Microcephaly-Capillary Malformation Syndrome

Abstract

Microcephaly-capillary malformation is a relatively new syndrome, which has been reported since 2011 by three different research groups. It is an ultra-rare syndrome characterized by the co-occurrence of microcephaly and multiple capillary malformations in the skin, distal limb anomalies (ranging from nail dystrophy to total absence of one or more phalanxes and mostly localized in the foot), facial dysmorphisms, brain structural anomalies (reduced gyration, widened axial spaces, thin cortex, optic nerve atrophy), early-onset severe intractable epilepsy, and profound mental delay. Autosomal recessive mutations in STAMBP gene (2p13.1) have been reported as the only cause of the disorder, with a high penetrance. Currently, no definitive cure is available for the disorder, and treatment is mainly based on multiple antiepileptic drugs for the treatment of seizures, especially in the first years of life. Data on life-long concerns have not been reported, the older patient described so far being an 8-year-old boy.

Keywords

microcephaly - capillary malformation - limb anomalies - mental delay - epilepsy - STAMBP gene

• References

• 1 Carter MT, Boycott KM. Microcephaly-capillary malformation syndrome: a story of rapid emergence of a new recognizable entity. Am J Med Genet A 2011; 155A [phone]
• 2 Carter MT, Geraghty MT, De La Cruz L. , et al. A new syndrome with multiple capillary malformations, intractable seizures, and brain and limb anomalies. Am J Med Genet A 2011; 155A [phone]
• 3 Mirzaa GM, Paciorkowski AR, Smyser CD, Willing MC, Lind AC, Dobyns WB. The microcephaly-capillary malformation syndrome. Am J Med Genet A 2011; 155A [phone]
• 4 McDonell LM, Mirzaa GM, Alcantara D. , et al; FORGE Canada Consortium. Mutations in STAMBP, encoding a deubiquitinating enzyme, cause microcephaly-capillary malformation syndrome. Nat Genet 2013; 45 (05) 556-562
• 5 Ruggieri M, Polizzi A. From Aldrovandi's “Homuncio” (1592) to Buffon's girl (1749) and the “Wart Man” of Tilesius (1793): antique illustrations of mosaicism in neurofibromatosis?. J Med Genet 2003; 40 (03) 227-232
• 6 Ruggieri M, Praticò AD, Caltabiano R, Polizzi A. Rediagnosing one of Smith's patients (John McCann) with “neuromas tumours” (1849). Neurol Sci 2017; 38 (03) 493-499
• 7 Ruggieri M, Praticò AD, Scuderi A, Sorge G, Polizzi A. The multiple faces of artwork diagnoses. Lancet Neurol 2017; 16 (06) 417-418
• 8 Ruggieri M, Praticò AD, Caltabiano R, Polizzi A. Early history of the different forms of neurofibromatosis from ancient Egypt to the British Empire and beyond: first descriptions, medical curiosities, misconceptions, landmarks, and the persons behind the syndromes. Am J Med Genet A 2018; 176 (03) 515-550
• 9 Ruggieri M, Praticò AD, Serra A. , et al. Early history of neurofibromatosis type 2 and related forms: earliest descriptions of acoustic neuromas, medical curiosities, misconceptions, landmarks and the pioneers behind the eponyms. Childs Nerv Syst 2017; 33 (04) 549-560
• 10 Ruggieri M, Gabriele AL, Polizzi A. , et al. Natural history of neurofibromatosis type 2 with onset before the age of 1 year. Neurogenetics 2013; 14 (02) 89-98
• 11 Ruggieri M, Polizzi A, Spalice A. , et al. The natural history of spinal neurofibromatosis: a critical review of clinical and genetic features. Clin Genet 2015; 87 (05) 401-410
