Dental anomalies as a possible clue of 1p36 deletion syndrome due to germline mosaicism: a case report.

BACKGROUND: Monosomy 1p36 is the most common terminal deletion syndrome with an autosomal dominant pattern of inheritance. This syndrome is defined by an extremely wide spectrum of characteristics; however, developmental delay and intellectual disability of various degree are present in all patients and about the 90% of patients have a severe intellectual disability. Dental agenesis or other dental anomalies have not been described in previous reports. CASE PRESENTATION: We report the case of two little sisters born from healthy and non-consanguineous parents, presenting with dental anomalies and one of them with epilepsy, dilated cardiomyopathy with left-ventricular non-compaction, strabismus, history of poor growth, hypotonia and mild language delay. Patients were evaluated in several departments (genetic, child neuropsychiatric, cardiology, odontostomatology, ophthalmology, otorhinolaryngology) of Institute for Maternal and Child Health, IRCCS Burlo Garofolo, Trieste, Italy. They underwent investigations such as electrocardiogram, echocardiogram, dental orthopantomography X-Ray and Computed Tomography, electroencephalograms, abdomen ultrasound, blood tests, IQ tests, genetic analysis. They both have an Intelligence Quotient greater than 70 and a negative neurologic exam. Each sister carries the same 1p36 deletion of about 2.3 Mb. Genetic analysis of the parents' blood samples (Single Nucleotide Polymorphism- array, karyotype and Fluorescent In Situ Hybridization) did not reveal any deletion, translocation or inversion and confirmed the paternity. A third sib of the probands does not carry the 1p36 deletion or other quantitative alterations. CONCLUSION: This report describes a new trait linked to monosomy 1p36, namely a mild intellectual outcome associated with significant dental anomalies. Our finding suggests that 1p36 deletion syndrome may present with a mild cognitive impairment or even with a normal intellectual development: this is very important for the genetic counselling, especially in a prenatal setting. Moreover, we report the third study with recurrent 1p36 deletion syndrome in two siblings, likely due to germline mosaicism. Finally, we believe that the dental anomalies should be investigated in 1p36 deletion syndrome and that the spectrum of the condition could be broader than we assume.

Phenotypic and Molecular Cytogenetic Analysis of a Case of Monosomy 1p36 Syndrome due to Unbalanced Translocation.

Monosomy 1p36 syndrome is one of the most common submicroscopic deletion syndromes, which is characterized by the presence of delayed developmental milestones, intellectual disability, and clinically recognizable dysmorphic craniofacial features. The syndrome comprises 4 cytogenetic groups including pure terminal deletions, interstitial deletions, complex rearrangements, and derivative chromosomes 1 due to unbalanced translocations, where unbalanced translocations represent the least percentage of all cases of monosomy 1p36 (7%). Most patients with monosomy 1p36 due to an unbalanced translocation can be cytogenetically diagnosed using conventional techniques. However, chromosomal microarray analysis is mandatory in these cases to detect copy number variance and size of the deletion and allows for setting a phenotype-genotype correlation. Here, we studied a 1.5-year-old female patient who showed intellectual disability, delayed milestones, hypotonia, seizures, and characteristic dysmorphic features including brachycephaly, straight eyebrows, deep-set eyes, downslanting palpebral fissures, midface hypoplasia, depressed nasal bridge, long philtrum, and pointed chin. Conventional cytogenetic analysis (CCA), microarray study, and fluorescence in situ hybridization (FISH) analysis were performed. CCA showed a translocation involving chromosomes 1 and 21, 45,XX,der(1)t(1;21)(p36.32;q21.1)dn. Microarray analysis revealed copy number losses at both 1p36 and proximal 21q. FISH confirmed the presence of the 1p36 deletion, but was not performed for 21q. We have concluded that phenotype-genotype correlation for monosomy 1p36 syndrome can be performed for the fundamental clinical manifestations; however, the final aspect of the syndrome depends on composite factors. Monosomy 1p36 due to unbalanced translocation may present either classically or with additional altered features of various severity based on the copy number variations involving different chromosomes.

Electroclinical features of epilepsy monosomy 1p36 syndrome and their implications.

