Beckwith-Wiedemann syndrome due to paternal uniparental disomy of chromosome 11
General Information (adopted from Orphanet):
| Synonyms, Signs: |
UPD(11)pat Mosaic paternal uniparental disomy of chromosome 11 |
| Number of Symptoms | 35 |
| OrphanetNr: | 96193 |
| OMIM Id: |
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| ICD-10: |
Q87.3 |
| UMLs: |
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| MeSH: |
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| MedDRA: |
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| Snomed: |
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Prevalence, inheritance and age of onset:
| Prevalence: | No data available. |
| Inheritance: |
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| Age of onset: |
Antenatal Neonatal 1356785 [IBIS] |
Disease classification (adopted from Orphanet):
| Parent Diseases: |
Beckwith-Wiedemann syndrome
-Rare cardiac disease -Rare developmental defect during embryogenesis -Rare genetic disease -Rare maxillo-facial surgical disease -Rare oncologic disease -Rare otorhinolaryngologic disease -Rare renal disease Uniparental disomy of paternal origin -Rare developmental defect during embryogenesis -Rare genetic disease |
Comment:
| Beckwith-Wiedemann syndrome (BWS) is a complex, multigenic disorder associated, in up to 90% of patients, with alteration in the expression or function of one or more genes in the 11p15.5 imprinted gene cluster. There are several molecular anomalies associated with BWS and the large proportion of cases, about 85%, is sporadic and karyotypically normal. One of the major categories of BWS molecular alteration (10–20% of cases) is represented by mosaic paternal uniparental disomy (pUPD), namely patients with two paternally derived copies of chromosome 11p15 and no maternal contribution for that. In these patients, in addition to the effects of IGF2 overexpression, a decreased level of the maternally expressed gene CDKN1C may contribute to the BWS phenotype. It has been demonstrated that BWS patients with paternal UPD always show mosaicisms, suggesting that all cases had arisen as a postzygotic event; a possible explanation is that lack of one or more chromosome 11 maternally expressed genes may lead to embryonic lethality. The critical region for pUPD is telomeric to chromosome 11p13 and always includes the region where map some BWS genes (IGF2, H19 and CDKN1C). Some cases with mosaic pUPD for the whole chromosome 11 have been also described and the clinical findings did not differ from patients with pUPD restricted to a small part of 11p. Although the extent of segmental disomy and proportion of cells with pUPD is variable, in all BWS cases the paternal UPD is isodisomic (PMID:21248736). BWS patients with mosaic paternal isodisomy affecting 11p15.5 exhibit reduced levels of CDKN1C expression in somatic tissues including the kidney and liver relative to normal controls. Although overall expression was reduced, some expression from the paternally derived CDKN1C allele was evident, consistent with incomplete paternal imprinting of the gene. One patient showed evidence of maternal allele silencing in addition to allele imbalance (PMID:10424812). 20% of BWS cases are caused by paternal uniparental isodisomy for chromosome 11p ( pUPD11p), which leads to a combined loss of p57/CDKN1C and KCNQ1 expression as well as biallelic IGF2 expression. This same genetic change, pUPD11p, can lead to classic BWS, but can often lead to more subtle features including isolated hemihypertrophy of a limb or isolated overgrowth of an organ (PMID:26545876). UPD is a post-zygotic event presenting as a mosaic phenomenon and, therefore, not always detectable on blood leukocyte DNA, but demonstrable at the tissue level in many BWS patients (PMID:22015620). |
Symptom Information:
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(HPO:0001627) | Abnormal heart morphology | Rare [IBIS] | 25898929 | IBIS | 19 / 7739 | |
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(HPO:0001520) | Large for gestational age | Frequent [IBIS] | 10424812; 26863215; 23197114; 26545876 | IBIS | 34 / 7739 | |
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(HPO:0002150) | Hypercalciuria | 25898929 | IBIS | 45 / 7739 | ||
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(HPO:0001943) | Hypoglycemia | Frequent [IBIS] | 1675767; 25898929 | IBIS | 131 / 7739 | |
