Premature calvarial synostosis and epidermal hyperplasia (Beare-Stevenson syndrome-like anomalies) resulting from a P250R missense mutation in the gene encoding fibroblast growth factor receptor 3

We report on a patient with a severe premature calvarial synostosis and epidermal hyperplasia. The phenotype was consistent with that of a mild presentation of Beare-Stevenson syndrome but molecular analysis of the IgIII-transmembrane linker region and the transmembrane domain of the gene encoding the FGFR2 receptor, revealed wild-type sequence only. Subsequently, molecular analysis of the FGFR3 receptor gene identified a heterozygous P250R missense mutation in both the proposita and her mildly affected father. This communication extends the clinical spectrum of the FGFR3 P250R mutation to encompass epidermal hyperplasia and documents the phenomenon of activated FGFR receptors stimulating common downstream developmental pathways, resulting in overlapping clinical outcomes. (C) 2001 Wiley-Liss, Inc.

Clinical and biochemical consequences of p450 oxidoreductase deficiency

Patients with P450 oxidoreductase (POR) deficiency typically present with adrenal insufficiency, genital anomalies and bony malformations resembling the Antley-Bixler craniosynostosis syndrome. Since our first report in 2004, more than 40 POR mutations have been identified in over 65 patients. POR is the obligate electron donor to all microsomal P450 enzymes, including the steroidogenic enzymes CYP17A1, CYP21A2 and CYP19A1. POR deficiency may cause disordered sexual development manifested as genital undervirilization in 46, XY newborns as well as overvirilization in those who are 46, XX. This may be explained by impaired aromatization of fetal androgens that may cause maternal virilization and low urinary estriol levels during pregnancy. In addition, the alternate 'backdoor' pathway of androgen biosynthesis, which leads to dihydrotestosterone production bypassing androstenedione and testosterone, may also play a role. Functional assays studying the effects of POR mutations on steroidogenesis showed that several POR variants impaired CYP17A1, CYP21A2 and CYP19A1 activities to different degrees, indicating that each POR variant must be studied separately for each potential target P450 enzyme. POR variants may also affect skeletal development and drug metabolism. As most drugs are metabolized by hepatic microsomal P450 enzymes, studies of the impact of POR mutations on drug-metabolizing P450s are particularly important.

P450 oxidoreductase deficiency - a new form of congenital adrenal hyperplasia

Patients with adrenal insufficiency, genital anomalies and bony malformations resembling the Antley- Bixler syndrome (a craniosynostosis syndrome), are likely to have P450 oxidoreductase (POR) deficiency. Since our first report in 2004, about 26 recessive POR mutations have been identified in 50 patients. POR is the obligate electron donor to all microsomal (type II) P450 enzymes, including the steroidogenic enzymes CYP17A1, CYP21A2 and CYP19A1. POR deficiency may cause disordered sexual development manifested as genital undervirilization in 46,XY newborns as well as overvirilization in those who are 46,XX. This may be explained by impaired aromatization of fetal androgens which may also lead to maternal virilization and low urinary estriol levels during pregnancy. A role for the alternate 'backdoor' pathway of androgen biosynthesis, leading to dihydrotestosterone production bypassing androstenedione and testosterone, has been suggested in POR deficiency but remains unclear. POR variants may play an important role in drug metabolism, as most drugs are metabolized by hepatic microsomal P450 enzymes. However, functional assays studying the effects of specific POR mutations on steroidogenesis showed that several POR variants impaired CYP17A1, CYP21A2 and CYP19A1 activities to different degrees, indicating that each POR variant must be studied separately for each potential target P450 enzyme. Thus, the impact of POR mutations on drug metabolism by hepatic P450s requires further investigation.

Phylogenetic analysis of receptor FgfrL1 shows divergence of the C-terminal end in rodents

FGFRL1 is a member of the fibroblast growth factor receptor (FGFR) family. Similar to the classical receptors FGFR1-FGFR4, it contains three extracellular Ig-like domains and a single transmembrane domain. However, it lacks the intracellular tyrosine kinase domain that would be required for signal transduction, but instead contains a short intracellular tail with a peculiar histidine-rich motif. This motif has been conserved during evolution from mollusks to echinoderms and vertebrates. Only the sequences of FgfrL1 from a few rodents diverge at the C-terminal region from the canonical sequence, as they appear to have suffered a frameshift mutation within the histidine-rich motif. This mutation is observed in mouse, rat and hamster, but not in the closely related rodents mole rat (Nannospalax) and jerboa (Jaculus), suggesting that it has occurred after branching of the Muridae and Cricetidae from the Dipodidae and Spalacidae. The consequence of the frameshift is a deletion of a few histidine residues and an extension of the C-terminus by about 40 unrelated amino acids. A similar frameshift mutation has also been observed in a human patient with a craniosynostosis syndrome as well as in several patients with colorectal cancer and bladder tumors, suggesting that the histidine-rich motif is prone to mutation. The reason why this motif was conserved during evolution in most species, but not in mice, is not clear.

