Further delineation of deletion 1p36 syndrome in 60 patients: A recognizable phenotype and common cause of developmental delay and mental retardation

Stella Maris Clinical Research Institute for Child and Adolescent Neurology and Psychiatry, Via dei Giacinti 2, 56018 Calambrone, Pisa, Italy.
PEDIATRICS (Impact Factor: 5.47). 02/2008; 121(2):404-10. DOI: 10.1542/peds.2007-0929
Source: PubMed


Deletion 1p36 syndrome is a recently delineated disorder, considered to be the most common subtelomeric microdeletion syndrome (1 in 5000 newborns). 1p36.3 deletions account for 0.5% to 1.2% of idiopathic mental retardation; thus, knowledge about the condition is important for pediatricians caring for such patients. Despite 100 reported cases, little is known about its natural history. Our aim was to delineate the natural history of deletion 1p36 and develop complete and accurate information with which to answer families' questions in the clinical setting.
We evaluated 60 patients with the 1p36 deletion syndrome (41 female, 19 male). All underwent physical and neurologic assessments, and most received a psychological evaluation. Standard cytogenetics, fluorescence in situ hybridization of the subtelomeric regions, or array comparative genomic hybridization were used for diagnosis.
Fourteen cases were detected by standard cytogenetics, and 46 were detected by fluorescence in situ hybridization of the subtelomeric regions or array comparative genomic hybridization. Occipitofrontal circumference was at < or = 2nd centile in 95%, and height and weight ranged between the < 3rd and 90th centiles. All patients had straight eyebrows, deep-set eyes, midface hypoplasia, broad nasal root/bridge, long philtrum, and pointed chin. Other features included microbrachycephaly (65%), epicanthus (50%), large, late-closing anterior fontanel (77%), and posteriorly rotated, low-set, abnormal ears (40%). Brachy/camptodactyly and short feet were prominent. Seventy-one percent exhibited heart defects, including 23% with a "noncompaction cardiomyopathy." Fifty-two percent had eye/visual abnormalities, and 64% had visual inattentiveness. Twenty-eight percent had sensorineural deafness, 41% had skeletal anomalies, 25% had abnormal genitalia, and 22% had renal abnormalities. Eighty-eight percent had central nervous system anomalies, and 44% had seizures. All patients demonstrated developmental delay with poor/absent speech; 95% had hypotonia. Twenty-six percent were able to walk alone, and 47% had a behavior disorder. Constant developmental progress was observed in all cases over time. Noncompaction cardiomyopathy and most seizures were controlled by pharmacotherapy.
These 60 patients with deletion 1p36 represent the largest clinical series to date and provide new information on several aspects of this disorder, which is characterized by neurodevelopmental disability and a recognizable pattern of malformation.

