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CHAPTER 23

Overgrowth syndromes

PROTEUS SYNDROME

Epidemiology

<1/1,000,000.

Age of onset

Usually postnatal onset.

Cutaneous findings

• Cerebriform or nodular gross thickening of the palms and soles (Figures 23.1 and 23.2)

• Linear verrucous epidermal nevi (distributed along Blaschko’s lines) (Figure 23.3)

Figure 23.1 Proteus syndrome.

Figure 23.2 Proteus syndrome.

Figure 23.3 Proteus syndrome.

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Material Cerebriform or nodular gross thickening of the

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Taylor & Francis

486 Atlas of Genodermatoses

• Hamartomatous masses of subcutaneous tissue consisting of adipose tissue or various combina-tions of adipose and lymphatic–angiomatous tis-sue (Figure 23.4)

• Vascular malformations (capillary, venous or lym-phatic)

• Café-au-lait macules• Hypopigmented spots

Extracutaneous findings

• Progressive and asymmetric macrodactyly (Fig-ure 23.5)

• Macrocephaly and skull exostosis• Body hemihypertrophy (Figure 23.4)

• Scoliosis and spinal canal stenosis• Bullous lung abnormalities• Ocular manifestations (strabismus, high myopia,

retinal pigmentary anomalies, and epibulbar der-moids)

• Usually normal mental function, but central ner-vous system abnormalities are possible (intellec-tual disability, seizures, hemimegalencephaly, hydrocephalus, and other brain malformations)

• Renal/urologic �ndings (renal asymmetry, renal cysts, hydroureters, hydronephrosis)

• Reported but uncommon neoplasms include monomorphic adenoma of the parotid gland, cystadenomas of the ovary, testicular tumors, meningiomas, and mesothelioma

Laboratory findings

Radiography shows bone and soft-tissue hypertro-phies.

Genetics and pathogenesis

• 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.

• Since 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 diagnosis

• Neuro�bromatosis type 1• Klippel–Trénaunay–Weber 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 and milder forms

Figure 23.4 Proteus syndrome.

Figure 23.5 Proteus syndrome.

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Progressive and asymmetric macrodactyly (FigCopyrighted

Progressive and asymmetric macrodactyly (Figure 23.5)Copyrighted

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Macrocephaly and skull exostosisBody hemihypertrophy (Figure 23.4)

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Body hemihypertrophy (Figure 23.4)

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has been identi�ed in more than 90% of individuals meeting the diagnostic criteria.Taylor

viduals meeting the diagnostic criteria.Since PTEN down-regulates AKT1 by decreasing Taylor

Since PTEN down-regulates AKT1 by decreasing phosphorylation, the �nding of an activating

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FrancisKlippel–Trénaunay–Weber syndrome

Hemihyperplasia–lipomatosis syndrome

FrancisHemihyperplasia–lipomatosis syndrome

Overgrowth syndromes 487

• Propensity for neoplastic changes• Surgical approach for gigantism and asymmetry• Antithrombotic prophylaxis should be consid-

ered when undergoing a surgical procedure• Pulmonary cystic lesions should be carefully

monitored

Bibliography

Biesecker LG, Sapp JC. Proteus syndrome. In: Pagon RA, Bird TD, Dolan CR, Stephens K, Adam MP, editors. GeneReviews® [Internet]. Seattle, WA: University of Wash-ington, Seattle; August 9, 1993–2012.

Cohen MM Jr. Proteus syndrome review: Molecular, clini-cal, and pathologic features. Clin Genet 2014; 85(2): 111–9.

Eng C. PTEN hamartoma tumor syndrome (PHTS). In: Pagon RA, Adam MP, Ardinger HH, Bird TD, Dolan CR, Fong CT, Smith RJH, Stephens K, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2014. November 29, 2001 [updated January 23, 2014]. http://www.ncbi.nlm.nih.gov/pubmed/20301661.

Lindhurst MJ, Sapp JC, Teer JK et al. A mosaic activating mutation in AKT1 associated with the Proteus syndrome. N Engl J Med 2011; 365(7): 611–9.

