Zimmermann-Laband Syndrome Research Articles

Syndromes with supernumerary teeth.

While most supernumerary teeth are idiopathic, they can be associated with a number of Mendelian syndromes. However, this can also be a coincidental finding, since supernumerary teeth occur in 6% or more of the normal population. To better define this relationship, we analyzed the evidence for specific associations. We excluded conditions with a single affected patient reported, supernumerary teeth adjacent to clefts or other forms of alveolar disruption (as secondary rather than primary findings), and natal teeth, which can involve premature eruption of a normal tooth. Since, the cause of supernumerary teeth shows considerable heterogeneity, certain findings are less likely to be coincidental, such as five or more supernumerary teeth in a single patient, or locations outside of the premaxilla. We found only eight genetic syndromes with strong evidence for an association: cleidocranial dysplasia; familial adenomatous polyposis; trichorhinophalangeal syndrome, type I; Rubinstein-Taybi syndrome; Nance-Horan syndrome; Opitz BBB/G syndrome; oculofaciocardiodental syndrome; and autosomal dominant Robinow syndrome. There is also suggestive evidence of an association with two uncommon disorders, Kreiborg-Pakistani syndrome (craniosynostosis and dental anomalies), and insulin-resistant diabetes mellitus with acanthosisnigricans. An association of a Mendelian disorder with a low frequency manifestation of supernumerary teeth is difficult to exclude without large numbers, but several commonly cited syndromes lacked evidence for clear association, including Hallermann-Streiff syndrome, Fabry disease, Ehlers-Danlos syndrome, Apert and Crouzon syndromes, Zimmermann-Laband syndrome, and Ellis-van Creveld syndrome. © 2016 Wiley Periodicals, Inc.

Epilepsy in KCNH1-related syndromes.

KCNH1 mutations have been identified in patients with Zimmermann-Laband syndrome and Temple-Baraitser syndrome, as well as patients with uncharacterized syndromes with intellectual disability and overlapping features. These syndromes include dysmorphic facial features, nail hypo/aplasia, thumb and skeletal anomalies, intellectual disability, and seizures. We report the epilepsy phenotype in patients with KCNH1 mutations. Demographic data, electroclinical features, response to antiepileptic drugs, and results of significant diagnostic investigations of nine patients carrying mutations in KCNH1 were obtained from referring centres. Epilepsy was present in 7/9 patients. Both generalized and focal tonic-clonic seizures were observed. Complete seizure control was achieved with pharmacological treatment in 2/7 patients; polytherapy was required in 4/7 patients. Status epilepticus occurred in 4/7 patients. EEG showed a diffusely slow background in 7/7 patients with epilepsy, with variable epileptiform abnormalities. Cerebral folate deficiency and an increase in urinary hypoxanthine and uridine were observed in one patient. Epilepsy is a key phenotypic feature in most individuals with KCNH1-related syndromes, suggesting a direct role of KCNH1 in epileptogenesis, although the underlying mechanism is not understood.

'Splitting versus lumping': Temple-Baraitser and Zimmermann-Laband Syndromes.

KCNH1 mutations have recently been described in six individuals with Temple-Baraitser syndrome (TMBTS) and six individuals with Zimmermann-Laband syndrome (ZLS). TMBTS is characterized by intellectual disability (ID), epilepsy, dysmorphic facial features, broad thumbs and great toes with absent/hypoplastic nails. ZLS is characterized by facial dysmorphism including coarsening of the face and a large nose, gingival enlargement, ID, hypoplasia of terminal phalanges and nails and hypertrichosis. In this study, we present four additional unrelated individuals with de novo KCNH1 mutations from ID cohorts. We report on a novel recurrent pathogenic KCNH1 variant in three individuals and add a fourth individual with a previously TMBTS-associated KCNH1 variant. Neither TMBTS nor ZLS was suspected clinically. KCNH1 encodes a voltage-gated potassium channel, which is not only highly expressed in the central nervous system, but also seems to play an important role during development. Clinical evaluation of our mutation-positive individuals revealed that one of the main characteristics of TMBTS/ZLS, namely the pronounced nail hypoplasia of the great toes and thumbs, can be mild and develop over time. Clinical comparison of all published KCNH1 mutation-positive individuals revealed a similar facial but variable limb phenotype. KCNH1 mutation-positive individuals present with severe ID, neonatal hypotonia, hypertelorism, broad nasal tip, wide mouth, nail a/hypoplasia, a proximal implanted and long thumb and long great toes. In summary, we show that the phenotypic variability of individuals with KCNH1 mutations is more pronounced than previously expected, and we discuss whether KCNH1 mutations allow for "lumping" or for "splitting" of TMBTS and ZLS.