KRAS gene mutations in Noonan syndrome familial cases cluster in the vicinity of the switch II region of the G-domain: Report of another family with metopic craniosynostosis

Noonan syndrome (NS) and Noonan-related disorders [cardio-facio-cutaneous (CFC), Costello, Noonan syndrome with multiple lentigines (NS-ML), and neurofibromatosis-Noonan syndromes (NFNS)] are a group of developmental disorders caused by mutations in genes of the RAS/MAPK pathway. Mutations in the KRAS gene account for only a small proportion of affected Noonan and CFC syndrome patients that present an intermediate phenotype between these two syndromes, with more frequent and severe intellectual disability in NS and less ectodermal involvement in CFC syndrome, as well as atypical clinical findings such as craniosynostosis. Recently, the first familial case with a novel KRAS mutation was described. We report on a second vertical transmission (a mother and two siblings) with a novel mutation (p.M72L), in which the proband has trigonocephaly and the affected mother and sister, prominent ectodermal involvement. Metopic suture involvement has not been described before, expanding the main different cranial sutures which can be affected in NS and KRAS gene mutations. The gene alteration found in the studied family is in close proximity to the one reported in the other familial case (close to the switch II region of the G-domain), suggesting that this specific region of the gene could have less severe effects on intellectual ability than the other KRAS gene mutations found in NS patients and be less likely to hamper reproductive fitness. (c) 2012 Wiley Periodicals, Inc.

46,XX DSD and Antley-Bixler syndrome due to novel mutations in the cytochrome P450 oxidoreductase gene

Deficiency of the enzyme P450 oxidoreductase is a rare form of congenital adrenal hyperplasia with characteristics of combined and partial impairments in steroidogenic enzyme activities, as P450 oxidoreductase transfers electrons to CYP21A2, CYP17A1, and CYP19A1. It results in disorders of sex development and skeletal malformations similar to Antley-Bixley syndrome. We report the case of a 9-year-old girl who was born with virilized genitalia (Prader stage V), absence of palpable gonads, 46,XX karyotype, and hypergonadotropic hypogonadism. During the first year of life, ovarian cyst, partial adrenal insufficiency, and osteoarticular changes, such as mild craniosynostosis, carpal and tarsal synostosis, and limited forearm pronosupination were observed. Her mother presented severe virilization during pregnancy. The molecular analysis of P450 oxidoreductase gene revealed compound heterozygosis for the nonsense p.Arg223*, and the novel missense p.Met408Lys, inherited from the father and the mother, respectively. Arq Bras Endocrinol Metab. 2012;56(8):578-85

Comparison of periodontal parameters in individuals with syndromic craniosynostosis

Craniosynostosis syndromes are characterized by premature closure of one or more cranial sutures, associated with other malformations, the most frequent of which are the Crouzon and Apert syndromes. Few studies in the literature have addressed the oral health of these individuals. The purpose of this study was to compare the periodontal status of individuals with Apert, Crouzon, Pfeiffer and Saethre-Chotzen syndromes before toothbrushing and compare the efficiency of plaque removal before and after mechanical toothbrushing. The probing depth, plaque index (according to Löe and O'Leary), clinical attachment level, gingival index (according to Silness and Löe) and amount of keratinized mucosa were evaluated before toothbrushing, and the O'Leary plaque index was assessed before and immediately after toothbrushing, on the same day, in 27 individuals aged 11 to 36 years. There was statistically significant difference in the mean probing depth and clinical attachment level among regions (p=0.00; p=0.01, respectively). The gingival index did not reveal statistically significant differences. With regard to the plaque index, the left region exhibited higher plaque index values than the right and anterior regions. No significant results were found in the analysis of keratinized mucosa. Comparison of the O'Leary plaque index before and after toothbrushing revealed statistically significant difference for all syndromes except for the Pfeiffer syndrome (p<0.05). In conclusion, there was no difference in the periodontal status among individuals with syndromic craniosynostosis. The posterior region was more affected than the anterior region as to the presence of plaque, loss of insertion and probing depth. Individuals with Pfeiffer syndrome exhibited greater toothbrushing efficiency than individuals with the other craniosynostosis syndromes.

