Chromosome 1 Disorders

Provided by Dr. Iosif Lurie
Chromosome 1


Deletion 1p36

The whole 1p36 segment is relatively large (~ 28 Mb). Actually, however, most patients have deletions of 3-4 Mb in the distal part of 1p36. Such small deletions cannot be recognized using "standard" cytogenetic tests. It explains the fact that although this syndrome occurs relatively often (some investigators believe that it affects ~ 1:5000 newborns) it has not been known before 1990. Cytogenetic defect in patients tested using molecular methods may be written as del(1)(p36.2), del(1)(p36.22), del (1)(p36.23) etc. Approximately 10% of patients have interstitial deletions, when the most distal part of 1p36 is preserved; the cytogenetic formulas in such children will be written as del(1)(p36.32p36.33) [if deletion involved 2 sub-bands] or del(1)(p36.33p36.33) [if deletion involves only one sub-band]. Another 10-15% of patients have more complex rearrangements sometimes involving other chromosomes. Clinical studies showed that patients with terminal and interstitial deletions of the distal part of 1p36 have very similar clinical manifestations. There is no strong correlation between severity of syndrome and length of deleted segment. Several investigators showed that even children with non-overlapping deletions in this area have the same complex of abnormalities. This is possible if most clinical manifestations are the results of a "positional effect" of rearrangement, but not caused by effect of missing genes. From the clinical point of view it allows to analyze all cytogenetic variants as one entity under the name "1p36 deletion syndrome". It has to be noted, however, that deletions affecting the "proximal" part of 1p36 [1p36.11-1p36.13] currently are virtually unknown. There is an opinion that up to 1% of all patients with intellectual disability of unknown origin may be caused by deletions within 1p36.

The ratio boys to girls among children with del 1p36 is approximately 1:2. As a rule babies with del 1p36 are born after uncomplicated and generally normal pregnancies. Almost all infants are small for gestational age. Most children have brachycephaly (decrease of head in anterio-posterior direction). Microcephaly may become evident later. Typical facial abnormalities (deep-set eyes, broad nasal bridge, midface hypoplasia, long philtrum), short digits and short feet may be unrecognized by the parents, but obvious to a pediatrician or to a geneticist. The large anterior fontanel is usually late-closing. The most frequent ocular problems are anomalies of refraction or nystagmus; structural eye defects (cataract, coloboma) are relatively uncommon. Almost half of the patients have different hearing problems, both sensori-neural and conductive. Some children manifest skeletal abnormalities, mostly scoliosis and different rib defects, which may be recognized upon X-ray examination. Cleft palate although reported in several patients is relatively uncommon.

Heart defects are the most common internal malformation. Approximately 2/3 of patients have structural heart defects (septal defects, stenosis of aorta or pulmonary artery) or cardiomyopathy, when the ventricles become spongy and cannot pump enough blood to the organs.

Renal abnormalities although relatively common (~20%), are presented by dilatation of renal pelvis or ectopic kidneys. They usually do not affect function of kidneys but may predispose to urinary tract infections. Structural defects of the brain are uncommon, although several patients had hydrocephalus or polymicrogyria. A significant part of the patients with this syndrome has hypothyroidism.

More than half of children with deletion 1p36 syndrome develop different forms of seizures, which begin mostly during the first year. In some patients seizures may stop and these children may be off anti-convulsive medications. In other patients, however, seizures are getting worse. The attempts of treating the so-called infantile spasms by steroids are controversial: in most children seizures stopped, but some developed severe epilepsy, that is not-responsive to anti-epileptic drugs.

The delay of intellectual development (in most children significant) is a common sign of patients with monosomy 1p36. Head control, ability to sit without support and to walk is obtained at higher age than usual. Expressive language is also commonly affected. Some children may say several isolated words or short sentences, but others do not speak at all. Most children with this syndrome have behavioral problems: fits of temper, self-biting of hands, stereotypies (holding hands in front of face, hand flapping, head shaking). Both problems with behavior and speech development are usually improving with age.

Because the symptoms of the syndrome involve different systems of the body, a patient should be followed by several specialists (cardiologists, urologist [to exclude renal defects], neurologist, ophthalmologist, etc.). The child may need participation of psychologist, speech therapist or physiotherapist for partial compensation his/her functional limitations.