• 12 Ruggieri M, Praticò AD, Evans DGE. Diagnosis, management and new therapeutic options in childhood neurofibromatosis type 2 and related disorders. Semin Pediatr Neurol 2015; 22 (04) 240-258
• 13 Ruggieri M, Praticò AD, Serra A. , et al. Childhood neurofibromatosis type 2 (NF2) and related disorders: from bench to bedside and biologically targeted therapies. Acta Otorhinolaryngol Ital 2016; 36 (05) 345-367
• 14 Caltabiano R, Magro G, Polizzi A. , et al. A mosaic pattern of INI1/SMARCB1 protein expression distinguishes Schwannomatosis and NF2-associated peripheral schwannomas from solitary peripheral schwannomas and NF2-associated vestibular schwannomas. Childs Nerv Syst 2017; 33 (06) 933-940
• 15 Ruggieri M, Iannetti P, Clementi M. , et al. Neurofibromatosis type 1 and infantile spasms. Childs Nerv Syst 2009; 25 (02) 211-216
• 16 Ruggieri M. Familial hypomelanosis of ito: implications for genetic counselling. Am J Med Genet 2000; 95 (01) 82-84
• 17 Ruggieri M, Magro G, Ruggieri M, Polizzi A. Tumors and hypomelanosis of Ito. Arch Pathol Lab Med 2001; 125 (05) 599-601
• 18 Ruggieri M, Mastrangelo M, Spalice A. , et al. Bilateral (perisylvian and opercular) polymicrogyria and neurofibromatosis type 1. Am J Med Genet 2011; 155: 582-585
• 19 Pavone P, Praticò AD, Ruggieri M, Falsaperla R. Hypomelanosis of Ito: a round on the frequency and type of epileptic complications. Neurol Sci 2015; 36 (07) 1173-1180
• 20 Carter MT, Mirzaa G, McDonell LM, Boycott KM. Microcephaly-capillary malformation syndrome. In: Pagon RA, Adam MP, Ardinger HH, Wallace SE, Amemiya A, Bean LJH. , et al., eds. GeneReviews(R). Seattle (WA): 1993. . Available at: https://www.ncbi.nlm.nih.gov/pubmed/24354023 . Accessed October 12, 2017
• 21 Iannetti P, Parisi P, Spalice A, Ruggieri M, Zara F. Addition of verapamil in the treatment of severe myoclonic epilepsy in infancy. Epilepsy Res 2009; 85 (01) 89-95
• 22 Matricardi S, Spalice A, Salpietro V. , et al. Epilepsy in the setting of full trisomy 18: a multicenter study on 18 affected children with and without structural brain abnormalities. Am J Med Genet C Semin Med Genet 2016; 172 (03) 288-295
• 23 Ruggieri M, Rizzo R, Pavone P, Babeli S, Sorge G, Happle R. Temporal triangular alopecia in a mother and her daughter associated with mental retardation and seizures. Arch Dermatol 2000; 136: 426-427
• 24 Pavone P, Falsaperla R, Ruggieri M. , et al. Clinical course of NMDAr encephalitis and effectiveness of cyclophosphamide treatment. J Pediatr Neurol 2017; 15: 84-89
• 25 Praticò AD, Falsaperla R, Ruggieri M, Corsello G, Pavone P. Prognostic challenges of SCN1A genetic mutations: report on two children with mild features. J Pediatr Neurol 2016; 14: 82-88
• 26 Papetti L, Tarani L, Nicita F. , et al. Macrocephaly-capillary malformation syndrome: description of a case and review of clinical diagnostic criteria. Brain Dev 2012; 34 (02) 143-147
• 27 Ruggieri M, Milone P, Pavone P. , et al. Nevus vascularis mixtus (cutaneous vascular twin nevi) associated with intracranial vascular malformation of the Dyke-Davidoff-Masson type in two patients. Am J Med Genet A 2012; 158A (11) 2870-2880
• 28 Ruggieri M, Polizzi A, Strano S. , et al. Mixed vascular nevus syndrome: a report of four new cases and a literature review. Quant Imaging Med Surg 2016; 6 (05) 515-524
• 29 Barbagallo M, Ruggieri M, Incorpora G. , et al. Infantile spasms in the setting of Sturge-Weber syndrome. Childs Nerv Syst 2009; 25 (01) 111-118