Apert syndrome: clinical and radiographic features and case report

PURPOSE: Apert syndrome is a rare type I acrocephalosyndactyly syndrome characterized by craniosynostosis, severe syndactyly of the hands and feet, and dysmorphic facial features. Presents autosomal dominant inheritance assigned to mutations in the fibroblast growth factor receptors gene. The oral cavity of Apert patients includes a reduction in the size of the maxilla, tooth crowding, anterior open-bite of the maxilla, impacted teeth, delayed eruption, ectopic eruption, supernumerary teeth, and thick gingiva. The mandible usually is within normal size and shape, and simulates a pseudoprognathism. CASE DESCRIPTION: A female patient, 13 years old, with diagnosis of Apert syndrome, attended a dental radiology clinic. The clinical signs were occular anomalies, dysmorphic facial features, syndactyly and oral features observed clinically and radiographically. The patient was referred to a specialized center of clinical care for patients with special needs. CONCLUSION: Because of the multiple alterations in patients with Apert syndrome, a multidisciplinary approach, including dentists and neurosurgeons, plastic surgeons, ophthalmologists and geneticists, is essential for a successful planning and treatment.

Saethre-Chotzen Syndrome, Pro136His TWIST Mutation, Hearing Loss, and External and Middle Ear Structural Anomalies: Report on a Brazilian Family

Objective: To describe the clinical, speech, hearing, and imaging findings in three members of a Brazilian family with Saethre-Chotzen syndrome (SCS) who presented some unusual characteristics within the spectrum of the syndrome. Design: Clinical evaluation was performed by a multidisciplinary team. Direct sequencing of the polymerase chain reaction amplified coding region of the TWIST1 gene, routine and electrophysiological hearing evaluation, speech evaluation, and imaging studies through computed tomography (CT) scan and magnetic resonance imaging (MRI) were performed. Results: TWIST1 gene analysis revealed a Pro136His mutation in all patients. Hearing evaluation showed peripherial and mixed hearing loss in two of the patients, one of them with severe unilateral microtia. Computed tomography scan showed structural middle ear anomalies, and MRI showed distortion of the skull contour as well as some of the brain structures. Conclusions: We report a previously undescribed TWIST1 gene mutation in patients with SCS. There is evidence that indicates hearing loss (conductive and mixed) can be related both with middle ear (microtia, high jugular bulb, and enlarged vestibules) as well as with brain stem anomalies. Here we discuss the relationship between the gene mutation and the clinical, imaging, speech, and hearing findings.

Novel mutation in the tyrosine kinase domain of FGFR2 in a patient with Pfeiffer syndrome.

Mutations in the fibroblast growth factor receptor 2 (FGFR2) cause a variety of craniosynostosis syndromes. The mutational spectrum tends to be narrow with the majority of mutations occurring in either exon IIIa or IIIc or in the intronic sequence preceding exon IIIc. Mutations outside of this hotspot are uncommon and the few identified mutations have demonstrated wide clinical variability, making it difficult to establish a clear-cut genotype-phenotype correlation. To better delineate the clinical picture associated with these unusual mutations, we describe a severely affected patient with Pfeiffer syndrome and a missense mutation in the tyrosine kinase (TK) domain of FGFR2.

Carpenter Syndrome: Extended RAB23 Mutation Spectrum and Analysis of Nonsense-mediated mRNA Decay

Carpenter syndrome, a rare autosomal recessive disorder characterized by a combination of craniosynostosis, polysyndactyly, obesity, and other congenital malformations, is caused by mutations in RAB23, encoding a member of the Rab-family of small GTPases. In 15 out of 16 families previously reported, the disease was caused by homozygosity for truncating mutations, and currently only a single missense mutation has been identified in a compound heterozygote. Here, we describe a further 8 independent families comprising 10 affected individuals with Carpenter syndrome, who were positive for mutations in RAB23. We report the first homozygous missense mutation and in-frame deletion, highlighting key residues for RAB23 function, as well as the first splice-site mutation. Multi-suture craniosynostosis and polysyndactyly have been present in all patients described to date, and abnormal external genitalia have been universal in boys. High birth weight was not evident in the current group of patients, but further evidence for laterality defects is reported. No genotype-phenotype correlations are apparent. We provide experimental evidence that transcripts encoding truncating mutations are subject to nonsense-mediated decay, and that this plays an important role in the pathogenesis of many RAB23 mutations. These observations refine the phenotypic spectrum of Carpenter syndrome and offer new insights into molecular pathogenesis. (C) 2011 Wiley-Liss, Inc.

