European Journal of Endocrinology (2008) 159 243–249 ISSN 0804-4643

CLINICAL STUDY and acanthosis nigricans: a new syndrome due to the p.Lys650Thr mutation in the fibroblast growth factor 3 gene? Lidia Castro-Feijo´o*, Lourdes Loidi1,*, Anxo Vidal2, Silvia Parajes1, Elena Roso´n3,AnaA´ lvarez4, Paloma Cabanas, Jesu´s Barreiro, Adela Alonso4, Fernando Domı´nguez1,2 and Manuel Pombo Unidad de Endocrinologı´a Pedia´trica, Crecimiento y Adolescencia, Departamento de Pediatrı´a, Hospital Clı´nico Universitario y Universidad de Santiago de Compostela, 15706 Santiago de Compostela, Spain, 1Unidad de Medicina Molecular, Fundacio´nPu´blica Galega de Medicina Xeno´mica, 15706 Santiago de Compostela, Spain, 2Departamento de Fisiologı´a, Universidad de Santiago de Compostela, 15702 Santiago de Compostella, Spain, 3Servicio de Dermatologı´a, Complejo Hospitalario de Pontevedra, 36001 Pontevedra, Spain and 4Servicio de Radiologı´a, Hospital Clı´nico Universitario de Santiago de Compostela, 15706 Santiago de Compostela, Spain (Correspondence should be addressed to M Pombo; Email: [email protected]) *L Castro-Feijo´o and L Loidi contributed equally to this work

Abstract Background: Hypochondroplasia (HCH) is a skeletal dysplasia inherited in an autosomal dominant manner due, in most cases, to mutations in the fibroblast 3 (FGFR3). Acanthosis nigricans (AN) is a velvety and papillomatous pigmented hyperkeratosis of the skin, which has been recognized in some genetic disorders more severe than HCH involving the FGFR3 gene. Objective and design: After initial study of the proband, who had been consulted for short stature and who also presented AN, the study was extended to the patient’s mother and to 12 additional family members. Methods: Clinical, biochemical and radiological studies were performed on the family.In addition, exons 11 and 13 of FGFR3 were analyzed. Results: The proband and ten relatives presented HCH plus AN and the analysis of FGFR3 showed the p.Lys650Thr mutation. The members with normal phenotypes were non-carriers of the mutation. Conclusion: This is the first report of a large pedigree with the clinical phenotype of HCH plus AN due to a FGFR3 mutation, p.Lys650Thr. This finding demonstrates the coexistence of both conditions due to the same mutation and it might represent a true complex, which should be further established by searching for AN in mild HCH patients or for HCH in patients with AN.

European Journal of Endocrinology 159 243–249

Introduction and II, and severe with developmental delay and acanthosis nigricans (SADDAN). FGFR3 Hypochondroplasia (HCH) (OMIM 146000) is a skeletal mutations have also been described in Muenke and dysplasia similar to achondroplasia but less severe and Crouzon syndromes with acanthosis nigricans (AN) (2); rarely recognized before the age of 2 years. It is camptodactyly, tall stature and hearing loss syndrome characterized by short stature, short limbs and lumbar (3); lacrimo-auriculo-dento-digital syndrome (4) and, , although these features are variable and can be recently, in familial AN (5). almost normal in mildly affected subjects. The diagnosis FGFR3 is a member of a family that comprises four of HCH on clinical and radiological grounds is often related receptors (FGFR1–4). Structurally, they are difficult and some patients may be diagnosed as characterized by an extracellular ligand-binding domain idiopathic short stature. As with other skeletal dyspla- consisting of three immunoglobulin-like subdomains (Ig- sias, HCH is caused by heterozygous mutations in the like domains I–III), a transmembrane domain and two fibroblast growth factor receptor 3 gene (FGFR3); intracellular tyrosine kinase domains responsible for the nevertheless, genetic heterogeneity is suspected because catalytic activity (6). Up to now, different mutations in not all patients with presumed HCH have demonstrable FGFR3 have been identified in HCH patients: two of them, mutations in FGFR3 (1). HCH is inherited in an which result in p.Asn540Lys exchange (6–11),account autosomal dominant manner, and in the majority of for 72% of cases. There are other mutations that account new cases of HCH, the mutations appear de novo. Other for fewer than 2% of cases (12–17) and two among them skeletal dysplasias associated with mutations in FGFR3 are associated with a slightly milder skeletal phenotype, include achondroplasia, types I p.Lys650Asn and p.Lys650Gln (16).