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    • "The deep-set eyes in our patients could be related to the genes on most distal sub-band of chromosome 1p36. Previous reports described the clinical picture of 1p36 deletion region and sub-region in the form of ID, seizures, growth impairment , hypotonia, heart defects, dysmorphic features including microcephaly, large anterior fontanels, deep-set eyes, and flat nose [Heilstedt et al., 2003a; Battaglia et al., 2008].Other authors "
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    ABSTRACT: We describe a large family from the Gaza Strip presented with multiple congenital anomalies. The proband was presented with intellectual disability and multiple congenital anomalies including cleft palate, low-set ears, everted upper lip, diaphragmatic hernia, and arthrogryposis. Pedigree analysis showed 19 affected patients over five generations, only 6 were alive and 11 individuals were obligate carriers. The proband had an apparently normal karyotype, although FISH studies showed a derivative chromosome 1 with duplication of 16p13.3 and deletion of the 1p subtelomere. Her father however had a balanced translocation. The seven affected patients had a similar phenotype, one of them died before genetic testing was carried out and the living six patients had the same unbalanced translocation. Array CGH revealed an 8.8 Mb duplication in 16p13 and 200,338 bp deletion in 1p36.3. Accordingly, intellectual disability, hypertelorism, cupped ears, everted upper lip, and limb anomalies were presenting clinical features of the 16p13 duplication syndrome while deep set eyes were perhaps related to the 1p terminal deletion. Prevention of recurrent intellectual disability in this family can be achieved through carrier detection and prenatal genetic diagnosis. © 2014 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part A 01/2015; 167(1). DOI:10.1002/ajmg.a.36834 · 2.16 Impact Factor
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    • "4.1. Previous genetic studies on the 1p36 deletion syndrome Many cohort studies have been performed to delineate the phenotypic features of patients with 1p36 deletion syndrome and to evaluate the frequency of complications [1] [6] [7]. It has been reported that there is no correlation between the deletion size and the number of observed clinical features [24], while the critical region responsible for core phenotypic features, including clefting , hypothyroidism, cardiomyopathy, hearing loss, large fontanel, and hypotonia, has been narrowed down to a region 2.2 Mb from the telomere [3]. "
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    ABSTRACT: Objective: Monosomy 1p36 syndrome is the most commonly observed subtelomeric deletion syndrome. Patients with this syndrome typically have common clinical features, such as intellectual disability, epilepsy, and characteristic craniofacial features. Method: In cooperation with academic societies, we analyzed the genomic copy number aberrations using chromosomal microarray testing. Finally, the genotype-phenotype correlation among them was examined. Results: We obtained clinical information of 86 patients who had been diagnosed with chromosomal deletions in the 1p36 region. Among them, blood samples were obtained from 50 patients (15 males and 35 females). The precise deletion regions were successfully genotyped. There were variable deletion patterns: pure terminal deletions in 38 patients (76%), including three cases of mosaicism; unbalanced translocations in seven (14%); and interstitial deletions in five (10%). Craniofacial/skeletal features, neurodevelopmental impairments, and cardiac anomalies were commonly observed in patients, with correlation to deletion sizes. Conclusion: The genotype-phenotype correlation analysis narrowed the region responsible for distinctive craniofacial features and intellectual disability into 1.8-2.1 and 1.8-2.2 Mb region, respectively. Patients with deletions larger than 6.2 Mb showed no ambulation, indicating that severe neurodevelopmental prognosis may be modified by haploinsufficiencies of KCNAB2 and CHD5, located at 6.2 Mb away from the telomere. Although the genotype-phenotype correlation for the cardiac abnormalities is unclear, PRDM16, PRKCZ, and RERE may be related to this complication. Our study also revealed that female patients who acquired ambulatory ability were likely to be at risk for obesity.
    Brain and Development 08/2014; 37(5). DOI:10.1016/j.braindev.2014.08.002 · 1.88 Impact Factor
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    • "Approximately 90% of the 1p rearrangements are less than 10 Mb in size [3], and it is assumed that quite a number of subjects are misdiagnosed [3]. Moreover, several subjects diagnosed with monosomy 1p36 have been reported to have mild or atypical phenotypes or presenting features that overlap with other genetic syndromes [11,27-29]. "
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    ABSTRACT: Deletion of the subtelomeric region of 1p36 is one of the most common subtelomeric deletion syndromes. In monosomy 1p36, the presence of obesity is poorly defined, and glucose metabolism deficiency is rarely reported. However, the presence of a typical Prader-Willi-like phenotype in patients with monosomy 1p36 is controversial. In this report, we describe two female patients, one who is 6 years 2 months of age and another who is 10 years 1 month of age, both referred to our hospital for obesity and a Prader-Willi-like phenotype. These patients presented with severe obesity (body mass index [BMI] was 26.4 and 27.7, respectively), hyperphagia and developmental delay. Analysis of basal hormone levels showed normal thyroid function and adrenal function but considerable basal hyperinsulinism (the insulin levels were 54.5 and 49.2 muU/ml, respectively). In patient 1, glycaemia was 75 mg/dl (HOMA-R 10.09), and the HbA1c level was 6.1%; in patient 2, glycaemia was 122 mg/dl, and the HbA1c level was 6.6% (HOMA-R 14.82). An oral glucose tolerance test demonstrated impaired glucose tolerance and diabetes mellitus with marked insulin resistance (the peak insulin level for each patient was 197 and 279 muU/mL, respectively, while the 120' insulin level of each patient was 167 and 234 muU/mL, respectively). some patients with monosomy 1p36 may show Prader-Willi-like physical and physiologic characteristics such as obesity and hyperinsulinism with impaired glucose metabolism, which can cause type II diabetes mellitus. Further studies are necessary to evaluate these findings.
    BMC Medical Genetics 01/2014; 15(1):16. DOI:10.1186/1471-2350-15-16 · 2.08 Impact Factor
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