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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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Overgrowth syndromes
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Material Cerebriform or nodular gross thickening of the
Material Cerebriform or nodular gross thickening of the
Material Figure 23.2
Material Figure 23.2- Taylor
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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
ure 23.5)Macrocephaly and skull exostosis
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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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Material •
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has been identi�ed in more than 90% of indiTaylor
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
Taylor phosphorylation, the �nding of an activating AKT1 mutation in Proteus syndrome corrobo
Taylor AKT1 mutation in Proteus syndrome corroborates that Proteus syndrome is a
Taylor rates that Proteus syndrome is a
& Differential diagnosis& Differential diagnosisFrancis
Neuro�bromatosis type 1Francis
Neuro�bromatosis type 1Klippel–Trénaunay–Weber syndrome
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,
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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
Follow-up and therapyTaylor
Follow-up and therapy
Monitoring for paraspinal high-�ow lesions with Taylor
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
Copyrighted Increased rate of growth during the latter half of pregnancy and in the �rst few years of life
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Increased rate of growth during the latter half Material
Increased rate of growth during the latter half Material
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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Predisposition to embryonal malignancies that often occur in the �rst 8–10 years of life with
Copyrighted often occur in the �rst 8–10 years of life with very few being reported beyond this age; most
Copyrighted very few being reported beyond this age; most common are Wilms tumors and hepatoblasto
Copyrighted common are Wilms tumors and hepatoblastomas. Other embryonal tumors include rhabdo
Copyrighted mas. Other embryonal tumors include rhabdomyosarcomas, adrenocortical carcinomas and
Copyrighted myosarcomas, adrenocortical carcinomas and Material
myosarcomas, adrenocortical carcinomas and Material
myosarcomas, adrenocortical carcinomas and
Individuals with uniparental paternal disomy
Material
Individuals with uniparental paternal disomy (UPD) of 11p15.5 or gain of methylation at the
Material (UPD) of 11p15.5 or gain of methylation at the imprinting center for domain 1 (IC1) carry the
Material imprinting center for domain 1 (IC1) carry the highest risk of developing Wilms tumors or hep
Material highest risk of developing Wilms tumors or hep-
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Taylor CL
Taylor CLAPO syndrome.
Taylor APO syndrome.& APO syndrome.& APO syndrome.Francis
Francis
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• 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
Bleeding, infection, swelling, and vesicle forma
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Bleeding, infection, swelling, and vesicle formation of the affected skin
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tion of the affected skinMalocclusion
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MalocclusionNormal development and mental status
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Normal development and mental statusNo increased risk of tumors
Copyrighted No increased risk of tumors
Neither internal nor visceral abnormalities were
Copyrighted Neither internal nor visceral abnormalities were Material
Neither internal nor visceral abnormalities were Material
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No vascular etiology for partial overgrowth and
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