CHAPTER 23 OvergrowthCopyrighted syndromes

PROTEUS SYNDROME

Epidemiology <1/1,000,000.

Age of onset Material Usually postnatal onset.

Cutaneous findings • Cerebriform or nodular gross thickening of the palms and soles (Figures 23.1 and 23.2) Figure 23.2 Proteus syndrome. • Linear verrucous epidermal nevi (distributed - along Blaschko’s lines) (Figure 23.3) Taylor

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Figure 23.1 Proteus syndrome. Figure 23.3 Proteus syndrome.

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• Hamartomatous masses of subcutaneous tissue • Scoliosis and spinal canal stenosis consisting of adipose tissue or various combina- • Bullous lung abnormalities tions of adipose and lymphatic–angiomatous tis- • Ocular manifestations (strabismus, high myopia, sue (Figure 23.4) retinal pigmentary anomalies, and epibulbar der- • Vascular malformations (capillary, venous or lym- moids) phatic) • Usually normal mental function, but central ner- • Café-au-lait macules vous system abnormalities are possible (intellec- • Hypopigmented spots tual disability, seizures, hemimegalencephaly, hydrocephalus, and other brain malformations) • Renal/urologic ndings (renal asymmetry, renal Extracutaneous findings cysts, hydroureters, hydronephrosis) • Progressive and asymmetric macrodactyly (Fig- • Reported but uncommon neoplasms include ure 23.5)Copyrighted monomorphic adenoma of the parotid gland, • Macrocephaly and skull exostosis cystadenomas of the ovary, testicular tumors, • Body hemihypertrophy (Figure 23.4) meningiomas, and mesothelioma

Laboratory findings Radiography shows bone and soft-tissue hypertro- phies.

Genetics and pathogenesis Material • The disease is inherited in an autosomal domi- nant manner. • Some individuals with Proteus syndrome were found to have germline PTEN mutations. • Paradominant inheritance is possible (see Chap- ter 25). • A mosaic somatic mutation of the AKT1 gene - has been identi ed in more than 90% of indi- viduals meeting the diagnostic criteria. • SinceTaylor PTEN down-regulates AKT1 by decreasing phosphorylation, the nding of an activating AKT1 mutation in Proteus syndrome corrobo- rates that Proteus syndrome is a PTEN-pathway- opathy. & Differential diagnosisFrancis • Neuro bromatosis type 1 • Klippel–Trénaunay–Weber syndrome Figure 23.4 Proteus syndrome. • Maffucci syndrome • CLOVES syndrome • Hemihyperplasia–lipomatosis syndrome • Beckwith-Wiedemann syndrome

Course and prognosis The disease is slowly progressive and dependent on the extent and severity of extracutaneous lesions. About 20% of patients with Proteus syndrome have premature deaths. Deep Vein Thrombosis is common.

Follow-up and therapy • Great variability between extremely severe forms Figure 23.5 Proteus syndrome. and milder forms

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• Propensity for neoplastic changes CLOVES SYNDROME • Surgical approach for gigantism and asymmetry • Antithrombotic prophylaxis should be consid- Synonyms ered when undergoing a surgical procedure • Pulmonary cystic lesions should be carefully Congenital lipomatous asymmetric overgrowth monitored of the trunk, lymphatic, capillary, venous, and combined-type vascular malformations, epidermal nevi, skeletal, and spinal anomalies. Bibliography Biesecker LG, Sapp JC. Proteus syndrome. In: Pagon RA, Bird TD, Dolan CR, Stephens K, Adam MP, editors. Age of onset GeneReviews® [Internet]. Seattle, WA: University of Wash- At birth. ington, CopyrightedSeattle; August 9, 1993–2012. Cohen MM Jr. Proteus syndrome review: Molecular, clini- cal, and pathologic features. Clin Genet 2014; 85(2): 111–9. Cutaneous findings Eng C. PTEN hamartoma tumor syndrome (PHTS). In: • Epidermal nevi Pagon RA, Adam MP, Ardinger HH, Bird TD, Dolan CR, • Complex congenital overgrowth of lipomatous Fong CT, Smith RJH, Stephens K, editors. GeneReviews® tissues (typically manifesting as a truncal lipo- [Internet]. Seattle (WA): University of Washington, Seattle; matous mass) (Figure 23.6) 1993–2014. November 29, 2001 [updated January 23, 2014]. http://www.ncbi.nlm.nih.gov/pubmed/20301661. • Combined lymphatic and vascular malforma- tions (Figure 23.7) Lindhurst MJ, Sapp JC, Teer JK et al. A mosaic activating • Deeply grooved plantar thickening, not consis- mutation in AKT1 associated with the ProteusMaterial syndrome. tent with a cerebriform connective tissue nevus N Engl J Med 2011; 365(7): 611–9.

