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Genetic Causes of Lymphedema 3 Matthieu J Genetic Causes of Lymphedema 3 Matthieu J. Schlögel , Pascal Brouillard , Laurence M. Boon , and Miikka Vikkula Key Points • Panel-based targeted next-generation sequenc- • Careful patient examination for all signs and ing is the most effi cient approach for diagnos- symptoms is important for precise clinical tic screens. diagnosis. • Secondary lymphedema may be infl uenced by • Primary lymphedema has a high underlying genetic predisposition. genetic heterogeneity. Currently, 20 genes are implicated. • Neonatal edema, including non-immune Introduction hydrops fetalis, can also be caused by muta- tions in some of these genes. Lymphedema is known since the middle of the • Genetic predisposing factors are unknown for nineteenth century, yet the fi rst genes associated a large fraction of patients. with this condition have been discovered only in • There is large variability in clinical expressiv- the twenty-fi rst century. Since then, more than ity and often incomplete penetrance for all 20 genes have been linked to the development of signs and symptoms. primary lymphedema. Originally discovered using linkage analysis in large families or animal models, the more recent approach using Next- Generation Sequencing (NGS) has allowed to discover genes using smaller families and even sporadic cases. In parallel, detailed in vitro and M. J. Schlögel , M.Sc. • P. Brouillard , Ph.D. in vivo studies on molecular and cellular mecha- Laboratory of Human Molecular Genetics, de Duve Institute , Université catholique nisms involved in lymphangiogenesis have unrav- de Louvain , Brussels , Belgium eled numerous novel functional candidate genes. L. M. Boon , M.D., Ph.D. Primary lymphedema can be present as an Cliniques universitaires Saint-Luc, Center inherited or a sporadic trait. It can be dominant, for Vascular Anomalies , Universite catholique recessive (with consanguinity or not), or linked to de Louvain , Brussels , Belgium the X-chromosome. There is important heteroge- M. Vikkula , M.D., Ph.D. (*) neity in the clinical appearance of lymphedema. Laboratory of Human Molecular Genetics, Primary lymphedema can be the unique sign, de Duve Institute , Université catholique de Louvain , Brussels , Belgium affect different parts of the body (limb(s), arms, hands, head and neck, abdomen, etc.), be unilat- Walloon Excellence in Lifesciences and Biotechnology (WELBIO) , Brussels , Belgium eral or bilateral, and appear at different ages at e-mail: [email protected] onset. It can also be part of a complex syndrome, A.K. Greene et al. (eds.), Lymphedema: Presentation, Diagnosis, and Treatment, 19 DOI 10.1007/978-3-319-14493-1_3, © Springer International Publishing Switzerland 2015 [email protected] 20 M.J. Schlögel et al. some of which are very rare, with only few cases edema when mutated. The penetrance of lymph- reported. edema is though often incomplete, i.e., even Our current knowledge on the environmental though an individual carries a familial mutation, and genetic variability as the cause of primary (s)he does not necessarily have lymphedema. lymphedema is limited. Most of the Mendelian This is also true for the other associated signs and mutations have been identifi ed in a limited num- symptoms listed in Table 3.1 . ber of patients or even only few families used in The cardiovascular system is often affected; the original linkage study, several of the genes varicose veins are not infrequent. Hydrocele can have been identifi ed very recently limiting the be present in at least four of the entities time they have been used in clinical setting for (Table 3.1 ). In the nervous system, symptoms diagnostic screening, the number of patients range from hearing loss to learning diffi culties screened in reports is often very limited, and and macrocephaly. Cutaneous and subcutaneous most screens have been done on gene-by-gene symptoms are frequent, including infection, pap- basis. Moreover, some of the clinical signs may illomas, and cellulitis, many of which are consid- be missed, and thus, the clinical classifi cation is ered secondary. Yet there are subtype-specifi c not necessarily correct. This renders it diffi cult to differences in prevalence (Table 3.1 ). In the mus- have a representative and a comprehensive over- culoskeletal system, syndactyly or camptodac- view of the current state of the art. tyly is observed. Mutations in GATA2 affect the In this chapter, we make an extensive review respiratory system, generating pulmonary alveo- of the medical literature. Clinical data was col- lar proteinosis. Mutations in GATA2, as well as lected for all patients with a proven mutation, IKBKG, also predispose to severe infections. taking into account each mentioned sign and Involvement of the digestive system