Letters to the Editor
897
Familial hypochondroplasia and acanthosis nigricans with FGFR3 K650T mutation Editor Acanthosis nigricans (AN) is a proliferative epidermal disorder described clinically by velvety brown plaques in skin folds, although other parts of the skin and mucosa can occasionally be affected.1 There are currently seven accepted types of AN, listed by Schwartz as: benign, associated with obesity (pseudoacanthosis nigricans), syndromic, paraneoplastic, acral, unilateral and drug induced.2 Syndromic AN is reported in inherited skeletal dysplasias caused by heterozygous mutations in the fibroblast growth factor receptor 3 (FGFR3) gene.3 We describe AN associated with hypochondroplasia (HCH) caused by a p.Lys650Thr missense mutation in the FGFR3 gene. The proband was a 14-year-old healthy boy who presented to the dermatology clinic with a 2-year history of hyperpigmented skin on his anterior neck (Fig. 1). Examination revealed brown velvety skin coloration on his neck and axillas. Numerous solar lentigines were noted on his face, hands and upper back the latter showing several slightly verrucous keratoses. Small stature (143 cm, 2 SDS), normal BMI (21.5), macrocephaly (+2 SDS), short limbs, broad hands and hyperlordosis were also found. Facial dysmorphia and cognitive impairment were absent. Skin biopsy of the cervical hyperpigmented skin and of a verrucous keratosis revealed hyperkeratosis and papillomatosis with moderate irregular acanthosis compatible with AN. All the biochemical studies were within normal limits. Drug intake, hyperandrogenism, insulin resistance, autoimmune disease or metabolic disorders were not found. Skeletal survey revealed characteristic features of HCH including fibula longer than tibia and lack of widening of vertebral interpedicular distance. Subsequent family examination revealed a similar phenotype in the father and the two younger brothers (Fig. 2). The mother was unaffected. Genetic and molecular
(a)
analysis confirmed a heterozygous p.Lys650Thr (exon 15: AAG ⇒ ACG) missense mutation in FGFR3 gene in all affected member of the family. An array of vastly different diagnoses is caused by similar FGFR3 mutations, including syndromes affecting skeletal development (HCH, achondroplasia, thanatophoric dysplasia, Crouzon with AN), skin (epidermal nevi, seborrhoeic keratosis, AN) and cancer (multiple myeloma, prostate and bladder carcinoma, seminoma).4 FGFR3 is a regulator of skeletal growth, which disturbs the endochondral process via inhibition of chondrocyte proliferation and differentiation. All known mutations are gain-of-function mutations, they activate FGFR3 by increasing its phosphorylation. Although the exact mechanism varies depending on the location of given mutation, the end result is shortening of long bones with a graded spectrum of severity. In addition, FGFR3 mutation is known for producing excessive cell proliferation in benign and malignant disorders, suggesting a pro-mitogenic role. In 2005, a transgenic mouse model confirmed the role of FGFR3 in the activation of keratinocytic proliferation responsible for AN formation.5 HCH is an autosomal dominant skeletal disorder less severe than achondroplasia. A recurrent FGFR3 mutation (p. Lys650Asn) is identified in 70% of HCH cases which does not exhibit AN.6 To date, few reports have documented patients with HCH and AN. Concerning p.Lys650Thr mutation, Castro-Feijoo et al.3 reported a family with HCH, AN, numerous naevi, solar lentigos and cafe-aulait macules, while Berk et al.7 reported a family with AN, short stature, but no other abnormalities. To our knowledge, this is the second description of a family with HCH and AN associated to a FGFR3 p.Lys650Thr mutation. Our case highlight that this association is not fortuitous and that as previously reported, AN can be a marker of inherited skeletal dysplasia. Interestingly, the presence of early-onset solar lentigines and seborrheic-like verrucous keratoses show the wide spectrum of clinical manifestation due to FGFR3 mutations. Physicians should be aware of those associations especially when evaluating a family with short stature.
(b)
Figure 1 (a–b): Proband patient demonstrating (a) cervical acanthosis nigricans (arrow) and multiple solar lentigines and flat seborrheiclike verrucous keratoses (b).