Extracutaneous findings • Skeletal anomalies include scoliosis, wide hands and feet, macrodactyly, and prominent sandal- gap toes (Figure 23.8). -• Renal agenesis/hypoplasia. • SplenicTaylor lesions.

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Figure 23.6 CLOVES syndrome.

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Figure 23.7 CLOVESOVES syndrome.

Figure 23.9 Hemihyperplasia-multiple lipomatosis Material syndrome.

• Hemihyperplasia–multiple lipomatosis syn- drome (Figure 23.9) • Neuro bromatosis type I - Follow-upTaylor and therapy Monitoring for paraspinal high-ow lesions with spinal cord ischemia, central phlebectasias and thromboembolism.

Bibliography & Figure 23.8 CLOVES syndrome. Mirzaa G, Conway R, Graham JM, Dobyns WB. PIK- 3CArelated segmental overgrowth.Francis In: Pagon RA, Adam MP, Bird TD, Dolan CR, Fong CT, Stephens K, editors. GeneReviews® [Internet]. Seattle, WA: University of Wash- • Neurological ndings: Neural tube defects, teth- ington, Seattle; 1993–2013. August 15, 2013. http://www. ered cord, megalencephaly/hemimegalenceph- ncbi.nlm.nih.gov/pubmed/23946963. aly, Chiari malformation and polymicrogyria. • Seizures. Sapp JC, Turner JT, van de Kamp JM, van Dijk FS, Lowry • Tumors reported in CLOVES syndrome include RB, Biesecker LG. Newly delineated syndrome of con- chorangioma, extradural spinal tumor, heman- genital lipomatous overgrowth, vascular malformations, gioma, and multiple angiomatosis. and epidermal nevi (CLOVE syndrome) in seven patients. Am J Med Genet A 2007; 143A(24): 2944–58.

Genetics and pathogenesis Heterozygous (somatic mosaic) mutations of PIK3CA are causative.

Differential diagnosis • Proteus syndrome • Klippel–Trénaunay syndrome

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BECKWITH–WIEDEMANN SYNDROME (BWS)

Epidemiology 1:13,700.

Age of onset At birth.

CutaneousCopyrighted findings • Hemangiomas • Macroglossia, which can lead to dif culties in feeding, speech and, less frequently, sleep apnea (Figure 23.10) • Posterior helical pits

Extracutaneous findings • Increased rate of growth during the latter half of pregnancy and in the rst fewMaterial years of life (Figure 23.11) • Prematurity Figure 23.11 Beckwith–Wiedemann syndrome (BWS). • Neonatal hypoglycemia • Hemihyperplasia • Abdominal wall defects (omphalocele, umbilical hernia and diastasis recti) (Figure 23.12) • Visceromegaly - • Unilateral or bilateral renal anomalies may include primary malformations, renal medullary Taylor dysplasia, nephrocalcinosis, and nephrolithiasis • Cardiac malformations • Prominent eyes with infraorbital creases, mid- facial hypoplasia, full lower face with a promi- nent mandible and anterior earlobe creases & Francis Figure 23.12 Beckwith–Wiedemanniedemann syndrome (BWS).

• Cleft palate (rare) • Cancer proneness

Laboratory findings • Advanced bone age • Neonatal hypoglycemia

Genetics and pathogenesis • BWS is caused by various epigenetic and/or genetic alterations that dysregulate imprinted genes on chromosome 11p15.5. Molecular sub- groups are associated with different recurrence risks and different clinical ndings (e.g., tumor Figure 23.10 Beckwith–Wiedemann syndrome (BWS). risks).