• 30 Ruggieri M, D'Arrigo G, Abbate M, Distefano A, Upadhyaya M. Multiple coronary artery aneurysms in a child with neurofibromatosis type 1. Eur J Pediatr 2000; 159 (07) 477-480
• 31 Ruggieri M, Packer RJ. Why do benign astrocytomas become malignant in NF1?. Neurology 2001; 56 (07) 827-829
• 32 Ruggieri M, Polizzi A. Choroidal abnormalities and mental retardation in neurofibromatosis type 1. Lancet 2001; 357 (9252): 311-312
• 33 Ruggieri M, Pavone V, Tiné A. , et al. Ossifying fibroma of the skull in a patient with neurofibromatosis type 1. Case report. J Neurosurg 1996; 85 (05) 941-944
• 34 Eerola I, Boon LM, Mulliken JB. , et al. Capillary malformation-arteriovenous malformation, a new clinical and genetic disorder caused by RASA1 mutations. Am J Hum Genet 2003; 73 (06) 1240-1249
• 35 Isidor B, Barbarot S, Bénéteau C, Le Caignec C, David A. Multiple capillary skin malformations, epilepsy, microcephaly, mental retardation, hypoplasia of the distal phalanges: report of a new case and further delineation of a new syndrome. Am J Med Genet A 2011; 155A [phone]
• 36 Bueno AN, Shrestha RK, Ronau JA. , et al. Dynamics of an active-site flap contributes to catalysis in a JAMM family metallo deubiquitinase. Biochemistry 2015; 54 (39) 6038-6051
• 37 Davies CW, Paul LN, Kim MI, Das C. Structural and thermodynamic comparison of the catalytic domain of AMSH and AMSH-LP: nearly identical fold but different stability. J Mol Biol 2011; 413 (02) 416-429
• 38 Ishii N, Owada Y, Yamada M. , et al. Loss of neurons in the hippocampus and cerebral cortex of AMSH-deficient mice. Mol Cell Biol 2001; 21 (24) 8626-8637
• 39 Faqeih EA, Bastaki L, Rosti RO. , et al. Novel STAMBP mutation and additional findings in an Arabic family. Am J Med Genet A 2015; 167A [phone]
• 40 Pavlović M, Neubauer D, Al Tawari A, Heberle LC. The microcephaly-capillary malformation syndrome in two brothers with novel clinical features. Pediatr Neurol 2014; 51 (04) 560-565
• 41 Naseer MI, Sogaty S, Rasool M. , et al. Microcephaly-capillary malformation syndrome: brothers with a homozygous STAMBP mutation, uncovered by exome sequencing. Am J Med Genet A 2016; 170 (11) 3018-3022
• 42 Ruggieri M, Iannetti P, Pavone L. Delineation of a newly recognized neurocutaneous malformation syndrome with “cutis tricolor”. Am J Med Genet A 2003; 120A [phone]
• 43 Ruggieri M, Iannetti F, Polizzi A. , et al. Cataracts in the setting of a newly recognised neurocutaneous malformation syndrome with cutis tricolor. Br J Ophthalmol 2009; 93: 175-176
• 44 Ruggieri M, Roggini M, Kennerknecht I, Polizzi A, Distefano A, Pavone V. Spectrum of skeletal abnormalities in a complex malformation syndrome with “cutis tricolor” (Ruggieri-Happle syndrome). Acta Paediatr 2011; 100 (01) 121-127
• 45 Nicita F, Spalice A, Roggini M. , et al. Complex malformation (Ruggieri-Happle) phenotype with “cutis tricolor” in a 10-year-old girl. Brain Dev 2012; 34 (10) 869-872
• 46 Ruggieri M, Polizzi A, Schepis C. , et al. Cutis tricolor: a literature review and report of five new cases. Quant Imaging Med Surg 2016; 6 (05) 525-534
• 47 Lionetti E, Pavone P, Kennerknecht I. , et al. Neurological manifestations in individuals with pure cutaneous or syndromic (Ruggieri-Happle syndrome) phenotypes with “cutis tricolor”: a study of 14 cases. Neuropediatrics 2010; 41 (02) 60-65
• 48 Pavone P, Praticò AD, Rizzo R. , et al. A clinical review on megalencephaly: a large brain as a possible sign of cerebral impairment. Medicine (Baltimore) 2017; 96 (26) e6814
