Robert J. Gorlin

Mutations in the chemokine receptor gene CXCR4 are associated with WHIM syndrome, a combined immunodeficiency disease

WHIM syndrome is an immunodeficiency disease characterized by neutropenia, hypogammaglobulinemia and extensive human papillomavirus (HPV) infection. Despite the peripheral neutropenia, bone marrow aspirates from affected individuals contain abundant mature myeloid cells, a condition termed myelokathexis. The susceptibility to HPV is disproportionate compared with other immunodeficiency conditions, suggesting that the product of the affected gene may be important in the natural control of this infection. We describe here the localization of the gene associated with WHIM syndrome to a region of roughly 12 cM on chromosome 2q21 and the identification of truncating mutations in the cytoplasmic tail domain of the gene encoding chemokine receptor 4 (CXCR4). Haplotype and mutation analyses in a pedigree transmitting myelokathexis as an apparently autosomal recessive trait support genetic heterogeneity for this aspect of the WHIM syndrome phenotype. Lymphoblastoid cell lines carrying a 19-residue truncation mutation show significantly greater calcium flux relative to control cell lines in response to the CXCR4 ligand, SDF-1, consistent with dysregulated signaling by the mutant receptor. The identification of mutations in CXCR4 in individuals with WHIM syndrome represents the first example of aberrant chemokine receptor function causing human disease and suggests that the receptor may be important in cell-mediated immunity to HPV infection.

Localized mutations in the gene encoding the cytoskeletal protein filamin A cause diverse malformations in humans

Remodeling of the cytoskeleton is central to the modulation of cell shape and migration. Filamin A, encoded by the gene FLNA, is a widely expressed protein that regulates re-organization of the actin cytoskeleton by interacting with integrins, transmembrane receptor complexes and second messengers. We identified localized mutations in FLNA that conserve the reading frame and lead to a broad range of congenital malformations, affecting craniofacial structures, skeleton, brain, viscera and urogenital tract, in four X-linked human disorders: otopalatodigital syndrome types 1 (OPD1; OMIM 311300) and 2 (OPD2; OMIM 304120), frontometaphyseal dysplasia (FMD; OMIM 305620) and Melnick–Needles syndrome (MNS; OMIM 309350). Several mutations are recurrent, and all are clustered into four regions of the gene: the actin-binding domain and rod domain repeats 3, 10 and 14/15. Our findings contrast with previous observations that loss of function of FLNA is embryonic lethal in males but manifests in females as a localized neuronal migration disorder, called periventricular nodular heterotopia (PVNH; refs. 3–6). The patterns of mutation, X-chromosome inactivation and phenotypic manifestations in the newly described mutations indicate that they have gain-of-function effects, implicating filamin A in signaling pathways that mediate organogenesis in multiple systems during embryonic development.

THE CALCIFYING ODONTOGENIC CYST: A POSSIBLE ANALOGUE OF THE CUTANEOUS CALCIFYING EPITHELIOMA OF MALHERBE

Abstract The existence of a new odontogenic lesion—the calcifying odontogenic cyst—is documented by fifteen examples and its histogenesis is described. There appears to be no predilection for sex, age, or location. In only one case has there been a recurrence. The similarity of this cyst to the cutaneous calcifying epithelioma of Malherbe and other lesions is discussed.

The syndrome of palmar-plantar hyperkeratosis and premature periodontal destruction of the teeth

Statistical analysis of 46 well-documented cases of the syndrome of (a) hyperkeratosis palmoplantaris and (b) premature periodontoclasia has suggested that possibly an additional component should be added making the syndrome a triad: (c) calcification of the dura. The family history data are compatible with the hypothesis that the syndrome results from homozygosity for autosomal recessive genes. There is no evidence for nongenetic causes. The frequency of the disorder is estimated roughly at 1 to 4 per million persons in the general population. Careful documentation of additional cases with permit more adequate genetic analysis. The carrier frequency appears to be 2 to 4 per 1,000 population.

Leukoplakia, lichen planus, and other oral keratoses in 23,616 white Americans over the age of 35 years

This investigation provides the first detailed population-based reporting of white keratotic lesions of the oral mucosa in a United States population. More than 21% of 3,783 oral mucosal and connective tissue lesions reported from 23,616 white Americans, usually over 35 years of age, were keratotic lesions, representing 3.4% of the entire group of examinees. Leukoplakia was the most common of all lesions diagnosed and was the most common of the keratotic lesions (85.5% of the latter). The prevalence rate for leukoplakia was 28.9/1,000 white Americans over 35 years of age and was twice as high for males as for females (43.2/1,000 males versus 20.9/1,000 females). Age-specific leukoplakia prevalence rates demonstrated a tenfold increase for males from the third to the eighth decade of life, and twofold increase for females from the fourth to the seventh decade. Sites of leukoplakia involvement, in decreasing order of frequency, were lip vermillion, buccal mucosa, mandibular gingiva, tongue, oral floor, hard palate, maxillary gingiva, lip mucosa, and soft palate. Almost 7% of leukoplakias demonstrated carcinoma or severe dysplasia microscopically. Prevalence rates for other white oral mucosal lesions were tobacco/snuff pouch keratosis, 1.6/1,000; chronic cheek bite, 1.2/1,000; lichen planus, 1.1/1,000; palatitis nicotina, 0.7/1,000; and leukoedema, 0.3/1,000.