The articles by Bahi-Buisson et al. (2009) and Battaglia et al. (2009) [available from CDO library] may give further details about deletion 1p36.

Genetic counseling: In ~15% of patients with apparently terminal deletions one of the parents may be a carrier of a balanced translocation or inversion. Cytogenetic examination of both parents is a prerequisite for evaluation of a genetic risk for further offspring of the couple. If the parents are cytogenetically normal the recurrence risk is very low. If one of the parents has translocation (or inversion) the recurrence risk may reach 15-20% (depending on the precise formula of rearrangement). Although it is possible that an interstitial deletion may be caused by chromosomal insertion in one of the parents, the probability of such rearrangement is very low; in all so far described patients with interstitial deletions 1p36 these aberrations were sporadic (with negligible recurrence risk for further children).

Deletion 1q21.1

The genetic size of the whole chromosome 1 is ~246 MB. The segment 1q21.1 occupies only ~4 Mb (from ~141.5 Mb to 145.9 Mb) and both deletions and duplications within this segment became recognizable only for the last years when molecular cytogenetic methods became available.

Surprisingly there are two conditions, related to deletions 1q21.1. There is a well-know syndrome TAR (Thrombocytopenia - Absent Radius). The main manifestations of this entity are evident from its title. Thrombocytopenia may be accompanied by leucopenia. The characteristic defect of extremities is an absence of radial bones with preservation of thumbs (in most other syndromes when radial bones are absent the thumbs as absent also). TAR was considered to be an autosomal-recessive condition. The molecular studies showed a very small deletion 1q21.1 [only ~350 Kb (from 144.1 Mb to 144.5 Mb)] in all persons with this syndrome. This segment, although small, contains more than 10 genes. (It remains also unclear, which of these genes contributes for the occurrence of TAR syndrome). Although in most patients this deletion occurred de novo, at least in 25% of families the same deletion was found in one of the healthy parents. These data allowed conclusion that deletion is necessary but not sufficient for the occurrence of TAR-syndrome, and development of clinical manifestations depends on interaction between the deleted segment and other (still unknown) factor.

The other condition, related to 1q21.1 deletion is caused by larger deletion of the more distal part of 1q21.1 (144.8 Mb -145.9 Mb). Sometimes this deletion is called the "distal 1q21.1 deletion" (to distinguish from "proximal" or "TAR-related" 1q21.1 deletion). At first this deletion was found in several patients with congenital heart disease. Later it became evident that manifestations of this condition are very variable. Currently it is very difficult to present a real clinical spectrum of this deletion because different groups had different criteria of selection of the patients for chromosomal examination.

Most patients do not have microcephaly but typically head circumference is near to the lower part of normal distribution. Facial features include frontal bossing, deep set eyes and bulbous nose, although nobody can recognize this condition upon clinical examination. Congenital heart disease is found in 30% of patients. Although most of heart defects are relatively mild (septal defects, bicuspid aortic valve, patent ductus arteriosus) some patients have very serious defects (interrupted aortic arch, arterial trunk, transposition of great arteries).

Different types of polydactyly were found in ~15% of patients. Trigonocephaly, hydrocephaly, cleft palate, microphthalmia, cataracts were also repeatedly reported. There are isolated descriptions of numerous other defects such as absence of one kidney, hydronephrosis, pyloric stenosis etc. However, ~40% of patients with this deletion do not have any birth defects (above some peculiar facial features, if any). The patients may suffer from seizures. There are indications that this deletion may be associated with autism and schizophrenia although sometimes the presence of autism and/or schizophrenia was a criterion for selection of patients for study.

It is obvious that a real clinical picture of the "distal" 1q21.1 deletion will become clear when it will be possible a) to implement a common protocol for evaluation and description of these patients; b) to follow up the children who were too young at the moment of the examination.

The size of deletion may vary, but typically it is between 1.0 and 1.9 Mb. In some persons deletion involves also TAR-region but it does not cause any additional abnormalities (deletion of TAR-region may produce abnormal findings only which accompanied by other [still unknown] genetic factors).