• 49 Pavone P, Nigro F, Falsaperla R. , et al. Hemihydranencephaly: living with half brain dysfunction. Ital J Pediatr 2013; 39: 3
• 50 Polizzi A, Pavone P, Ciancio E, La Rosa C, Sorge G, Ruggieri M. Hypertrichosis cubiti (hairy elbow syndrome): a clue to a malformation syndrome. J Pediatr Endocrinol Metab 2005; 18 (10) 1019-1025
• 51 Spalice A, Ruggieri M, Grosso S. , et al. Dysembryoplastic neuroepithelial tumors: a prospective clinicopathologic and outcome study of 13 children. Pediatr Neurol 2010; 43 (06) 395-402
• 52 Brancati F, Travaglini L, Zablocka D. , et al; International JSRD Study Group. RPGRIP1L mutations are mainly associated with the cerebello-renal phenotype of Joubert syndrome-related disorders. Clin Genet 2008; 74 (02) 164-170
• 53 Ruggieri M. Cutis tricolor: congenital hyper- and hypopigmented lesions in a background of normal skin with and without associated systemic features: further expansion of the phenotype. Eur J Pediatr 2000; 159 (10) 745-749
• 54 Ruggieri M, Pavone P, Polizzi A. , et al. Ophthalmological manifestations in segmental neurofibromatosis type 1. Br J Ophthalmol 2004; 88 (11) 1429-1433
• 55 Ruggieri M, Polizzi A. Segmental neurofibromatosis. J Neurosurg 2000; 93 (03) 530-532
• 56 Ruggieri M, Tigano G, Mazzone D, Tiné A, Pavone L. Involvement of the white matter in hypomelanosis of Ito (incontinentia pigmenti achromiens). Neurology 1996; 46 (02) 485-492
• 57 Ruggieri M. Mosaic (segmental) neurofibromatosis type 1 (NF1) and type 2 (NF2): no longer neurofibromatosis type 5 (NF5). Am J Med Genet 2001; 101 (02) 178-180
• 58 Ruggieri M, Pavone V, De Luca D, Franzò A, Tiné A, Pavone L. Congenital bone malformations in patients with neurofibromatosis type 1 (Nf1). J Pediatr Orthop 1999; 19 (03) 301-305
• 59 Sorge G, Ruggieri M, Polizzi A, Scuderi A, Di Pietro M. SHORT syndrome: a new case with probable autosomal dominant inheritance. Am J Med Genet 1996; 61 (02) 178-181
• 60 Polizzi A, Pavone P, Parano E, Incorpora G, Ruggieri M. Lack of progression of brain atrophy in Aicardi-Goutières syndrome. Pediatr Neurol 2001; 24 (04) 300-302
• 61 Zaqout S, Morris-Rosendahl D, Kaindl AM. Autosomal recessive primary microcephaly (MCPH): an update. Neuropediatrics 2017; 48 (03) 135-142
• 62 Praticò AD, Caraci F, Pavone P, Falsaperla R, Drago F, Ruggieri M. Propranolol: effectiveness and failure in infantile cutaneous hemangiomas. Drug Saf Case Rep 2015; 2 (01) 6
• 63 Happle R. Capillary malformations: a classification using specific names for specific skin disorders. J Eur Acad Dermatol Venereol 2015; 29 (12) 2295-2305
• 64 Burns AJ, Navarro JA, Cooner RD. Classification of vascular anomalies and the comprehensive treatment of hemangiomas. Plast Reconstr Surg 2009; 124 (1, Suppl): 69e-81e
• 65 Walton RG, Jacobs AH, Cox AJ. Pigmented lesions in newborn infants. Br J Dermatol 1976; 95 (04) 389-396
• 66 Ruggieri M, Praticò AD. Mosaic neurocutaneous disorders and their causes. Semin Pediatr Neurol 2015; 22 (04) 207-233
• 67 Jacobs AH, Walton RG. The incidence of birthmarks in the neonate. Pediatrics 1976; 58 (02) 218-222
• 68 Tarquinio DC, Hou W, Berg A. , et al. Longitudinal course of epilepsy in Rett syndrome and related disorders. Brain 2017; 140 (02) 306-318
• 69 Sachdeva R, Donkers SJ, Kim SY. Angelman syndrome: a review highlighting musculoskeletal and anatomical aberrations. Clin Anat 2016; 29 (05) 561-567