CLOVES SYNDROME

Synonyms

Congenital lipomatous asymmetric overgrowth of  the trunk, lymphatic, capillary, venous, and combined-type vascular malformations, epidermal nevi, skeletal, and spinal anomalies.

Age of onset

At birth.

Cutaneous findings

• Epidermal nevi• Complex congenital overgrowth of lipomatous

tissues (typically manifesting as a truncal lipo-matous mass) (Figure 23.6)

• Combined lymphatic and vascular malforma-tions (Figure 23.7)

• Deeply grooved plantar thickening, not consis-tent with a cerebriform connective tissue nevus

Extracutaneous findings

• Skeletal anomalies include scoliosis, wide hands and feet, macrodactyly, and prominent sandal-gap toes (Figure 23.8).

• Renal agenesis/hypoplasia.• Splenic lesions.

Figure 23.6 CLOVES syndrome.

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GeneReviewsCopyrighted

GeneReviews® [Internet]. Seattle, WA: University of WashCopyrighted

® [Internet]. Seattle, WA: University of Washington, Seattle; August 9, 1993–2012.Copyrighted

ington, Seattle; August 9, 1993–2012.

Cohen MM Jr. Proteus syndrome review: Molecular, clini

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Cohen MM Jr. Proteus syndrome review: Molecular, clinical, and pathologic features.

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cal, and pathologic features.

Eng C. PTEN hamartoma tumor syndrome (PHTS). In:

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Eng C. PTEN hamartoma tumor syndrome (PHTS). In: Pagon RA, Adam MP, Ardinger HH, Bird TD, Dolan CR,

Copyrighted

Pagon RA, Adam MP, Ardinger HH, Bird TD, Dolan CR, Fong CT, Smith RJH, Stephens K, editors.

Copyrighted Fong CT, Smith RJH, Stephens K, editors. [Internet]. Seattle (WA): University of Washington, Seattle;

Copyrighted [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2014. November 29, 2001 [updated January 23,

Copyrighted 1993–2014. November 29, 2001 [updated January 23, 2014]. http://www.ncbi.nlm.nih.gov/pubmed/20301661.

Copyrighted 2014]. http://www.ncbi.nlm.nih.gov/pubmed/20301661.

Lindhurst MJ, Sapp JC, Teer JK et al. A mosaic activating

Copyrighted Lindhurst MJ, Sapp JC, Teer JK et al. A mosaic activating mutation in AKT1 associated with the Proteus syndrome.

Copyrighted mutation in AKT1 associated with the Proteus syndrome. Material

Lindhurst MJ, Sapp JC, Teer JK et al. A mosaic activating Material

Lindhurst MJ, Sapp JC, Teer JK et al. A mosaic activating mutation in AKT1 associated with the Proteus syndrome. Material

mutation in AKT1 associated with the Proteus syndrome.

•

Material •- •- • Renal agenesis/hypoplasia.- Renal agenesis/hypoplasia.Taylor

gap toes (Figure 23.8).Taylor

gap toes (Figure 23.8).Taylor

Renal agenesis/hypoplasia.Taylor

Renal agenesis/hypoplasia.Splenic lesions.Taylor

Splenic lesions.Taylor & Francis

488 Atlas of Genodermatoses

• Neurological �ndings: Neural tube defects, teth-ered cord, megalencephaly/hemimegalenceph-aly, Chiari malformation and polymicrogyria.

• Seizures.• Tumors reported in CLOVES syndrome include

chorangioma, extradural spinal tumor, heman-gioma, and multiple angiomatosis.

Genetics and pathogenesis

Heterozygous (somatic mosaic) mutations of PIK3CA are causative.

Differential diagnosis

• Proteus syndrome• Klippel–Trénaunay syndrome

• Hemihyperplasia–multiple lipomatosis syn-drome (Figure 23.9)

• Neuro�bromatosis type I

Follow-up and therapy

Monitoring for paraspinal high-�ow lesions with spinal cord ischemia, central phlebectasias and thromboembolism.

