- Low-set, small ears/Ear asymmetry: Ears are abnormally low set on the head and may be small. They may not be the same shape or size, or not lined up.
- Deep set eyes
- Thickened ear helices: Ear helices are the outer rings of cartilage of the ears.
- Short, narrow and slanting palpebral fissures: Palpebral fissures are the gaps between the upper and lower eyelids, or the opening of the eyes.
- Midface Hypoplasia: This is where the middle of the face is underdeveloped, leading to a concave-looking face. The bridge of the nose looks sunken in and the eyes are set widely apart and often protrude out of the sockets.
- Small mouth with down-turned corners
- Orofacial clefting: This is a relatively common birth defect in which the fetus develops with deformities of the upper lip, gum, and roof of the mouth. Children with 1p36 have been noted to have orofacial clefting involving the lip and/or palate or uvula (the small piece of flesh hanging down inside the mouth at the back of the palate).
There are many growth abnormalities associated with 1p36 deletion syndrome. One common problem is delayed growth or difficulty in gaining weight. Even though some of the children may eat well, they still may not grow normally. In contrast, some children may develop hyperphagia, which is overeating, and may become obese. These children clinically resemble children with Prader-Willi syndrome. Developmental delay has also been severe in the patients with the Prader-Willi like characteristics.
- Hypotonia: Hypotonia is a decreased or low muscle tone. This may explain the delayed motor skills in children with 1p36.
- Hypothyroidism: Hypothyroidism is insufficient production of the thyroid hormone. Symptoms include weight gain, constipation, dry skin, and sensitivity to the cold. Around one third of children with the syndrome have this low thyroid function, which is also called underactive thyroid, and leads to slow metabolism and fatigue.
- Heart defects:
- Infantile dilated cardiomyopathy: Dilated cardiomyopathy (DCM) is a disease of the heart muscle that causes the heart to become enlarged, and to pump less strongly. This causes fluid to build up in the lungs, which therefore become congested, and results in a feeling of breathlessness. Children with DCM due to their 1p36 deletion syndrome typically do not worsen over time, though some of them may need to continue taking medication.
- Patent ductus arteriosus: This is the most common structural heart defect in children with 1p36. It is a condition in which the connecting blood vessel between the pulmonary artery and the aorta in fetal circulation stays open in the newborn. The defect often corrects itself within several months of birth, but may require the infusion of chemicals, the placement of "plugs" via catheters, or surgical closure.
- Tetralogy of Fallot: Tetralogy of Fallot includes a ventricular septal defect, a hole between the two bottom chambers (ventricles) of the heart. These defects can cause less blood flow to the lungs, the mixing of oxygen-rich and oxygen-poor blood inside the heart, and low levels of oxygen in the blood. When oxygen levels are low, the baby's skin, fingertips, or lips have a bluish tint. This condition is called cyanosis.
- Increased Risk for Neoplasia: Chromosome 1p36 alterations, mostly deletions, have been reported to occur in various types of neoplastic growths or tumors which may be benign or malignant. The 1p36 region contains a number of tumor-suppressor genes, which are genes that act to prevent cell growth. The deletion of one or more of these genes can cause malignancy (cancer). Some of the neoplasms involved in the 1p36 are neuroblastoma, prostate cancer, lung cancer, melanoma, hepatoma, cervical cancer, breast cancer, colorectal cancer, ovarian cancer, and non-Hodgkin lymphoma. This is not to say that the children with 1p36 deletion syndrome will get these cancers, but this is a theory that has been put forth.
- Genital hypoplasia: Genital hypoplasia is the underdevelopment of the genital areas. Some of the genital problems in children with 1p36 are:
- Cryptorchidism: This is the failure of one or both of the testicles to descend into the scrotum.
- Shawl Scrotum: A condition in which the scrotum tends to surround the penis.
- Small Genitalia
Dilation of the renal collecting system
The collecting system is the structure that collects urine directly from the kidney tissue and routes it by way of the ureter to the bladder. Structural renal abnormalities are rare in both sexes.
Hearing loss affects approximately two thirds of 1p36 deletion patients. It can be of different types. Sensorineural hearing loss is a type of hearing impairment caused by damage that occurs to the inner ear (cochlea) or to the nerve used for hearing (vestibulocochlear nerve). Conductive hearing loss is a hearing loss associated with the functioning of the outer or middle ear. This type is most common in children with 1p36 deletion syndrome. It ranges from mild loss at various frequencies, to severe loss at all frequencies.
Puberty in children with 1p36 deletion syndrome can be early, normal, or delayed.
Only a few spinal deformities have been seen in children with 1p36. The deformities found are:
- Kyphoscoliosis: Spinal deformity combining a sideways curvature with a hunching forward of the upper part of the spine.
- Postural Kyphosis: Also called postural "round back". This was found secondary to hypotonia in some children with 1p36.
Treatments and therapy
Although 1p36 Deletion Syndrome can be debilitating in many ways, patients do respond to various treatments and therapies. These include the following:
American Sign Language: Because few individuals with Monosomy 1p36 develop complex speech, an alternate form of communication is critical to development. Most patients can learn basic signs to communicate their needs and wants. This also appears to reduce frustration and may reduce self-injurious tendencies. Children with hearing loss will often qualify for locally sponsored sign language classes.
Music: Music has been shown to aid children with 1p36 deletion in various developmental areas. It serves as an excellent auditory stimulus and can teach listening skills. Songs with actions help the child to develop coordination and motor skills.
Physical Therapy: Due to low muscle tone, patients with 1p36 Deletions take a great deal of time to learn to roll over, sit up, crawl and walk. However, regular physical therapy has shown to shorten the length of time needed to achieve each of those developmental milestones.
- Orphanet, 1p36 Deletion Syndrome, Clinical Description (pdf)
- The Swedish Rare Disease Database, 
- GeneReview/NCBI/NIH/UW entry on 1p36 Deletion Syndrome
- DECIPHER database entry for 1p36 deletion syndrome
- 1p36 Deletion Support & Awareness: What is 1p36 Deletion Syndrome