Subtle radiographic findings of achondroplasia in patients with Crouzon syndrome with acanthosis nigricans due to an Ala391Glu substitution in FGFR3.

A unique type of craniofacial dysostosis, Crouzon syndrome with acanthosis nigricans (CAN), has been attributed to a specific substitution (Ala391Glu) in the fibroblast growth factor receptor 3 (FGFR3) gene. At birth, individuals with this disorder have craniosynostosis, ocular proptosis, midface hypoplasia, choanal atresia, hydrocephalus, and they experience the onset of acanthosis nigricans during childhood. We report three cases and compare the clinical characteristics of our cases with the previously reported cases of this disorder. Since the Ala391Glu substitution in FGFR3 is close to the substitutions in the transmembrane domain that result in achondroplasia, we carefully reviewed the skeletal findings in six patients. We identified subtle radiographic findings of achondroplasia in all six cases including narrow sacrosciatic notches, short vertebral bodies, lack of the normal increase in interpediculate distance from the upper lumbar vertebrae caudally, and broad, short metacarpals and phalanges. Even before acanthosis nigricans appears, the presence of choanal atresia and hydrocephalus in an individual with features of Crouzon syndrome should suggest the diagnosis of CAN, and subtle skeletal findings can lend further support to this diagnosis.     

Hyperinsulinemia and acanthosis nigricans in African Americans.

Compared with the US white, non-Hispanic population, the African-American population has a nearly two-fold higher prevalence of noninsulin-dependent diabetes mellitus (NIDDM). Obesity, which usually precedes NIDDM, is associated with the skin lesion acanthosis nigricans in African Americans. This study was undertaken to determine what the relationship of acanthosis nigricans was to hyperinsulinemia, a major risk factor for NIDDM. Eighty-nine African-American subjects with acanthosis nigricans and 25 others without the skin lesion were evaluated using oral glucose tolerance testing and responsiveness to insulin. Noninsulin-dependent diabetes mellitus was present in 19 of the subjects with acanthosis nigricans. The prevalence of NIDDM in this group increased with increasing age, reaching 50% among those in their 40s. Fasting plasma insulin concentration was in direct proportion to the severity of the acanthosis nigricans involvement of the neck. These data suggest that among African Americans, this skin lesion is a marker for hyperinsulinemia and insulin resistance. Furthermore, the presence of acanthosis nigricans identifies a subset with a much higher prevalence of NIDDM than is present in African Americans in the general population.     

Subtle radiographic findings of achondroplasia in patients with Crouzon syndrome with acanthosis nigricans due to an Ala391Glu substitution in FGFR3

A unique type of craniofacial dysostosis, Crouzon syndrome with acanthosis nigricans (CAN), has been attributed to a specific substitution (Ala391Glu) in the fibroblast growth factor receptor 3 (FGFR3) gene. At birth, individuals with this disorder have craniosynostosis, ocular proptosis, midface hypoplasia, choanal atresia, hydrocephalus, and they experience the onset of acanthosis nigricans during childhood. We report three cases and compare the clinical characteristics of our cases with the previously reported cases of this disorder. Since the Ala391Glu substitution in FGFR3 is close to the substitutions in the transmembrane domain that result in achondroplasia, we carefully reviewed the skeletal findings in six patients. We identified subtle radiographic findings of achondroplasia in all six cases including narrow sacrosciatic notches, short vertebral bodies, lack of the normal increase in interpediculate distance from the upper lumbar vertebrae caudally, and broad, short metacarpals and phalanges. Even before acanthosis nigricans appears, the presence of choanal atresia and hydrocephalus in an individual with features of Crouzon syndrome should suggest the diagnosis of CAN, and subtle skeletal findings can lend further support to this diagnosis. © 2001 Wiley‐Liss, Inc.     