OBJECTIVIES: Monosomy 1p36 syndrome is a recognized syndrome with multiple congenital anomalies; medical problems of this syndrome include developmental delay, facial dysmorphisms, hearing loss, short stature, brain anomalies, congenital heart defects. Epilepsy can be another feature but there are few data about the types of seizures and long term prognosis. The aim of this work was to analyse the electroclinical phenotype and the long-term outcome in patients with monosomy 1p36 syndrome and epilepsy. MATERIALS AND METHODS: Data of 22 patients with monosomy 1p36 syndrome and epilepsy were reconstructed by reviewing medical records. For each patient we analysed age at time of diagnosis, first signs of the syndrome, age at seizure onset, seizure type and its frequency, EEG and neuroimaging findings, the response to antiepileptic drugs treatment and clinical outcome up to the last follow-up assessment. RESULTS: Infantile Spasm (IS) represents the most frequent type at epilepsy onset, which occurs in 36.4% of children, and a half of these were associated with hypsarrhythmic electroencephalogram. All patients with IS had persistence of seizures, unlike other patients with different seizures onset. Children with abnormal brain neuroimaging have a greater chance to develop pharmacoresistant epilepsy. CONCLUSION: This syndrome represents a significant cause of IS: these patients, who develop IS, can suffer from pharmacoresistent epilepsy, that is more frequent in children with brain abnormalities.

Cutis laxa in a patient with 1p36 deletion syndrome.

Chromosome 1p36 deletion is the most common subtelomeric deletion syndrome characterized by variable features including unique facial appearance, intellectual disability, developmental delay, cardiac defects, seizures and hypotonia. Here, we report a patient with developmental delay, dilated cardiomyopathy, seizures, hirsutism and cutis laxa who was diagnosed with 1p36 deletion syndrome by chromosome microarray analysis. This patient is the first reported case of 1p36 deletion syndrome associated with cutis laxa and our results suggest that the 1p36 region contains one or more genes relevant to cutis laxa. This case also indicates the importance of considering chromosome abnormalities (microdeletion/microduplication syndromes) in patients presenting skin disorders combined with unexplained developmental delay, intellectual disability or multiple congenital abnormalities.

Electroclinical features of epilepsy associated with 1p36 deletion syndrome: A review.

1p36 terminal deletion is a recently recognized syndrome with multiple congenital anomalies and intellectual disability. It occurs approximately in 1 out of 5000 to 10,000 live births and is the most common subtelomeric microdeletion observed in human. Medical problems commonly caused by terminal deletions of 1p36 include developmental delay, intellectual disability, seizures, vision problems, hearing loss, short stature, brain anomalies, congenital heart defects, cardiomyopathy, renal anomalies and distinctive facial features. Although the syndrome is considered clinically recognizable, there is significant phenotypic variation among affected individuals. Genotype-phenotype correlation in this syndrome is complicated, because of the similar clinical evidence seen in patients with different deletion sizes. We review 34 scientific articles from 1996 to 2016 that described 315 patients with 1p36 delection syndrome. The aim of this review is to find a correlation between size of the 1p36-deleted segments and the neurological clinical phenotypes with the analysis of electro-clinical patterns associated with chromosomal aberrations, that is a major tool in the identification of epilepsy susceptibility genes. Our finding suggest that developmental delay and early epilepsy are frequent findings in 1p36 deletion syndrome that can contribute to a poor clinical outcome for this reason this syndrome should be searched for in patients presenting with infantile spasms associated with a hypsarrhythmic EEG, particulary if they are combined with dismorphic features, severe hypotonia and developmental delay.