Bibliography

Mirzaa G, Conway R, Graham JM, Dobyns WB. PIK-3CArelated segmental overgrowth. In: Pagon RA, Adam MP, Bird TD, Dolan CR, Fong CT, Stephens K, editors. GeneReviews® [Internet]. Seattle, WA: University of Wash-ington, Seattle; 1993–2013. August 15, 2013. http://www.ncbi.nlm.nih.gov/pubmed/23946963.

Sapp JC, Turner JT, van de Kamp JM, van Dijk FS, Lowry RB, Biesecker LG. Newly delineated syndrome of con-genital lipomatous overgrowth, vascular malformations, and epidermal nevi (CLOVE syndrome) in seven patients. Am J Med Genet A 2007; 143A(24): 2944–58.

Figure 23.9 Hemihyperplasia-multiple lipomatosis syndrome.

Figure 23.7 CLOVES syndrome.

Figure 23.8 CLOVES syndrome.

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Copyrighted OVES syndrome.

Copyrighted OVES syndrome.

Material •

Material •

Material - Follow-up and therapy- Follow-up and therapyTaylor

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Monitoring for paraspinal high-�ow lesions with spinal cord ischemia, central phlebectasias and

Taylor spinal cord ischemia, central phlebectasias and thromboembolism.

Taylor thromboembolism.

Bibliography

Taylor Bibliography & Mirzaa G, Conway R, Graham JM, Dobyns WB. PIK& Mirzaa G, Conway R, Graham JM, Dobyns WB. PIKFrancis

Mirzaa G, Conway R, Graham JM, Dobyns WB. PIKFrancis

Mirzaa G, Conway R, Graham JM, Dobyns WB. PIK3CArelated segmental overgrowth. In: Pagon RA, Adam Francis

3CArelated segmental overgrowth. In: Pagon RA, Adam MP, Bird TD, Dolan CR, Fong CT, Stephens K, editors.

FrancisMP, Bird TD, Dolan CR, Fong CT, Stephens K, editors.

® [Internet]. Seattle, WA: University of Wash

Francis® [Internet]. Seattle, WA: University of Wash

ington, Seattle; 1993–2013. August 15, 2013. http://www.

Francisington, Seattle; 1993–2013. August 15, 2013. http://www.ncbi.nlm.nih.gov/pubmed/23946963.

Francisncbi.nlm.nih.gov/pubmed/23946963.

Sapp JC, Turner JT, van de Kamp JM, van Dijk FS, Lowry

FrancisSapp JC, Turner JT, van de Kamp JM, van Dijk FS, Lowry RB, Biesecker LG. Newly delineated syndrome of con

FrancisRB, Biesecker LG. Newly delineated syndrome of con

Overgrowth syndromes 489

BECKWITH–WIEDEMANN SYNDROME (BWS)

Epidemiology

1:13,700.

Age of onset

At birth.

Cutaneous 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 few years of life (Figure 23.11)

• Prematurity• 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 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

• 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 risks).Figure 23.10 Beckwith–Wiedemann syndrome (BWS).

Figure 23.11 Beckwith–Wiedemann syndrome (BWS).

Figure 23.12 Beckwith–Wiedemann syndrome (BWS).

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Cutaneous findingsCopyrighted

Cutaneous findings

Hemangiomas

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HemangiomasMacroglossia, which can lead to dif�culties in

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Macroglossia, which can lead to dif�culties in feeding, speech and, less frequently, sleep apnea

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feeding, speech and, less frequently, sleep apnea (Figure 23.10)

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(Figure 23.10)Posterior helical pits

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Posterior helical pits

tracutaneous findings

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Increased rate of growth during the latter half

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of pregnancy and in the �rst few years of life Material

of pregnancy and in the �rst few years of life

Abdominal wall defects (omphalocele, umbilical

Material Abdominal wall defects (omphalocele, umbilical

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Francisiedemann syndrome (BWS).

Francisiedemann syndrome (BWS).