q 2008 European Society of Endocrinology DOI: 10.1530/EJE-08-0393 Online version via www.eje-online.org

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FGFR3 is a negative regulator of bone growth and all disorders involving FGFR3 (22) like mutations characterized to date in skeletal dysplasias (23), SADDAN syndrome (21), long-term survivors of and cancer cause constitutive activation of the receptor. thanatophoric dysplasia (24), one single case of These are gain-of-function mutations that activate the achondroplasia (25) and one single case of osteochon- negative growth control exerted by the FGFR3 pathway drodysplasia (26). (18, 19). Hence, the different phenotypes related to In this report, we present an extended family with a FGFR3 mutations are due to various degrees of ligand- phenotype of mild HCH plus AN associated with the independent activation of the receptor (2). The Lys650 p.Lys650Thr mutation in FGFR3. residue of FGFR3, which is located within a critical region of the tyrosine kinase domain activation loop, has been particularly studied because amino acid sub- stitutions at this site result in the autophosphorylation Patient and family of tyrosine residues within the intracellular domain. The proband was a boy from northwestern Spain, who Mutations at this site are responsible for developmental was referred to the paediatric endocrinologist at 12.5 disorders that show different clinical severity. Thus, years of age because of short stature. He was born at p.Lys650Glu and p.Lys650Met mutations strongly term from non-consanguineous parents. Pregnancy activate the receptor and are associated with two was uncomplicated and the delivery was by cesarean severe forms of dwarfism: thanatophoric dysplasia section. Birth weight was 3515 g (SDS C0.06), birth type II (20) and SADDAN (21) respectively. By contrast, length 51 cm (SDS C0.32) and head circumference p.Lys650Asn and p.Lys650Gln mutations that activate (HC) 35 cm (SDS C0.12). The patient presented poor the receptor to a lesser degree are associated with milder growth and clinical features of HCH including relative forms of dysplasia, such as HCH. The mutation , high arched palate and slightly abnor- p.Lys650Thr also showed weak activation in vitro (16). mal body proportions with short upper and thighs AN is a velvety and papillomatous pigmented (Fig. 1). He also presented mild limitation in elbow hyperkeratosis of the skin, which appears mainly on extension and small and broad hands. He complained the flexures and neck. It is recognized in some genetic of mild and ankle pain while doing exercise.

Figure 1 Overall appearance of patients. (a–e) Hypochondroplasia characterized by relatively short extremities. Arrows, specific acanthosis nigricans areas in patients (more severe in women). (f and g) Pattern of acanthosis nigricans in the back (observe the hyperchromic spot in (g)). (h) Skin detail of acanthosis nigricans characterized by thick, velvety and hyperpigmented plaque. (a) II.5, (b) III.3, (c) III.4, (d) III.5, (e) III.7, (f) II.5, (g) III.4 and (h) II.9.