Oculofaciocardiodental and Lenz microphthalmia syndromes result from distinct classes of mutations in BCOR.

Lenz microphthalmia is inherited in an X-linked recessive pattern and comprises microphthalmia, mental retardation, and skeletal and other anomalies. Two loci associated with this syndrome, MAA (microphthalmia with associated anomalies) and MAA2, are situated respectively at Xq27–q28 (refs. 1,2) and Xp11.4–p21.2 (ref. 3). We identified a substitution, nt 254C→T; P85L, in BCOR (encoding BCL-6-interacting corepressor, BCOR) in affected males from the family with Lenz syndrome previously used to identify the MAA2 locus. Oculofaciocardiodental syndrome (OFCD; OMIM 300166) is inherited in an X-linked dominant pattern with presumed male lethality and comprises microphthalmia, congenital cataracts, radiculomegaly, and cardiac and digital abnormalities. Given their phenotypic overlap, we proposed that OFCD and MAA2-associated Lenz microphthalmia were allelic, and we found different frameshift, deletion and nonsense mutations in BCOR in seven families affected with OFCD. Like wild-type BCOR, BCOR P85L and an OFCD-mutant form of BCOR can interact with BCL-6 and efficiently repress transcription. This indicates that these syndromes are likely to result from defects in alternative functions of BCOR, such as interactions with transcriptional partners other than BCL-6. We cloned the zebrafish (Danio rerio) ortholog of BCOR and found that knock-down of this ortholog caused developmental perturbations of the eye, skeleton and central nervous system consistent with the human syndromes, confirming that BCOR is a key transcriptional regulator during early embryogenesis.

In frame fibrillin-1 gene deletion in autosomal dominant Weill-Marchesani syndrome

Weill-Marchesani syndrome (WMS) is a connective tissue disorder characterised by short stature, brachydactyly, joint stiffness, and characteristic eye anomalies including microspherophakia, ectopia of the lenses, severe myopia, and glaucoma. Both autosomal recessive (AR) and autosomal dominant (AD) modes of inheritance have been described and a gene for AR WMS has recently been mapped to chromosome 19p13.3-p13.2. Here, we report on the exclusion of chromosome 19p13.3-p13.2 in a large AD WMS family and show that, despite clinical homogeneity, AD and AR WMS are genetically heterogeneous entities. Because two AD WMS families were consistent with linkage to chromosome 15q21.1, the fibrillin-1 gene was sequenced and a 24 nt in frame deletion within a latent transforming growth factor-β1 binding protein (LTBP) motif of the fibrillin-1 gene was found in a AD WMS family (exon 41, 5074_5097del). This in frame deletion cosegregated with the disease and was not found in 186 controls. This study strongly suggests that AD WMS and Marfan syndrome are allelic conditions at the fibrillin-1 locus and adds to the remarkable clinical heterogeneity of type I fibrillinopathies.

Melanotic neuroectodermal tumor of infancy‐A neoplasm of neural crest origin. Report of a case associated with high urinary excretion of vanilmandelic acid

A case of melanotic neuroectodermal tumor of infancy (melanotic progonoma, retinal anlage tumor, melanoameloblastoma) associated with high urinary excretion of vanilmandelic acid is presented for the first time and discussed in the light of probable origin from the neural crest. The VMA levels returned to normal after removal of the tumor. With regard to pathogenesis and its very frequent occurrence in the upper anterior jaw, the authors hypothesize that the tumor is not, in fact, odontogenic in origin as has been suggested but may arise from neural crest cells which migrate in many cases with the odontoblasts that form the dentin of the maxillary anterior teeth.

Association of germline mutation in the PTEN tumour suppressor gene and Proteus and Proteus-like syndromes.

The molecular aetiology of Proteus syndrome (PS) remains elusive. Germline mutations in PTEN cause Cowden syndrome and Bannayan-Riley-Ruvalcaba syndrome, which are hereditary hamartoma syndromes. Some features-eg, macrocephaly, lipomatosis, and vascular malformations-can be seen in all three syndromes. We examined PTEN in patients with PS and undefined Proteus-like syndromes (PS-like) and identified de-novo germline mutations in two of nine patients with PS and three of five patients with PS-like. Germline PTEN mutation analysis should be done in individuals with PS and PS-like because of its association with increased risk of cancer development and potential of germline-mutation transmission.

Multiple mucosal neuromas, pheochromocytoma and medullary carcinoma of the thyroid—a syndrome

An analysis of 17 cases of the syndrome of multiple mucosal neuromas, pheochromocytoma and medullary carcinoma of the thyroid is presented and its relationship to similar syndromes discussed. The mucosal neuromas primarily involve the lips, anterior tongue, conjunctiva and nasal and laryngeal mucosa. Medullated corneal nerve fibers traverse the cornea and anastomose in the pupillary area. A Marfanoid build and diverticulosis may be associated findings.