• 70 Kline AD, Calof AL, Schaaf CA. , et al. Cornelia de Lange syndrome: further delineation of phenotype, cohesin biology and educational focus, 5th Biennial Scientific and Educational Symposium abstracts. Am J Med Genet A 2014; 164A [phone]
• 71 de Koning TJ. Amino acid synthesis deficiencies. J Inherit Metab Dis 2017; 40 (04) 609-620
• 72 Salpietro V, Mankad K, Kinali M. , et al. Pediatric idiopathic intracranial hypertension and the underlying endocrine-metabolic dysfunction: a pilot study. J Pediatr Endocrinol Metab 2014; 27 (1-2): 107-115
• 73 Trifiletti RR, Incorpora G, Polizzi A, Cocuzza MD, Bolan EA, Parano E. Aicardi syndrome with multiple tumors: a case report with literature review. Brain Dev 1995; 17 (04) 283-285
• 74 Polizzi A, Pavone P, Iannetti P, Manfré L, Ruggieri M. Septo-optic dysplasia complex: a heterogeneous malformation syndrome. Pediatr Neurol 2006; 34 (01) 66-71
• 75 Polizzi A, Coghill S, McShane MA, Squier W. Acute ataxia complicating Langerhans cell histiocytosis. Arch Dis Child 2002; 86 (02) 130-131
• 76 Ruggieri M, Polizzi A, Pavone L, Musumeci S. Thalamic syndrome in children with measles infection and selective, reversible thalamic involvement. Pediatrics 1998; 101 (1 Pt 1): 112-119
• 77 O'Connor KC, Lopez-Amaya C, Gagne D. , et al. Anti-myelin antibodies modulate clinical expression of childhood multiple sclerosis. J Neuroimmunol 2010; 223 (1–2): 92-99
• 78 Salpietro V, Polizzi A, Bertè LF. , et al. Idiopathic intracranial hypertension: a unifying neuroendocrine hypothesis through the adrenal-brain axis. Neuroendocrinol Lett 2012; 33 (06) 569-573
• 79 Lionetti E, Francavilla R, Maiuri L. , et al. Headache in pediatric patients with celiac disease and its prevalence as a diagnostic clue. J Pediatr Gastroenterol Nutr 2009; 49 (02) 202-207
• 80 Praticò AD, Pavone P, Scuderi MG. , et al. Symptomatic hypocalcemia in an epileptic child treated with valproic acid plus lamotrigine: a case report. Cases J 2009; 2: 7394
• 81 Pratico AD, Ruggieri M, Falsaperla R, Pavone P. A probable topiramate-induced limbs paraesthesia and rigid fingers flexion. Curr Drug Saf 2018; 13 (02) 131-136
• 82 Passemard S, Titomanlio L, Elmaleh M. , et al. Expanding the clinical and neuroradiologic phenotype of primary microcephaly due to ASPM mutations. Neurology 2009; 73 (12) 962-969
• 83 Tunca Y, Vurucu S, Parma J. , et al. Prenatal diagnosis of primary microcephaly in two consanguineous families by confrontation of morphometry with DNA data. Prenat Diagn 2006; 26 (05) 449-453
• 84 Abdel-Hamid MS, Ismail MF, Darwish HA, Effat LK, Zaki MS, Abdel-Salam GM. Molecular and phenotypic spectrum of ASPM-related primary microcephaly: identification of eight novel mutations. Am J Med Genet A 2016; 170 (08) 2133-2140
• 85 Pavone P, Praticò AD, Ruggieri M, Rizzo R, Falsaperla R. Resuming the obsolete term “small head”: when microcephaly occurs without cognitive impairment. Neurol Sci 2017; 38 (09) 1723-1725
• 86 Henkemeyer M, Rossi DJ, Holmyard DP. , et al. Vascular system defects and neuronal apoptosis in mice lacking ras GTPase-activating protein. Nature 1995; 377 (6551): 695-701
• 87 Macmurdo CF, Wooderchak-Donahue W, Bayrak-Toydemir P. , et al. RASA1 somatic mutation and variable expressivity in capillary malformation/arteriovenous malformation (CM/AVM) syndrome. Am J Med Genet A 2016; 170 (06) 1450-1454
• 88 Pavone P, Praticò AD, Gentile G. , et al. A neurocutaneous phenotype with paired hypo- and hyperpigmented macules, microcephaly and stunted growth as prominent features. Eur J Med Genet 2016; 59 (05) 283-289