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• Somatic mosaicism accounts for some of the CLAPO SYNDROME BWS-associated clinical variability. • BWS usually occurs sporadically (85%), but Synonyms familial transmission occurs in 5% of cases. Capillary malformation of the lower lip, lymphatic Differential diagnosis malformation of the face and neck, asymmetry, and partial/generalized overgrowth. • Maternal diabetes mellitus • Simpson–Golabi–Behmel syndrome • Costello’s syndrome Epidemiology • Perlman’s syndrome This disease is very rare: six cases have been • Sotos syndrome reported in the literature. • Mucopolysaccaridosis type VI (Maroteaux–Lamy syndrome)Copyrighted • Mosaicism for trisomy 8 Age of onset At birth. Course and prognosis • Predisposition to embryonal malignancies that Cutaneous findings often occur in the rst 8–10 years of life with very few being reported beyond this age; most • Capillary malformations of the lower lip (port- common are Wilms tumors and hepatoblasto- wine stain, nevus ammeus or vascular marks) mas. Other embryonal tumors include rhabdo- with a midline and symmetrical pattern (Figures myosarcomas, adrenocortical carcinomas and 23.13 and 23.14) neuroblastomas. Material • Individuals with uniparental paternal disomy (UPD) of 11p15.5 or gain of methylation at the imprinting center for domain 1 (IC1) carry the highest risk of developing Wilms tumors or hep- atoblastomas. Follow-up and therapy - • Abdominal ultrasounds are used to assess the Taylor kidneys, liver, pancreas, and adrenal glands every 3/4 months in the rst 8–10 years of life. • α-fetoprotein can be measured periodically to the age of 4 years for the early detection of hep- atoblastomas. Figure 23.13 CLAPOCLAPO& syndrome. Bibliography Francis Baskin B, Choufani S, Chen YA, Shuman C, Parkinson N, Lemyre E, Micheil Innes A, Stavropoulos DJ, Ray PN, Weksberg R. High frequency of copy number variations (CNVs) in the chromosome 11p15 region in patients with Beckwith-Wiedemann syndrome. Hum Genet 2014; 133(3): 321–30.

Choufani S, Shuman C, Weksberg R. Molecular ndings in Beckwith–Wiedemann syndrome. Am J Med Genet C Semin Med Genet 2013; 163C(2): 131–40.

Moreira-Pinto J, Pereira J, Osório A, Enes C, Mota CR. Beckwith–Wiedemann syndrome, delayed abdominal wall closure, and neonatal intussusception—case report and literature review. Fetal Pediatr Pathol 2012; 31(6): 448–52.

Weksberg R, Shuman C, Beckwith JB. Beckwith–Wiede- mann syndrome. Eur J Hum Genet 2010; 18(1): 8–14. Figure 23.14 CLAPO syndrome.

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• Port-wine macrocheilia Differential diagnosis • Lymphatic malformations of the face and neck • BWS • Bleeding, infection, swelling, and vesicle forma- • PTEN hamartomas syndrome tion malocclusion • Macrocephaly–capillary malformations syndrome • Klippel–Trenaunay syndrome Extracutaneous findings • Proteus syndrome • Overgrown and large-for-gestational-age infants • Kaposiform hemangioendothelioma • Asymmetry of the face and limbs (Figure 23.14) • Tufted angioma • Partial or generalized overgrowth • Facial dysmorphism in one patient Follow-up and therapy CourseCopyrighted and prognosis • Surgical resection of lymphatic malformations • OK-432 sclerotherapy • Bleeding, infection, swelling, and vesicle forma- • CO laser photocoagulation tion of the affected skin 2 • Malocclusion • Normal development and mental status Bibliography • No increased risk of tumors López-Gutiérrez JC1, Lapunzina P. Capillary malforma- tion of the lower lip, lymphatic malformation of the face Laboratory findings and neck, asymmetry and partial/generalized over- growth (CLAPO): Report of six cases of a new syn- • Normal karyotypes drome/association. Am J Med Genet A 2008; 146A(20): • Neither internal nor visceral abnormalitiesMaterial were 2583–8. observed • No vascular etiology for partial overgrowth and disproportion of limbs KLIPPEL–TRÉNAUNAY SYNDROME Genetics and pathogenesis See Chapter 18. • Inheritance of this syndrome/association is not known. No recurrence of the disorder was - observed in six siblings of all six families. Taylor • There is a slight female preponderance. MACRCROCEPHALY–CAPILLARY • Somatic mosaicism is a theoretical possibility MALLFORMATIONRMAT SYNDROME due to patchy vascular markings of the skin and asymmetric overgrowth. See Chapter 18. & Francis

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