JEADV 2016, 30, 852–909
© 2015 European Academy of Dermatology and Venereology
Letters to the Editor
898
4
5
6
7
in the fibroblast growth factor receptor 3 gene. Eur J Endocrinol 2008; 159: 243–249. Foldynova-Trantikova S, Wilcox WR, Krejcj P. Sixteen years and counting: the current understanding of fibroblast growth factor receptor 3 (FGFR3) signaling in skeletal dysplasias. Hum Mutat 2012; 33: 29–41. Logie A, Dunois-Larde C, Rosty C, Levrel O, Blanche M, Ribeiro A, et al. Activating mutations of the tyrosine kinase receptor FGFR3 are associated with benign skin tumors in mice and humans. Hum Mol Genet 2005; 14: 1153–1160. Berk DR, Boente MDC, Montanari D, Guadalupe-Toloza M, Primc BN, et al. Acanthosis nigricans and hypochondroplasia in a child with a K650Q mutation in FGFR3. Pediatr Dermatol 2010; 27: 664–666. Berk DR, Spector EB, Bayliss SJ. Familial acanthosis nigricans due to K650T FGFR3 mutation. Arch Dermatol 2007; 143: 1153–1156.
DOI: 10.1111/jdv.13061
Targetoid haemosiderotic haemangioma in a 3-year-old girl
Figure 2 Overall appearance of the siblings (14, 11 and 5-yearold) showing square-built, short stature, hyperlordotic stance and broad hands.
M.A. Cossiez Cacard,1 J. Coulombe,2 P. Bernard,3 N. Kaci,4 J.M. Bressieux,5 P.F. Souchon,1 J. Motte,1 L. Legeai-Mallet,4 S. Hadj-Rabia,2,4,†,* C. Eschard3,† Service de pediatrie, American Memorial Hospital, CHU de Reims, fe rence des maladies Reims, 2Service de dermatologie, Centre de re tiques a expression cutane e, Institut Imagine, Ho ^pital Universitaire g ene ^pitaux de Paris, Necker-Enfants Malades, Assistance Publique-Ho Paris Descartes - Sorbonne Paris Cite , Paris, 3Service de Universite ^pital Robert Debre , CHU de Reims, Reims, 4INSERM dermatologie, Ho U1163, Hospital Necker-Enfants Malades, University Paris Descartes , Institut Imagine, Paris, 5Service de dermatologie, Sorbonne Paris Cite Centre hospitalier de Troyes, Troyes, France *Correspondence: S. Hadj-Rabia. E-mail: smail.hadj@ inserm.fr † Equal contribution 1
References 1 Pardavila R, Roson E, De la Torre C, Cruces M. Generalized familial acanthosis nigricans associated with hypochondroplasia. Actas Dermosifiliogr 2008; 99: 661–667. 2 Smeeta S, Schwartz RA. Juvenile acanthosis nigricans. J Am Acad Dermatol 2007; 57: 502–508. 3 Castro-Feijoo L, Lourdes L, Vidal A, et al. Hypochondrodysplasia and acanthosis nigricans: a new syndrome due to the p.Lys650Thr mutation
JEADV 2016, 30, 852–909
Editor A healthy 3-year-old Caucasian girl developed a skin lesion on the right palm of the hand. 1.5 years after the first lesion, there had been several 5-month-cycles of presentation with swelling, and healing of the skin, leaving normal skin. Besides pain at the time of the swelling, there were no symptoms. Recently, a new, smaller lesion appeared on the thumb of the right hand. The girl denied any type of trauma. Physical examination revealed an indurated plaque on the skin overlying the second metacarpal bone of the right hand, 2.5 cm in diameter, with a small crusta and several point-like haemorrhagic lesions. On the thumb, there was a comparable lesion of 1 cm in diameter, less indurated (Fig. 1). A skin biopsy was taken of the largest lesion which showed a normal epidermis. In the dermis, there was proliferation of the blood vessels. In the papillary dermis, prominent, dilated, thinwalled vessels were present with prominent endothelial cells, with a ‘hobnail’ appearance. The dermal vessels were covered with CD31positive and D2-40-negative endothelium, which proved them being blood vessels and no lymphatic vessels. The reticular dermis was infiltrated with more narrow vascular spaces. There was haemosiderin deposition and extravasation of erythrocytes (Fig. 2). The clinical presentation and the histological findings were consistent with the diagnosis ‘targetoid hemosiderotic hemangioma’. One year after the first visit, the smaller lesion had disappeared and not returned. The larger lesion started to give functional problems when using the hand. Therefore, we decided to send the patient to a plastic surgeon to excise the lesion. Histological examination of the excisional specimen confirmed the diagnosis, fulfilling the criteria for targetoid haemosiderotic haemangioma. Targetoid haemosiderotic haemangioma, or hobnail haemangioma, was first described in 1988 by Santa Cruz and Aronberg.1 It is a benign vascular tumour with a variable clinical appearance.