MICHELS SYNDROME IN A BRAZILIAN GIRL BORN TO CONSANGUINEOUS PARENTS

We report on a Brazilian girl born to consanguineous parents and presenting with craniosynostosis, telecanthus, blepharophimosis, blepharoptosis, epicanthus inversus, cleft lip and palate, skeletal defects, and hearing loss. This combination of anomalies appears to constitute the Michels syndrome. (C) 1995 Wiley-Liss, Inc.

Apert syndrome: Factors involved in the cognitive development

Apert syndrome is characterized by craniosynostosis, symmetric syndactyly and other systemic malformations, with mental retardation usually present. The objective of this study was to correlate brain malformations and timing for surgery with neuropsychological evaluation. We also tried to determine other relevant aspects involved in cognitive development of these patients such as social classification of families and parents' education. Eighteen patients with Apert syndrome were studied, whose ages were between 14 and 322 months. Brain abnormalities were observed in 55.6% of them. The intelligence quotient or developmental quotient values observed were between 45 and 108. Mental development was related to the quality of family environment and parents' education. Mental development was not correlated to brain malformation or age at time of operation. In conclusion, quality of family environment was the most significant factor directly involved in mental development of patients with Apert syndrome.

FGFR2 Mutation Confers a Less Drastic Gain of Function in Mesenchymal Stem Cells Than in Fibroblasts

Gain-of-function mutations in FGFR2 cause Apert syndrome (AS), a disease characterized by craniosynostosis and limb bone defects both due to abnormalities in bone differentiation and remodeling. Although the periosteum is an important cell source for bone remodeling, its role in craniosynostosis remains poorly characterized. We hypothesized that periosteal mesenchymal stem cells (MSCs) and fibroblasts from AS patients have abnormal cell phenotypes that contribute to the recurrent fusion of the coronal sutures. MSCs and fibroblasts were obtained from the periostea of 3 AS patients (S252W) and 3 control individuals (WT). We evaluated the proliferation, migration, and osteogenic differentiation of these cells. Interestingly, S252W mutation had opposite effects on different cell types: S252W MSCs proliferated less than WT MSCs, while S252W fibroblasts proliferated more than WT fibroblasts. Under restrictive media conditions, only S252W fibroblasts showed enhanced migration. The presence of S252W mutation increased in vitro and in vivo osteogenic differentiation in both studied cell types, though the difference compared to WT cells was more pronounced in S252W fibroblasts. This osteogenic differentiation was reversed through inhibition of JNK. We demonstrated that S252W fibroblasts can induce osteogenic differentiation in periosteal MSCs but not in MSCs from another tissue. MSCs and fibroblasts responded differently to the pathogenic effects of the FGFR2(S252W) mutation. We propose that cells from the periosteum have a more important role in the premature fusion of cranial sutures than previously thought and that molecules in JNK pathway are strong candidates for the treatment of AS patients.

Cellular interference in craniofrontonasal syndrome: males mosaic for mutations in the X-linked EFNB1 gene are more severely affected than true hemizygotes

Craniofrontonasal syndrome (CFNS), an X-linked disorder caused by loss-of-function mutations of EFNB1, exhibits a paradoxical sex reversal in phenotypic severity: females characteristically have frontonasal dysplasia, craniosynostosis and additional minor malformations, but males are usually more mildly affected with hypertelorism as the only feature. X-inactivation is proposed to explain the more severe outcome in heterozygous females, as this leads to functional mosaicism for cells with differing expression of EPHRIN-B1, generating abnormal tissue boundaries-a process that cannot occur in hemizygous males. Apparently challenging this model, males occasionally present with a more severe female-like CFNS phenotype. We hypothesized that such individuals might be mosaic for EFNB1 mutations and investigated this possibility in multiple tissue samples from six sporadically presenting males. Using denaturing high performance liquid chromatography, massively parallel sequencing and multiplex-ligation-dependent probe amplification (MLPA) to increase sensitivity above standard dideoxy sequencing, we identified mosaic mutations of EFNB1 in all cases, comprising three missense changes, two gene deletions and a novel point mutation within the 5' untranslated region (UTR). Quantification by Pyrosequencing and MLPA demonstrated levels of mutant cells between 15 and 69%. The 5' UTR variant mutates the stop codon of a small upstream open reading frame that, using a dual-luciferase reporter construct, was demonstrated to exacerbate interference with translation of the wild-type protein. These results demonstrate a more severe outcome in mosaic than in constitutionally deficient males in an X-linked dominant disorder and provide further support for the cellular interference mechanism, normally related to X-inactivation in females.