Most distal 1q21.1 deletions occurs de novo. However, in almost 25% of families the same deletion may be found in one parent (mother or father) who manifest some mild manifestations [psychological problems, learning disability or minimal dysmorphisms] or are clinically normal. The normal phenotype in persons with microdeletions may suggest that some microdeletions (including, but not limited to del 1q21.1) cause abnormalities because they reveal (unmask) some mutated genes on the normal (non-deleted) chromosome.

Genetic prognosis will depend on the karyotype of the parents. The recurrence risk is negligible if the parental chromosomes are normal. If one parent has asymptomatic deletion the chance to inherit this deletion will be 50% but its clinical significance remains unpredictable.

Deletion 1q43-q44

Deletions of the distal part of chromosome 1q have been recognized for many years. However, reliable diagnostic of this condition became available only after introduction of molecular cytogenetic methods. 1q44 is the most distal part of the long arm of chromosome 1; its genetic size is ~ 6 MB. The segment 1q43, which is approximately the same size is more proximal part of 1q. There are numerous cytogenetic variants of the distal deletions 1q: interstitial deletions 1q43q44, terminal deletions 1q43qter, deletions involving only segment 1q44. The comparison of clinical findings between these groups did not show significant differences. The absence of genetic material of 1q44 is the critical moment, and additional absence of the genetic material from 1q43 does not seem to be clinically significant.

Birth weight is usually less than normal, although in most babies prenatal hypoplasia is relatively mild. Postnatal growth of these patients is significantly delayed. Head circumference is usually below normal, many patients may have progressive microcephaly. The typical pattern of recognizable anomalies includes sparse fine hair, round face, epicanthus, low set ears, short broad nose with flat bridge, downturned corners of the mouth, microretrognathia [small chin]. These features are found in ~80% of patients with this syndrome. Approximately half of patients have small hands with tapering fingers or short curved 5th fingers, but more serious defects of fingers or toes are rare.Abnormalities of the brain and clinical consequences of these abnormalities are the most characteristic (and most serious) features of this condition.

Microcephaly which is found in ~90% of the patients causes significant delay in psycho-motor development. Seizures are common (~80%). Other consequences of abnormal brain development are floppiness (hypotonia), dysphagia (leading to difficulties in feeding) or autonomic dysfunction [disturbance in function of the cardiac muscle, smooth muscles and different glands]. Small occipital encephalocle may be found in ~10% of children. In 90% of examined patients, MRI of the brain shows absence (or hypoplasia) of the corpus callosum [part of the brain, connecting cerebral hemispheres]. Other not so common defect is Dandy-Walker malformation when dilatation of the 4th ventricle is associated with underdevelopment of cerebellum or absent (or hypopastic) cerebellar vermis. Because brain abnormalities are common findings in distal 1q deletions, MRI of the brain has to be an integral part of examination of these patients. There were several attempts to find a gene, responsible (when deleted) for underdevelopment of the corpus callosum. The critical region is currently limited to 360 Kb, which contains 4 possible candidate genes, but the responsible gene has not been yet determined.

Some children have small pits or additional skin tags before ear. Hearing impairment was reported in ~15% of examined patients. Cleft palate or bifid uvula is relatively common (~15%). Several children had coloboma of iris. Underdevelopment of the thyroid gland is not common, but was reported in several patients. Therefore, exclusion of hypothyroidism should be a part of clinical examination.

Heart defects (usually not life threatening) are the most common abnormality of internal organs. They are found in ~30% of the patients. Absence of one kidney, hydronephrosis and ectopic position of a kidney had been found each in several patients, however only a small part of children had examinations to exclude kidney defects. Some boys have hypospadias. Polydactyly, additional nipples, scoliosis, dislocation of the hips are uncommon. All these findings are known as manifestations of "pure" distal monosomy 1q (as interstitial or terminal deletion).

There are numerous descriptions of children with association of distal monosomy 1q and partial trisomy for another chromosome (usually due to translocation); patients with these associations may have additional abnormalities, caused by partial trisomy.

Genetic prognosis depends on the type of rearrangement. Almost all interstitial deletions are sporadic. Significant part of terminal deletions may be a result of parental translocations: examination of parental chromosomes will be a prerequisite for further decisions. Risk for the further children of the couple will be very low if parental karyotypes are normal. If one of the parents has a translocation risk will depend on exact type of this rearrangement and generally will be relatively high.