© 2015 European Academy of Dermatology and Venereology
897
Familial hypochondroplasia and acanthosis nigricans with FGFR3 K650T mutation Editor Acanthosis nigricans (AN) is a proliferative epidermal disorder described clinically by velvety brown plaques in skin folds, although other parts of the skin and mucosa can occasionally be affected.1 There are currently seven accepted types of AN, listed by Schwartz as: benign, associated with obesity (pseudoacanthosis nigricans), syndromic, paraneoplastic, acral, unilateral and drug induced.2 Syndromic AN is reported in inherited skeletal dysplasias caused by heterozygous mutations in the fibroblast growth factor receptor 3 (FGFR3) gene.3 We describe AN associated with hypochondroplasia (HCH) caused by a p.Lys650Thr missense mutation in the FGFR3 gene. The proband was a 14-year-old healthy boy who presented to the dermatology clinic with a 2-year history of hyperpigmented skin on his anterior neck (Fig. 1). Examination revealed brown velvety skin coloration on his neck and axillas. Numerous solar lentigines were noted on his face, hands and upper back the latter showing several slightly verrucous keratoses. Small stature (143 cm, 2 SDS), normal BMI (21.5), macrocephaly (+2 SDS), short limbs, broad hands and hyperlordosis were also found. Facial dysmorphia and cognitive impairment were absent. Skin biopsy of the cervical hyperpigmented skin and of a verrucous keratosis revealed hyperkeratosis and papillomatosis with moderate irregular acanthosis compatible with AN. All the biochemical studies were within normal limits. Drug intake, hyperandrogenism, insulin resistance, autoimmune disease or metabolic disorders were not found. Skeletal survey revealed characteristic features of HCH including fibula longer than tibia and lack of widening of vertebral interpedicular distance. Subsequent family examination revealed a similar phenotype in the father and the two younger brothers (Fig. 2). The mother was unaffected. Genetic and molecular
(a)
analysis confirmed a heterozygous p.Lys650Thr (exon 15: AAG ⇒ ACG) missense mutation in FGFR3 gene in all affected member of the family. An array of vastly different diagnoses is caused by similar FGFR3 mutations, including syndromes affecting skeletal development (HCH, achondroplasia, thanatophoric dysplasia, Crouzon with AN), skin (epidermal nevi, seborrhoeic keratosis, AN) and cancer (multiple myeloma, prostate and bladder carcinoma, seminoma).4 FGFR3 is a regulator of skeletal growth, which disturbs the endochondral process via inhibition of chondrocyte proliferation and differentiation. All known mutations are gain-of-function mutations, they activate FGFR3 by increasing its phosphorylation. Although the exact mechanism varies depending on the location of given mutation, the end result is shortening of long bones with a graded spectrum of severity. In addition, FGFR3 mutation is known for producing excessive cell proliferation in benign and malignant disorders, suggesting a pro-mitogenic role. In 2005, a transgenic mouse model confirmed the role of FGFR3 in the activation of keratinocytic proliferation responsible for AN formation.5 HCH is an autosomal dominant skeletal disorder less severe than achondroplasia. A recurrent FGFR3 mutation (p. Lys650Asn) is identified in 70% of HCH cases which does not exhibit AN.6 To date, few reports have documented patients with HCH and AN. Concerning p.Lys650Thr mutation, Castro-Feijoo et al.3 reported a family with HCH, AN, numerous naevi, solar lentigos and cafe-aulait macules, while Berk et al.7 reported a family with AN, short stature, but no other abnormalities. To our knowledge, this is the second description of a family with HCH and AN associated to a FGFR3 p.Lys650Thr mutation. Our case highlight that this association is not fortuitous and that as previously reported, AN can be a marker of inherited skeletal dysplasia. Interestingly, the presence of early-onset solar lentigines and seborrheic-like verrucous keratoses show the wide spectrum of clinical manifestation due to FGFR3 mutations. Physicians should be aware of those associations especially when evaluating a family with short stature.
(b)
Figure 1 (a–b): Proband patient demonstrating (a) cervical acanthosis nigricans (arrow) and multiple solar lentigines and flat seborrheiclike verrucous keratoses (b).