Body mass index percentile more sensitive than acanthosis nigricans for screening Native American children for diabetes risk

BackgroundMany Native American tribes use acanthosis nigricans to screen for type 2 diabetes risk. We hypothesized that acanthosis nigricans misses many children at risk for type 2 diabetes.MethodsWe evaluated 5- to 18-year-old Native American children and youth to assess the sensitivity and specificity of acanthosis nigricans as a marker for insulin resistance.ResultsIn a cohort of 161 youth (72 males/89 females), mean age was 10.7 years + 3.9. Mean body mass index (BMI) percentile was 76.8 ± 23.3, and 54% had a BMI at or above the 85th percentile. Acanthosis nigricans was present in 21.7% of the participants and was more common in 12- to 18-year-olds than in 5- to 11-year-olds (p = .02). Of those with acanthosis nigricans, 82.4% had insulin resistance (homeo-static model assessment of insulin resistance >4), but only 48.3% of those with insulin resistance had acanthosis nigri-cans. In contrast, BMI at or above the 85th percentile had a high sensitivity (74%) for insulin resistance, even though its specificity was lower (58%).ConclusionsThe presence of acanthosis nigricans alone was a specific, but not a sensitive, screening tool for identifying youth with insulin resistance. BMI at or above the 85th percentile was a more sensitive screening tool than acanthosis nigricans alone, or acanthosis nigricans and BMI together for identifying children and youth with IR who are at increased risk for type 2 diabetes.     

Complete reversibility of paraneoplastic acanthosis nigricans after operation

A patient with widespread acanthosis nigricans is described. No abdominal tumour was found. Explorative thoracotomy disclosed numerous enlarged lymph glands containing squamous cell carcinoma. The left lung was removed but meticulous search did not disclose any tumour. The glands were removed as radically as possible. After the operation the skin improved and the lesions have disappeared completely. The observation time is over three years.     

Crouzon with acanthosis nigricans. Further delineation of the syndrome

Patients with Crouzon and acanthosis nigricans syndrome show craniofacial features similar to those observed in patients with classic Crouzon syndrome, in addition to acanthosis nigricans with peculiar characteristics. More severe physical manifestations, such as Chiari malformation, hydrocephalus, and atresia or stenosis of the choanas, which are unusual in individuals with classic Crouzon syndrome, are reported in these patients. The molecular abnormality associated with Crouzon syndrome with acanthosis nigricans (CAN) is a transition in the transmembrane domain of the FGFR3 gene that results in an Ala391Glu mutation. We describe two unrelated patients showing this mutation and compare their clinical features with those of other patients with CAN reported in the literature. In addition to craniosynostosis with crouzonoid facies and acanthosis nigricans (present in all patients), melanocytic nevi, choanal atresia or stenosis, hydrocephalus, Chiari malformations and oral abnormalities were observed in the majority of the 35 patients analyzed. Vertebral anomalies and conductive hearing loss were present with less frequency. Some characteristics considered typical of this condition (jaw cementomas, acanthomas and finger abnormalities) were absent in most of the patients.     

Hepatic dysfunction in Alstr?m disease.

Alstr?m disease is a rare disorder; less than 20 cases have been reported. An 11-year-old girl is described with this condition. She has pigmentary retinopathy, sensory neural deafness, obesity, Type II diabetes mellitus, hyperlipidemia, and acanthosis nigricans. However, in addition she developed hepatic dysfunction, pathologically similar to chronic active hepatitis. This may be a further, previously undescribed systemic manifestation of Alstr?m disease.     