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His hearing and vision were normal, and his school tolerance test, homeostasis model assessment (HOMA) progress was satisfactory. His growth was uneventful index, insulin-like growth factor-I (IGF-I) and IGF- until 6 years of age, when it slowed substantially binding protein-3 (IGFBP-3) were also normal (Table 1). (Fig. 2). The onset of puberty was at 12.8 years with The growth hormone (GH) stimulatory tests showed a bone age (BA) of 11 years and his pubertal growth spurt GH peak of 17 mg/l. was poor. At 16 years (BA 16 years), his pubertal stage The mother of the patient reported the presence of was P5G5 with testis of 20 ml. His anthropometric hyperpigmented areas in her skin as well as in other measurements were as follows: height, 150.3 cm (SDS members of the family. Physical examination revealed K3.4); sitting height %, 55.8 (SDS C4.21); span, an important AN (Fig. 1) in the neck, abdomen (flanks) 147.5 cm (SDS K3.94); body mass index 24.2 and HC, and back, multiple pigmented nevi over trunk and 56.8 cm (SDS C1.23) (Table 1). In addition, he epidermal nevi in the neck. She also showed an HCH presented pigmented nevi and AN in the trunk and phenotype (Fig. 1), which was confirmed by the neck (Fig. 1). The radiological study of the skeleton was radiographic skeletal survey (Table 1; Fig. 3). Therefore, concordant with the diagnosis of HCH (27). It showed a familial condition was suspected and all the family moderate narrowing of interpedicular distances, ante- members were investigated. The study showed that all roposterior shortening of the pedicles and increased the members with HCH phenotype also presented AN, dorsal concavity of the vertebral bodies in the lumbar while others were normal for both conditions (Table 1; spine, short and broad femoral neck, shortening and Fig. 4). All affected adults presented short stature with relative squaring of the tubular bones, as well as body disproportion and referred to delayed puberty elongated distal end of the fibula with respect to the onset (menarche in all females occurred at 14 or 15 tibia (Table 1; Fig. 3). All the biochemical studies were years) and failure of the pubertal growth spurt. This within normal limits. Androgen levels, thyroid function growth pattern was revealed by the growth charts of the tests, liver function test, cholesterol and triglycerides proband (III.3) and one cousin (III.4) (Fig. 2). Their were normal (data not shown). The fasting insulin, heights were within normal range during childhood fasting glucose, glycosylated haemoglobin, oral glucose and at the same time they progressively deviate from the

Figure 2 Growth charts. (Left) proband; A (age 12.8 years, BA 11 years, P2G2, testis 4 ml); B (age 16 years, BA 16 years, P5G5, testis 20 ml); arrow, target height. (Right) patient III.4, AH, adult height. Observe the similar growth pattern and the failure of pubertal growth spurt in both.

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Downloaded from Bioscientifica.com at 09/25/2021 11:35:46AM via free access 246 L Castro-Feijo´o, L Loidi and others EUROPEAN JOURNAL OF ENDOCRINOLOGY (2008) 159 b radiology C 5.3 NA 2.4 7.9 b ears, 81–267); Gl, fasting glucose (mg/dl, normal nce (cm); BMI, body mass index; RSS, radiographic skeletal f the vertebral bodies in the lumbar spine, short and broad IGF-I Gl Ins OGTT HOMA HbA1c 211 92 4.4 Normal 0.9 4.9 172 190 457 97 7.0 Normal 1.6 4.6 Figure 3 Radiological HCH features in the patients. (a and b) Moderate narrowing of interpedicular distances. (c–e) Increased dorsal concavity of the vertebral bodies (note accentuated lumbar RSS C C C lordosis in (e)). (f and g) Short and broad femoral necks. (h and i) Disproportionate long fibula and short and plump tibia. (j) Moderate short and plump humerus. (a) III.3, (b) II.5, (c) III.3, (d) II.5, (e) II.1, (f) II.5, (g) II.1, (h) III.3, (I) II.5 and (f) II.5.

growth curve. This fact in addition to the poor growth 0.06) 28.1 NA 95 81 3.6 NA 0.7 4.4 0.27) 18.9 Normal 173 93 10.7 NA 2.4 4.5 spurt has resulted in adult short stature. The height SDS 0.24) 26.9 K K K