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(HPO:0001998) | Neonatal hypoglycemia | Frequent [IBIS] | 26863215; 23197114; 26545876 | IBIS | 22 / 7739 | |
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(HPO:0000825) | Hyperinsulinemic hypoglycemia | 26863215; 23197114; 26545876 | IBIS | 18 / 7739 | ||
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(HPO:0000158) | Macroglossia | Frequent [IBIS] | 1675767; 1356785; 10424812; 26863215; 26545876; 22015620 | IBIS | 119 / 7739 | |
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(HPO:0000729) | Autistic behavior | 25898929 | IBIS | 27 / 7739 | ||
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(HPO:0100553) | Hemihypertrophy of lower limb | 26863215 | IBIS | 1 / 7739 | ||
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(HPO:0001528) | Hemihypertrophy | Frequent [IBIS] | 21248736; 10424812; 26545876; 12138139; 22015620; 25898929 | IBIS | 13 / 7739 | |
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(HPO:0002884) | Hepatoblastoma | 10424812 | IBIS | 11 / 7739 | ||
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(HPO:0002240) | Hepatomegaly | 10424812; 26545876 | IBIS | 467 / 7739 | ||
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(HPO:0003271) | Visceromegaly | Frequent [IBIS] | 1675767; 1356785; 25898929 | IBIS | 8 / 7739 | |
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(HPO:0010866) | Abdominal wall defect | Frequent [IBIS] | 10424812; 26863215; 26545876; 25898929 | IBIS | 5 / 7739 | |
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(HPO:0001540) | Diastasis recti | Occasional [IBIS] | 22015620 | IBIS | 23 / 7739 | |
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(HPO:0001537) | Umbilical hernia | Occasional [IBIS] | 10424812; 26863215; 26545876; 25898929 | IBIS | 206 / 7739 | |
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(HPO:0001539) | Omphalocele | Occasional [IBIS] | 1675767 | IBIS | 102 / 7739 | |
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(HPO:0000356) | Abnormality of the outer ear | Frequent [IBIS] | 26545876 | IBIS | 85 / 7739 | |
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(HPO:0009908) | Anterior creases of earlobe | 10424812; 26863215 | IBIS | 10 / 7739 | ||
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(HPO:0001052) | Nevus flammeus | Frequent [IBIS] | 22015620 | IBIS | 88 / 7739 | |
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(HPO:0000995) | Melanocytic nevus | 23197114 | IBIS | 63 / 7739 | ||
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(HPO:0000077) | Abnormality of the kidney | Occasional [IBIS] | 12138139; 25898929 | IBIS | 73 / 7739 | |
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(HPO:0004742) | Abnormality of the renal collecting system | 22015620 | IBIS | 4 / 7739 | ||
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(HPO:0000126) | Hydronephrosis | 26863215 | IBIS | 119 / 7739 | ||
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(HPO:0000105) | Enlarged kidneys | 26863215; 22015620 | IBIS | 30 / 7739 | ||
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(HPO:0000121) | Nephrocalcinosis | 25898929 | IBIS | 57 / 7739 | ||
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(HPO:0000787) | Nephrolithiasis | 22015620 | IBIS | 78 / 7739 | ||
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(HPO:0005562) | Multiple renal cysts | 22015620 | IBIS | 16 / 7739 | ||
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(HPO:0002667) | Nephroblastoma | 21248736; 1675767; 10424812; 22015620 | IBIS | 30 / 7739 | ||
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(HPO:0000069) | Abnormality of the ureter | 10424812 | IBIS | 47 / 7739 | ||
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(HPO:0002664) | Neoplasm | 12138139; 25898929 | IBIS | 111 / 7739 | ||
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(HPO:0002898) | Embryonal neoplasm | Occasional [IBIS] | 25898929 | IBIS | 6 / 7739 | |
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(HPO:0001548) | Overgrowth | 1675767; 1356785; 22015620 | IBIS | 27 / 7739 | ||
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(MedDRA:10051879) | Tongue cyst | 26863215 | IBIS | 1 / 7739 | ||
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(OMIM) | Fetal lobulations of kidney | 10424812 | IBIS | 2 / 7739 |
Associated genes:
ClinVar (via SNiPA)
| Gene symbol | Variation | Clinical significance | Reference |
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