Long-term survival in typical thanatophoric dysplasia type 1

Thanatophoric dysplasia (TD), a severe skeletal dysplasia, is virtually always lethal neonatally, although a few previous reports have documented survival up to 4.75 years. We present a patient with survival beyond age 9 years and summarize his growth, development and medical history. The common Arg248Cys mutation in the extracellular region of fibroblast growth factor receptor 3 (FGFR3) was identified, eliminating the possibility that his long-term survival is attributable to an atypical mutation. This patient (and at least one other TD long-term survivor) have a rare skin disorder, acanthosis nigricans, which also occurs in Crouzon syndrome when caused by a FGFR3 mutation. Therefore, any molecular model of the origin of acanthosis nigricans secondary to FGFR3 mutations must account for the association of diverse mutations and these cutaneous effects. Am. J. Med. Genet. 70:427–436, 1997. © 1997 Wiley-Liss, Inc.     

Rearrangement of chromosome 15 in the region q11.2----q12 in an individual with obesity syndrome and her normal mother

Rearrangement of the proximal long arm of chromosome 15 have been found in most patients with the Prader-Willi syndrome (PWS) and in some with Angelman syndrome. We present an individual with syndromic obesity and her normal mother, who both have an abnormal chromosome 15. The proposita is a 26-year-old women with marked obesity, acanthosis, nigricans, short fingers, and severe cone degeneration of the retina. She has high plasma insulin levels, hypothyroidism, and an empty sella on CT scan. High-resolution chromosome banding demonstrated an increase in band 15q12. Further analysis showed the same abnormal 15 in her normal mother but not in her normal sister. This case and recent reports in the literature indicate that duplication of chromosome 15q in the PWS region may be associated with a syndrome of obesity, acanthosis nigricans, empty sella, and rodcore dystrophy as well as with a normal phenotype. Whether normal individuals with such a duplication carry increased risk of having offspring with an obesity syndrome is yet to be determined.     

Rearrangement of chromosome 15 in the region q11.2→q12 in an individual with obesity syndrome and her normal mother

Rearrangements of the proximal long arm of chromosome 15 have been found in most patients with the Prader-Willi syndrome (PWS) and in some with Angelman syndrome. We present an individual with syndromic obesity and her normal mother, who both have an abnormal chromosome 15. The proposita is a 26-year-old woman with marked obesity, acanthosis nigricans, short fingers, and severe cone degeneration of the retina. She has high plasma insulin levels, hypothyroidism, and an empty sella on CT scan. High-resolution chromosome banding demonstrated an increase in band 15q12. Further analysis showed the same abnormal 15 in her normal mother but not in her normal sister. This case and recent reports in the literature indicate that duplications of chromosome 15q in the PWS region may be associated with a syndrome of obesity, acanthosis nigricans, empty sella, and rodcore dystrophy as well as with a normal phenotype. Whether normal individuals with such a duplication carry increased risk of having offspring with an obesity syndrome is yet to be determined.     

Rabson-Mendenhall syndrome

Rabson-Mendenhall syndrome is characterized by growth retardation, dysmorphisms, lack of subcutaneous fat, acanthosis nigricans, enlarged genitalia, hirsutism, premature and dysplastic dentition, coarse facial features, paradoxical fasting hypoglycemia and post-prandial hyperglycemia, extreme hyperinsulinemia and pineal hyperplasia. We describe a six-month-old female child with physical features suggestive of the Rabson-Mendenhall syndrome. The child also had medullary nephrocalcinosis.     

Duplication of chromosome 15 in the region 15q11-13 in a patient with developmental delay and ataxia with similarities to Angelman syndrome.

Duplications of the proximal long arm of chromosome 15 have been seen in the Prader-Willi syndrome (PWS), and in subjects without the Prader-Willi phenotype but with other clinical features including short stature, diabetes, anal and jejunal atresia, and acanthosis nigricans. The non-PWS subjects all had different phenotypes despite the identical findings on cytogenetic analysis. A normal phenotype has also been observed in patients with similar duplications. We report a further patient with a duplication of 15q11-13 which was detected cytogenetically and confirmed on molecular genetic analysis. She has developmental delay, particularly concerning the acquisition of speech, and an ataxic gait. These are interesting clinical features in view of the association of Angelman syndrome with abnormalities of 15q11-13.     