K of the proband (III.3) at 4 years was 1.20 and at 16 years K3.4. The height SDS of III.4 at 5 years was K1 and at 18 years K2.38. The growth of the youngest patients pointed towards the same pattern. In case III.6, 4.71) 54.2 ( 1.72) 54.6 ( 4.11) 54 ( 3.92) 56 (1.52) 26.5 NA 239 73the SDS 2.8 height Normal 0.5diminished 4.2 from C0.74 at 4 years to 3.65) 54.6 (0.29) 28.3 NA 175 87 5.1 NA 1.1 4.8 4.81) 57 (1.37) 26.4 3.22) 56 (1.52) 25.8 NA 195 85 3.9 Normal 0.8 4.3 K K K K K K K K 1.23 at 13 years (Tanner stage P3G2). Patients III.5 and III.7 present so far a height SDS of K0.04 and K0.05 respectively. Besides, all of them presented slight body disproportion with relatively short upper arms and thighs (Table 1; Fig. 1). NA NA NA NA NA NA NAAdditionally, NA NA NA all deliveries NA were by cesarean section.

a Some of them (II.1, II.2 and II.5) presented degenerative 3.50) 55.5 140.6 ( 0.62) 52.2 170.6 ( 2.78)2.13) 56.2 55 144.8 ( 148 ( 4.57) 55.4 143 ( 1.53) 55.42.38) 151 ( 55.2 146.1 ( arthropathy and all presented normal mental 2.21) K K K K K K K development. K On the other hand, the AN presented in the family is

AH (SDS) % SH AS (SDS) HC (SDS) BMI characterized by thick, velvety, hyperpigmented plaques predominantly on the back, neck and abdomen (Fig. 1). The dermatological study had resulted in the diagnosis Age of familial benign AN, which was histopathologically confirmed (Fig. 5). The AN was more severe in females, UI/ml, normal range: 1.5–18.5); OGTT, oral glucose tolerance test; HOMA, homeostasis model assessment index, HbA1c, glycosylated haemoglobin %, m and in all the cases it appeared in early infancy with variable intensities (Fig. 1). The AN considerably increased and darkened in the periods of puberty onset Phenotype Anthropometric measurements Biochemical and hormonal data

HCH AN and pregnancy. Besides, all affected members presented multiple pigmented nevi and some of them (cases II.9, III.4 and III.6) also showed cafe´-au-lait spots in the flank (Fig. 1).

Genotype and phenotype of patients. Other conditions that may underlie the AN in the patients, like insulin resistance, were excluded (Table 1). The patients affirmed no drug ingestion and there were Estimated height in paraplegicAdult patient. onset diabetes mellitus. range: 74–105), Ins, fasting insulin ( Patient Genotype Table 1 II.2 Lys650Thr Yes Yes 49 141.2 ( HCH, hypochondroplasia; AN, acanthosis nigricans; AH, adult height (cm); SH, sitting height %; AS, adult arm span in adults (cm); HC, head circumfere a b survey; IGF-I (ng/ml; normal range: 6–8 years, 52–345; 9–11 years, 74–551; 12–16 years, 143–996; 17–20 years, 127–731; 21–40 years, 109–358; 41–60 y II.6 Wild type No No 48 160 ( III.1 Wild type No No 21 170.6 ( compatible with HCH: moderate narrowing of interpedicular distances, anteroposterior shortening of the pedicles and increased dorsal concavity o femoral neck, shortening and relative squaring of the tubular bones and elongated distal end of the fibula with respect to the tibia; NA, not available. II.5II.7 Lys650Thr Yes Lys650Thr Yes Yes Yes 46 40 145.5 ( 149.4 ( III.2II.1 Wild type Lys650Thr No Yes No Yes 51 24 144.3 ( 169.3 (0.81) NA NA NA NA Normal 245 86 5.2 NA 1.1 4.5 II.9III.4 Lys650Thr Yes Lys650Thr Yes Yes Yes 35 18 153.0 ( 147.9 ( III.5III.6III.7 Lys650Thr Yes Lys650Thr Yes Lys650Thr Yes Yes Yes 8 Yes 13 7 – – – 55.2 53.6 – 55.8 – – 54.8 (1.87) 56 (1) 53.5 (1.02) 20.6 NA 23 20.2 236 NA NA 88 362 150 90 3.8 92 NA 6.9 6.1 0.8 NA NA 4.5 1.5 1.3 4.6 4.7 III.3 Lys650Thr Yes Yes 16 –no malignant 55.8 – neoplasms 56.8 (1.23) 24.2 in the family. The serum