is relatively symptom. In the presentation, we divide the rare (GJC2 and IKBKG), and renal abnormalities genes (and associated lymphedemas) into two have been reported only in some cases (VEGFR3, groups. The fi rst category includes the genes that FOXC2, and SOX18). Patients with a GATA2 cause lymphedema as the major sign, which is mutation have a susceptibility to hematologic also the reason for medical consultation malignancies. (Table 3.1 ). The second group contains the genes that are related to a usually well-known syn- drome and for which lymphedema is minor sign Genetic Differential Diagnosis: Which (Table 3.2 ). Only a quarter of all cases are Gene to Screen? explained by mutations within the 20 genes. It appears that the historical classifi cation based on The unraveled high genetic heterogeneity in pri- the age of onset, i.e., congenital (at birth or early mary lymphedema has resulted in a high number in life), praecox (teenage years), and tarda (late in of clinical subcategories. Currently 21 geneti- life) is becoming irrelevant, as this does not cor- cally defi ned subgroups, as well as the subgroup relate with the genetic background. Instead, the of undefi ned ones, exist. Moreover, the latter clinical presentation of the signs and symptoms mostly likely involves several genes. Some of the can be helpful to associate the primary lymph- genetically defi ned 21 subgroups have typical edema to the most likely causative gene. signs, the presence of which can help in clinical diagnosis. In addition, familial history (Table 3.3 ) is an important factor in determining candidate Lymphedema as a Major Sign genes for diagnostic screens. The “unique” signs, i.e., those specifi c to one Phenotype of Patients or two genes, are variable. Isolated lower limb lymphedema present at birth (the classic presen- Lymphedema is the major sign for 14 of the tation of Milroy disease) suggests a FLT4/ genes currently known to cause primary lymph- VEGFR3 (FMS-like tyrosine kinase 4/vascular [email protected] 3 Genetic Causes of Lymphedema 21 ITGA9 (continued) [email protected] FLT4 FLT4 VEGFC FOXC2 PTPN14 GJC2 GJA1 KIF11 CCBE FAT4 GATA2 SOX18 IKBKG HGF Hydrops (fetalis) Lymphangiectasia Lymphatic anomaly Varicose veins ¶ – Vascular anomaly 36 % Hemangioma – – – Hydrocoele Telangiectasia 7 28 % % Heart 1/6 defect 4/7 ¶ – – ¶ Neurologic – defect – – 35 Microcephaly % – – 49 % – 2/4 Macrocephaly – – – – Ptosis – – – – 1 – Ophthalmologic % problem – Hearing 13 loss – – % – 42 25 – % % – – – – – – – Skin 1/5 infection – – 7 % ¶ Cellulitis – – – – – – 74 % Eczema – 23 – 1/7 – % – – Skin – problem 100 – – % 23 – % – Hair – – – problem – 7/9 – – – – – Nail or toe – – anomaly – – Distichiasis – – – – – – – 19 % – 25 Dental % – 59 anomaly % – – 10 30 % % – 28 – % – – 1/6 – – ¶ – 2/7 ¶ – – – ¶ 3/3 9 – % ¶ – – ¶ – – – 15 – – – 69 19 % – – % % – – – 12 – % – – 17 – 8 % – % – – – – – 91 – – % – – – – – – 1/4 – – – 1/8 – 46 – % – 42 % 33 % 50 – – – % – – 3/3 1/9 – – – 86 – – % – – – – – – – 100 – – % – – – – – 3/5 – – – – 8 – – – % – – ¶ – – 1/2 – – – – – – – – – – – – – – – – – – 7 – % 2/9 – – – – – – – – – – – 7 – % ¶ – – – – – – – – – – – – – – – – – – – – ¶ – – – – – – – – – – – – – 3/5 – – – – – 1/5 78 – % – – – – 5/5 1/2 – – – – – – – – – – – – – – – – – – – Signs and symptoms by mutated gene; lymphedema a cardinal sign Signs and symptoms by mutated gene; lymphedema a cardinal sign Table Table 3.1 System Cardiovascular Lymphedema Sign 81 % 8/8 71 % (139) Nervous 5/7 (10) (120) 100 % Intellectual (7) disability 1/5 51 % 5 % (12) 100 % – Integumentary 9/9 (5) Papilloma 15 (papule) % (75) 3 % (13) 5/6 10 – (9) % 13 % 20 % (110) 3/4 – – (6) 0/4 (70) – – (4) 69 % (12) – 69 % 7/9 – – – ¶ – – – – – – 1/5 – – – 22 M.J. Schlögel et al. ITGA9 studied is in parentheses. ¶ represents symptoms [email protected] FLT4 FLT4 VEGFC FOXC2 PTPN14 GJC2 GJA1 KIF11 CCBE FAT4 GATA2 SOX18 IKBKG HGF – – – – – – – – – 86 % – 24 % – – Cleft lip and Palate Dysmorphic face Thoracic/vertebral Joint – Syndactyly 4/5 – Choanal atresia – – Bone – 21 % ¶ – – Warts ¶ 7 % ¶ Hematological dysfunction – – – ¶ – – – – – Kidney – – – – – M:F > 2:1 2 % 7/7 – ¶ – – – – – 40 – % – – – 100 – % – – 2 % 9/9 – – – – 4/5 – ¶ – – – – – 27 7 % – % 31 7 % % – 1/5 – – – – – ¶ 2/8 – – – – – – – – ¶ – – – – – 38 – % – – – – 6/9 – – – – – – – – – – – – – – – – – – – – 53 – % – 10 – % – – – – – – – – – – 2/5 – – – – – – – – – (continued) Table 3.1 Table System Musculoskeletal Reduced growth Sign – – Respiratory Immunitary – (139) (10) Pulmonary Infection – (120) Digestive (7) Urogenital – – (12) Gastrointestinal Genitourinary – Malignancy – (5) – The frequency of observation is translated in percentage when the number examined patients was above 10. Number patient (75) – mentioned occasionally
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