A syndrome of insulin resistance resembling leprechaunism in five sibs of consanguineous parents.

Leprechaunism is a rare autosomal recessive disorder associated with extreme insulin resistance with paradoxical hypo-glycaemia. It is characterised by prenatal and postnatal growth retardation, reduced subcutaneous tissue, coarse features, acanthosis nigricans, enlarged genitalia, and death in the first year of life. Defects in both the insulin receptor and postreceptor steps of the insulin action pathway have been reported. At the molecular level, several mutations have been described. The patients reported here are from a Yemeni family with a syndrome of insulin resistance similar to leprechaunism in which the parents are second cousins and five of their eight children are affected. However, the phenotypes seem to be less severe than the classical leprechaunism previously described. All the children are alive (oldest 11 years), there is normal subcutaneous tissue, and a normal growth pattern in some of them. It may be that this is a milder type of leprechaunism with a better prognosis, perhaps caused by a different type of mutation from those previously described.     

Severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN): phenotypic analysis of a new skeletal dysplasia caused by a Lys650Met mutation in fibroblast growth factor receptor 3.

We previously discovered a novel missense mutation (Lys650Met) in the tyrosine kinase domain of the fibroblast growth factor receptor 3 (FGFR3) gene in four unrelated individuals with a condition we called "severe achondroplasia with developmental delay and acanthosis nigricans" (SADDAN) [Tavormina et al., 1999: Am. J. Hum. Genet. 64:722-731]. Here we present a more detailed clinical account of the SADDAN phenotype. The FGFR3 Lys650Met mutation results in severe disturbances in endochondral bone growth that approach and overlap those observed in thanatophoric dysplasia, type I. However, this mutation is most often compatible with survival into adulthood. Other unusual bone deformities, such as femoral bowing with reverse (i.e., posterior apex) tibial and fibular bowing and "ram's horn" bowing of the clavicle, are also seen in some patients. In addition to skeletal dysplasia, progressive acanthosis nigricans, and central nervous system structural anomalies, seizures and severe developmental delays are observed in surviving SADDAN patients. Despite its location within the same FGFR3 codon as the thanatophoric dysplasia type II mutation (Lys650Glu) and a similar effect on constitutive activation of the FGFR3 tyrosine kinase, the Lys650Met is not associated with cloverleaf skull or craniosynostosis.     

Second case of Beare-Stevenson syndrome with an FGFR2 Ser372Cys mutation

Beare-Stevenson syndrome is characterized by cutis gyrata, acanthosis nigricans, skin furrows, skin tags, craniosynostosis, Crouzonoid-like features in some cases and cloverleaf skull in others, anogenital anomalies, and prominent umbilical stump. Reported causes are an FGFR2 Tyr375Cys mutation in nine cases and an FGFR2 Ser372Cys mutation in one case. Here, we report on a second patient with the FGFR2 Ser372Cys mutation.     

Heterogeneity for congenital generalized lipodystrophy in seventeen patients from Oman

Seventeen children with congenital generalized lipodystrophy or Berardinelli-Seip Congenital Lipodystrophy (BSCL) from 12 consanguineous sibships were observed in Oman. All children had widespread absence of adipose tissue from infancy together with apparent muscle hypertrophy and hepatomegaly. They did not appear to represent a single homogenous entity, and it was possible to subclassify the cases into two distinct groups. In the first group of seven cases, the features were similar to other published cases with acanthosis nigricans, raised insulin levels, and insulin resistance. In this group, there was an association between the degree of acanthosis nigricans and the severity of the disorder. Molecular analysis of these cases showed homozygosity at the BSCL2 locus on chromosome 11q13 in four of the seven cases. In the second group of ten cases, there were striking abnormalities in both skeletal and nonskeletal muscle. Reduced exercise tolerance and percussion myoxedema were observed in skeletal muscle, while infantile hypertrophic pyloric stenosis, prominent veins (phlebomegaly), disturbance of cardiac rhythm, and cardiomyopathy were observed in nonskeletal muscle. There was evidence against homozygosity in some cases for the known loci for BSCL, and this group may represent a new clinical syndrome with lipodystrophy at a different genetic location.     