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Figure 4 Pedigree of family. Black symbols, patients with hypochondroplasia plus acanthosis nigricans; arrow, proband; white symbols, individuals with normal phenotype. II.4 exitus at 3 months from unknown cause. analysis for alkaline phosphatase, calcium, phosphorus, Genetic analysis androgen levels, thyroid function test, liver function test, cholesterol and triglycerides were within normal Blood samples were collected after obtaining informed limits (data not shown). consent from the proband and his relatives. DNA was extracted from leukocytes by standard procedures. Two pairs of primers were used to PCR amplify exons 11 and 13 of FGFR3: 11S, 50-AGCCTGTCACCGTAGCC- 0 0 0 Serum hormone assays GTGA-3 ; 11A, 5 -TTGCAGGTGTCGAAGGAGTAG-3 ; 13S, 50-AGAGGCTTCAGCCCTGCCTC-30 and 13A, 0 0 GH, IGF-I, IGFBP-3 and insulin were determined by an 5 -CAGGCGTCCTACTGGCATGA-3 . PCR products were automated chemoimmunoluminescence assay (Immu- purified and directly sequenced using the BigDye lite 2000; Siemens Medical Solutions Diagnostics, Los terminator and run in the 3730xl DNA analyzer Angeles, CA, USA). Testosterone and thyroid hormones (Applied Biosystems, Foster City, CA, USA). were determined by chemoimmunoluminescence (ADVIA Centaur; Siemens Medical Solutions Diagnos- tics). For the OGTT, 1.75 g glucose/kg ideal body Results weight, not to exceed 75 g, were administered and blood samples were obtained from an antecubital vein The proband (III.3) was a heterozygous carrier of the immediately before and 120 min after glucose admin- c.1988 AOC mutation (GenBank accession number istration for the measurement of plasma glucose and NM_000142), which leads to the p.Lys650Thr insulin. The HOMA index was calculated as the product mutation at the protein level (Fig. 6). The genetic of the fasting plasma insulin (mUI/ml) and glucose levels analysis in the proband’s relatives with the HCH plus (mmol/l) divided by 22.5. AN phenotype (II.1, II.2, II.5, II.7, II.9, III.4, III.5, III.6 and III.7) showed that they were heterozygous carriers of the same mutation (patient I.1 was not available for

Figure 5 Skin biopsy. Acanthosis and papillomatosis with mild Figure 6 Electropherogram showing the base change from adenine hyperkeratosis compatible with acanthosis nigricans (haematoxylin to cytosine in the FGFR3 gene, which leads to the substitution of and eosin, 100!). lysine 650 by threonine in the FGFR3 protein.