JEADV 2016, 30, 852–909
© 2015 European Academy of Dermatology and Venereology
Letters to the Editor
898
4
5
6
7
in the fibroblast growth factor receptor 3 gene. Eur J Endocrinol 2008; 159: 243–249. Foldynova-Trantikova S, Wilcox WR, Krejcj P. Sixteen years and counting: the current understanding of fibroblast growth factor receptor 3 (FGFR3) signaling in skeletal dysplasias. Hum Mutat 2012; 33: 29–41. Logie A, Dunois-Larde C, Rosty C, Levrel O, Blanche M, Ribeiro A, et al. Activating mutations of the tyrosine kinase receptor FGFR3 are associated with benign skin tumors in mice and humans. Hum Mol Genet 2005; 14: 1153–1160. Berk DR, Boente MDC, Montanari D, Guadalupe-Toloza M, Primc BN, et al. Acanthosis nigricans and hypochondroplasia in a child with a K650Q mutation in FGFR3. Pediatr Dermatol 2010; 27: 664–666. Berk DR, Spector EB, Bayliss SJ. Familial acanthosis nigricans due to K650T FGFR3 mutation. Arch Dermatol 2007; 143: 1153–1156.
DOI: 10.1111/jdv.13061
Targetoid haemosiderotic haemangioma in a 3-year-old girl
Figure 2 Overall appearance of the siblings (14, 11 and 5-yearold) showing square-built, short stature, hyperlordotic stance and broad hands.
M.A. Cossiez Cacard,1 J. Coulombe,2 P. Bernard,3 N. Kaci,4 J.M. Bressieux,5 P.F. Souchon,1 J. Motte,1 L. Legeai-Mallet,4 S. Hadj-Rabia,2,4,†,* C. Eschard3,† Service de pediatrie, American Memorial Hospital, CHU de Reims, fe rence des maladies Reims, 2Service de dermatologie, Centre de re tiques a expression cutane e, Institut Imagine, Ho ^pital Universitaire g ene ^pitaux de Paris, Necker-Enfants Malades, Assistance Publique-Ho Paris Descartes - Sorbonne Paris Cite , Paris, 3Service de Universite ^pital Robert Debre , CHU de Reims, Reims, 4INSERM dermatologie, Ho U1163, Hospital Necker-Enfants Malades, University Paris Descartes , Institut Imagine, Paris, 5Service de dermatologie, Sorbonne Paris Cite Centre hospitalier de Troyes, Troyes, France *Correspondence: S. Hadj-Rabia. E-mail: smail.hadj@ inserm.fr † Equal contribution 1
References 1 Pardavila R, Roson E, De la Torre C, Cruces M. Generalized familial acanthosis nigricans associated with hypochondroplasia. Actas Dermosifiliogr 2008; 99: 661–667. 2 Smeeta S, Schwartz RA. Juvenile acanthosis nigricans. J Am Acad Dermatol 2007; 57: 502–508. 3 Castro-Feijoo L, Lourdes L, Vidal A, et al. Hypochondrodysplasia and acanthosis nigricans: a new syndrome due to the p.Lys650Thr mutation
JEADV 2016, 30, 852–909
Editor A healthy 3-year-old Caucasian girl developed a skin lesion on the right palm of the hand. 1.5 years after the first lesion, there had been several 5-month-cycles of presentation with swelling, and healing of the skin, leaving normal skin. Besides pain at the time of the swelling, there were no symptoms. Recently, a new, smaller lesion appeared on the thumb of the right hand. The girl denied any type of trauma. Physical examination revealed an indurated plaque on the skin overlying the second metacarpal bone of the right hand, 2.5 cm in diameter, with a small crusta and several point-like haemorrhagic lesions. On the thumb, there was a comparable lesion of 1 cm in diameter, less indurated (Fig. 1). A skin biopsy was taken of the largest lesion which showed a normal epidermis. In the dermis, there was proliferation of the blood vessels. In the papillary dermis, prominent, dilated, thinwalled vessels were present with prominent endothelial cells, with a ‘hobnail’ appearance. The dermal vessels were covered with CD31positive and D2-40-negative endothelium, which proved them being blood vessels and no lymphatic vessels. The reticular dermis was infiltrated with more narrow vascular spaces. There was haemosiderin deposition and extravasation of erythrocytes (Fig. 2). The clinical presentation and the histological findings were consistent with the diagnosis ‘targetoid hemosiderotic hemangioma’. One year after the first visit, the smaller lesion had disappeared and not returned. The larger lesion started to give functional problems when using the hand. Therefore, we decided to send the patient to a plastic surgeon to excise the lesion. Histological examination of the excisional specimen confirmed the diagnosis, fulfilling the criteria for targetoid haemosiderotic haemangioma. Targetoid haemosiderotic haemangioma, or hobnail haemangioma, was first described in 1988 by Santa Cruz and Aronberg.1 It is a benign vascular tumour with a variable clinical appearance.
© 2015 European Academy of Dermatology and Venereology