490 Atlas of Genodermatoses

• Somatic mosaicism accounts for some of the BWS-associated clinical variability.

• BWS usually occurs sporadically (85%), but familial transmission occurs in 5% of cases.

Differential diagnosis

• Maternal diabetes mellitus• Simpson–Golabi–Behmel syndrome• Costello’s syndrome• Perlman’s syndrome• Sotos syndrome• Mucopolysaccaridosis type VI (Maroteaux–Lamy

syndrome)• Mosaicism for trisomy 8

Course and prognosis

• Predisposition to embryonal malignancies that often occur in the �rst 8–10 years of life with very few being reported beyond this age; most common are Wilms tumors and hepatoblasto-mas. Other embryonal tumors include rhabdo-myosarcomas, adrenocortical carcinomas and neuroblastomas.

• 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 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.

Bibliography

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.

CLAPO SYNDROME

Synonyms

Capillary malformation of the lower lip, lymphatic malformation of the face and neck, asymmetry, and partial/generalized overgrowth.

Epidemiology

This disease is very rare: six cases have been reported in the literature.

Age of onset

At birth.

Cutaneous findings

• Capillary malformations of the lower lip (port-wine stain, nevus �ammeus or vascular marks) with a midline and symmetrical pattern (Figures 23.13 and 23.14)

Figure 23.13 CLAPO syndrome.

Figure 23.14 CLAPO syndrome.

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Sotos syndromeCopyrighted

Sotos syndromeMucopolysaccaridosis type VI (Maroteaux–Lamy Copyrighted

Mucopolysaccaridosis type VI (Maroteaux–Lamy syndrome)

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syndrome)Mosaicism for trisomy 8

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Mosaicism for trisomy 8

Course and prognosis

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Course and prognosis

Predisposition to embryonal malignancies that

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Copyrighted mas. Other embryonal tumors include rhabdomyosarcomas, adrenocortical carcinomas and

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Individuals with uniparental paternal disomy

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Francis

Overgrowth syndromes 491

• Port-wine macrocheilia• Lymphatic malformations of the face and neck• Bleeding, infection, swelling, and vesicle forma-

tion malocclusion

Extracutaneous findings

• Overgrown and large-for-gestational-age infants• Asymmetry of the face and limbs (Figure 23.14)• Partial or generalized overgrowth• Facial dysmorphism in one patient

Course and prognosis

• Bleeding, infection, swelling, and vesicle forma-tion of the affected skin

• Malocclusion• Normal development and mental status• No increased risk of tumors

Laboratory findings

• Normal karyotypes• Neither internal nor visceral abnormalities were

observed• No vascular etiology for partial overgrowth and

disproportion of limbs

Genetics and pathogenesis

• Inheritance of this syndrome/association is not known. No recurrence of the disorder was observed in six siblings of all six families.

• There is a slight female preponderance.• Somatic mosaicism is a theoretical possibility

due to patchy vascular markings of the skin and asymmetric overgrowth.

Differential diagnosis

• BWS• PTEN hamartomas syndrome• Macrocephaly–capillary malformations syndrome• Klippel–Trenaunay syndrome• Proteus syndrome• Kaposiform hemangioendothelioma• Tufted angioma

Follow-up and therapy

• Surgical resection of lymphatic malformations• OK-432 sclerotherapy• CO2 laser photocoagulation

Bibliography

López-Gutiérrez JC1, Lapunzina P. Capillary malforma-tion of the lower lip, lymphatic malformation of the face and neck, asymmetry and partial/generalized over-growth (CLAPO): Report of six cases of a new syn-drome/association. Am J Med Genet A 2008; 146A(20): 2583–8.

KLIPPEL–TRÉNAUNAY SYNDROME

See Chapter 18.

MACROCEPHALY–CAPILLARY MALFORMATION SYNDROME

See Chapter 18.

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Course and prognosisCopyrighted

Course and prognosis

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tion of the affected skinMalocclusion

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Normal development and mental statusNo increased risk of tumors

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