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Downloaded from Bioscientifica.com at 09/25/2021 11:35:46AM via free access 248 L Castro-Feijo´o, L Loidi and others EUROPEAN JOURNAL OF ENDOCRINOLOGY (2008) 159 genetic analysis). Whereas the genetic study in the downstream of the activation of the receptor is likely to relatives with normal phenotype (II.6, III.1 and III.2) explain this phenomenon, uncoupling bone and skin showed that they were not mutation carriers (Fig. 4). phenotypes in FGFR3 germline mutations. Together with the previous mutation reports, our observation suggests an important role for residue Lys650 in the fine-tuning of FGFR3 function. This is supported by the reports of Discussion various clinical phenotypes ensuing from different amino Here, an extended family with a phenotype that acid substitutions at this same site, in skeletal disorders comprises mild HCH plus AN due to the p.Lys650Thr (Lys650Glu/Asn/Gln/Met), multiple myeloma (Lys650- mutation in the FGFR3 gene is presented. All the family Glu/Met) or bladder cancer (Lys650Glu/Met/Thr). It is members who harbour the mutation have an HCH plus also in agreement with the high degree of conservation AN phenotype, whereas none of the family members observed for this residue in other tyrosine kinase without the mutation present HCH or AN. Other possible receptors. It has been described that FGFR3 signals causes underlying AN, such as hyperinsulinaemia or through the activation of STAT1 and MEK/MAPK malignancy were excluded; moreover, the AN appeared pathways, both of which seem to be relevant to the in the trunk in addition to the flexures, which is typical of phenotypic consequences of achondroplasia (30).We AN in syndromes due to FGFR3 mutations (22). speculate that Lys650 is a critical residue involved in the A partial study of this family has been presented at activation of one of these downstream pathways, with the 46th European Society for Paediatric Endocrinology different consequences depending on the particular Meeting (28) and, recently, the same mutation has also influence of the affected pathway on the specific cell been described in an African-American family with AN type. Thus, it is possible that while sustained activation of (5), where the authors reported no associated MAPK pathway could have mild consequences in anomalies other than slight short stature. chondrocyte differentiation (since STAT1 may be unaf- The p.Lys650, which is located in the tyrosine kinase fected), it may cause a stronger impact on keratinocyte domain of the receptor, is an important residue for the proliferation. biological function of FGFR3. In fact, different amino Alternatively, different mutations in the Lys650 acid substitutions at this site have been described in residue could affect different intracellular localizations, skeletal dysplasias of diverse severity, but also in bladder which is now believed to have a role in chondrocyte cancer (29). Bellus and colleagues (16) had investi- defects observed in skeletal dysplasias (31). It should be gated, in vitro, the constitutive activation of the receptor noted that FGFR3 can be expressed as different isoforms, by all the possible amino acid substitutions resulting and while chondrocytes express the isoform IIIc, from single-nucleotide changes in the 650 codon of epithelial cells present the isoform IIIb. Despite this, FGFR3. They showed that the p.Lys650Thr mutation there is no apparent link of any isoform with specific leads to a constitutive activation of the FGFR3 tyrosine responses; we cannot rule out the possibility that the kinase equivalent to the activation produced by effect of mutations within the tyrosine kinase domain p.Lys650Asn and p.Lys650Gln, which are both associ- could be modulated for isoform-specific differences. ated with mild HCH. At the same time, it leads to a Further investigations are needed to address these issues. considerably lower activation than that produced by The finding of this family with the clinical phenotype p.Lys650Glu and p.Lys650Met mutations that are of HCH plus AN associated with the p.Lys650Thr in associated with more severe phenotypes. Thus, the FGFR3 demonstrates the coexistence of both conditions severity in the skeletal dysplasia was in concordance due to the same mutation, and it might represent a true with the degree of ligand-independent kinase activity of complex, which should be further established by the receptor. Because the growth inhibitory action of searching for AN in mild HCH patients or for HCH in FGF signalling is specific to chondrocytes, whereas patients with AN. mitogenic for other cell types such as cells in the bladder epithelium or keratinocytes, this was also in agreement with the fact that only severe forms of skeletal dysplasias Acknowledgements had been associated with AN. Here, we report a familycase ofHCH associated with AN We would like to thank the family for their cooperation in the context of the p.Lys650Thr germline mutation. in this study, and Marı´a Jesu´s Romero and Miguel Veryrecently,this substitution has been described to cause Abelleira for their technical assistance. Lidia Castro- familial AN with no obvious skeletal abnormalities except Feijo´o has support from Fundacio´n para la Investigacio´n slight short stature (5). Another report has linked AN to a y Desarrollo de la Endocrinologı´a Pedia´trica (FIDEP) and mild form of (26). Taken together, from USC (project 2007-CE470). Lourdes Loidi has these three reports argue against a simple model in which support from Fondo de Investigaciones Sanitarias del kinase activity of the FGFR3 mutant form explains Instituto de Salud Carlos III. Anxo Vidal is a Ramo´ny the severity of the manifestations, being skeletal defects Cajal Investigator and recipient of a consolidation grant or skin lesions. Complexity of intracellular signalling from Xunta de Galicia.

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