Una revisión actualizada del síndrome de deleción (monosomía) 1p36 / An updated review of 1p36 deletion (monosomy) syndrome

El síndrome de monosomía 1p36 forma parte del grupo de enfermedades conocidas como «enfermedades de baja prevalencia¼ o «enfermedades raras¼. El objetivo del presente trabajo es revisar los hallazgos de los principales estudios realizados en niños diagnosticados con el síndrome de monosomía 1p36. El fenotipo del síndrome de deleción (monosomía) 1p36 delineado desde 1997 incluye rasgos craneofaciales dismórficos: fontanela anterior grande, cejas rectas, ojos hundidos, epicanto, raíz/puente nasal anchos, hipoplasia del tercio medio facial, orejas implantadas anormalmente, filtrum largo y barbilla puntiaguda; alteraciones neurológicas: convulsiones e hidrocefalia (en casos aislados); malformaciones cerebrales observadas en imágenes por resonancia magnética (IRM): ensanchamiento ventricular, ensanchamiento de espacios subaracnoideos, alteraciones morfológicas del cuerpo calloso, entre otras. La IRM evidencia en algunos pacientes atrofia cortical, retraso en la mielinización, áreas multifocales hiperintensas, leucomalacia periventricular y heterotopia periventricular. Estos pacientes cursan con discapacidad intelectual, retrasos en el desarrollo motor, de la comunicación, del lenguaje, en el área personal-social y en la conducta adaptativa. También se observan alteraciones en el sistema auditivo, visual, cardiaco, endocrino, genitourinario, dermatológico y esquelético. Conclusiones: Existen datos de aproximadamente 100 casos en el mundo desde 1981. Esta enfermedad rara es el síndrome más común de microdeleción subtelomérica. La técnica de hibridación in situ con fluorescencia y la técnica de hibridación genómica comparativa (array-CGH) son las que mejor permiten su diagnóstico. Por el momento no existe ningún tratamiento médico efectivo para esta enfermedad.

The Monosomy 1p36 deletion syndrome is part of the group of diseases known as Rare Diseases. The objective of the present work is to review the characteristics of Monosomy 1p36 deletion syndrome. The monosomy 1p36 deletion syndrome phenotype includes: dysmorphic craniofacial features; large anterior fontanelle, unibrow, deep-set eyes, epicanthus, wide nasal root/bridge, mandible hypoplasia, abnormal location of the pinna, philtrum and pointed chin; neurological alterations: seizures and hydrocephalus (in some cases). Cerebral malformations: ventricular hypertrophy, increased subarachnoid space, morphological alterations of corpus callosum, cortical atrophy, delays in myelinisation, periventricular leukomalacia and periventricular heterotopia. These alterations produce intellectual disability and delays in motor growth, communication skills, language, social and adaptive behaviour. It is Hearing and vision impairments are also observed in subjects with this syndrome, as well as alterations of cardiac, endocrine and urinary systems and alterations at skin and skeletal level. Conclusions: Approximately 100 cases have been documented since 1981. This rare disease is the most common sub-telomeric-micro-deletion syndrome. In situ hybridization with fluorescence (FISH) and array-comparative genomic hybridization (CGH-array) are at present the two best diagnostic techniques. There is currently no effective medical treatment for this disease.

[An updated review of 1p36 deletion (monosomy) syndrome]. / Una revisión actualizada del síndrome de deleción (monosomía) 1p36.

The Monosomy 1p36 deletion syndrome is part of the group of diseases known as Rare Diseases. The objective of the present work is to review the characteristics of Monosomy 1p36 deletion syndrome. The monosomy 1p36 deletion syndrome phenotype includes: dysmorphic craniofacial features; large anterior fontanelle, unibrow, deep-set eyes, epicanthus, wide nasal root/bridge, mandible hypoplasia, abnormal location of the pinna, philtrum and pointed chin; neurological alterations: seizures and hydrocephalus (in some cases). Cerebral malformations: ventricular hypertrophy, increased subarachnoid space, morphological alterations of corpus callosum, cortical atrophy, delays in myelinisation, periventricular leukomalacia and periventricular heterotopia. These alterations produce intellectual disability and delays in motor growth, communication skills, language, social and adaptive behaviour. It is Hearing and vision impairments are also observed in subjects with this syndrome, as well as alterations of cardiac, endocrine and urinary systems and alterations at skin and skeletal level. CONCLUSIONS: Approximately 100 cases have been documented since 1981. This rare disease is the most common subtelomeric-micro-deletion syndrome. In situ hybridization with fluorescence (FISH) and array-comparative genomic hybridization (CGH-array) are at present the two best diagnostic techniques. There is currently no effective medical treatment for this disease.