Identification of three novel mutations in the insulin receptor gene in type A insulin resistant patients

Type A insulin resistance syndrome is characterized by the association of ovarian hyperandrogenism, acanthosis nigricans, and severe insulin resistance. We have identified three novel mutant alleles of the insulin receptor gene in 3 patients with type A syndrome, a severe form of insulin resistance. Two of the patients were sisters (A1, A2), 1 of them was a compound heterozygote for a mutation at the 3'-splice acceptor site of intron 21 (AG-->AA), and a missense mutation Val140Leu in exon 2. Her sister was a simple heterozygote for the 3'-splice acceptor mutation. The third patient (A3) was heterozygous for the missense mutation Ala1028Val in exon 17, in the consensus sequence for ATP binding.     

Prenatal and postnatal presentation of severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN) due to the FGFR3 Lys650Met mutation

We present prenatal and postnatal features of a patient with severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN). Mutation analysis confirmed the clinical diagnosis by detecting the FGFR3 Lys650Met mutation. This case, one of only six with molecular analysis reported in the literature, confirms the severe morbidity and adds to the reports with early mortality associated with SADDAN. Clinical-radiological characteristics of all reported cases of SADDAN are reviewed and discussed.     

Activating mutations of the tyrosine kinase receptor FGFR3 are associated with benign skin tumors in mice and humans

Specific germline activating point mutations in the gene encoding the tyrosine kinase receptor FGFR3 (fibroblast growth factor receptor 3) result in autosomal dominant human skeletal dysplasias. The identification in multiple myeloma and in two epithelial cancers-bladder and cervical carcinomas-of somatic FGFR3 mutations identical to the germinal activating mutations found in skeletal dysplasias, together with functional studies, have suggested an oncogenic role for this receptor. Although acanthosis nigricans, a benign skin tumor, has been found in some syndromes associated with germinal activating mutations of FGFR3, the role of activated FGFR3 in the epidermis has never been investigated. Here, we targeted an activated receptor mutant (S249C FGFR3) to the basal cells of the epidermis of transgenic mice. Mice expressing the transgene developed benign epidermal tumors with no sign of malignancy. These skin lesions had features in common with acanthosis nigricans and other benign human skin tumors, including seborrheic keratosis, one of the most common benign epidermal tumors in humans. We therefore screened a series of 62 cases of seborrheic keratosis for FGFR3 mutations. A large proportion of these tumors (39%) harbored somatic activating FGFR3 mutations, identical to those associated with skeletal dysplasia syndromes and bladder and cervical neoplasms. Our findings directly implicate FGFR3 activation as a major cause of benign epidermal tumors in humans.     

Microcephalic osteodysplastic primordial dwarfism with severe microdontia and skin anomalies: confirmation of a new syndrome

We report two related Thai children having a new syndrome of microcephalic osteodysplastic primordial dwarfism (MOPD). The findings which classify them as having MOPD include IUGR, microcephaly, prominent nose and nasal bridge, small pinnae, short stature, cone-shaped and ivory-epiphyses, delayed bone age, slender long bones, and abnormal pelvis. The findings that distinguish them as having newly recognized syndrome consist of severe microdontia, malformed teeth, single-rooted or rootless teeth, severely hypoplastic alveolar bone, café au lait spots, acanthosis nigricans, and areas of hypo- and hyperpigmented skin. The reported patients appear to have the same condition as the family reported by Kantaputra [2002: Am J Med Genet 111:420-428]. This article contains supplementary material, which may be viewed at the American Journal of Medical Genetics website at http://www.interscience.wiley.com/jpages/0148-7299/suppmat/index.html.