Mutations in KCNH1 and ATP6V1B2 cause Zimmermann-Laband syndrome.

Zimmermann-Laband syndrome (ZLS) is a developmental disorder characterized by facial dysmorphism with gingival enlargement, intellectual disability, hypoplasia or aplasia of nails and terminal phalanges, and hypertrichosis. We report that heterozygous missense mutations in KCNH1 account for a considerable proportion of ZLS. KCNH1 encodes the voltage-gated K(+) channel Eag1 (Kv10.1). Patch-clamp recordings showed strong negative shifts in voltage-dependent activation for all but one KCNH1 channel mutant (Gly469Arg). Coexpression of Gly469Arg with wild-type KCNH1 resulted in heterotetrameric channels with reduced conductance at positive potentials but pronounced conductance at negative potentials. These data support a gain-of-function effect for all ZLS-associated KCNH1 mutants. We also identified a recurrent de novo missense change in ATP6V1B2, encoding the B2 subunit of the multimeric vacuolar H(+) ATPase, in two individuals with ZLS. Structural analysis predicts a perturbing effect of the mutation on complex assembly. Our findings demonstrate that KCNH1 mutations cause ZLS and document genetic heterogeneity for this disorder.

Clinical and genetic study of two patients with Zimmermann–Laband syndrome and literature review

Zimmermann–Laband syndrome (ZLS) is a rare MCA/MR condition mainly characterized by gingival hypertrophy, hypo/aplastic nails and distal phalanges, hypertrichosis and intellectual disability. The molecular basis of ZLS is unknown. Most patients are sporadic, although familial aggregation is also observed with different inheritance patterns. We report on two unrelated children with full-blown characteristics of ZLS. Remarkable variability in expression included severity of neurocognitive involvement and extent of appendicular and facial features. In both, comparative genome hybridization array at a ∼75 Mb resolution resulted negative, while aminoacid metabolic screening revealed high plasma levels of hypoxanthine and xanthine in one. Literature review identified 50 previously published patients (27 females, 23 males), including 14 familial, clustered in four pedigrees, and 37 sporadic. Tabulation of clinical features confirmed the core phenotype and identified developmental delay as the unique major clinical problem (occurring in 40% of the cases) with a moderately high risk of epilepsy (13%). Segregation analysis in the 20 sporadic patients with available data on healthy sibs and a single pedigree with affected sibs was significantly in contrast with an autosomal recessive mutation. An autosomal dominant mutation with high mutation rate and rare instances of germinal mosaicism seems the most likely inheritance pattern. This work may represent a starting point for future molecular studies aimed at identifying the molecular basis of ZLS.

Zimmermann-Laband syndrome: A rare case report of father and son

The Zimmermann-Laband syndrome also known as Laband-Zimmermann syndrome or Laband's syndrome was reported by Zimmermann in the year 1928. It is a rare inherited autosomal dominant disease characterized by pathognomonic triad of extensive gingival enlargement (gingival fibromatosis), abnormalities of the nose and ears, absence or hyperplasia of the nails or terminal phalanges of the hands and feet. The syndromic characteristics are highly variable and complicated. The present study describes a case report of father and son aged 42 years and 13 years respectively, presenting features of Zimmermann-Laband syndrome.

The orthodontic and surgical management of Zimmerman-Laband syndrome

Zimmermann-Laband syndrome (ZLS) is a rare autosomal disorder characterized by gingival fibromatosis, abnormalities of the nose and/or ears, hypoplasia of the nails or terminal phalanges of the hands and feet, hyperextensibility of joints, hepatosplenomegaly, hirsutism, and intellectual disability. The characteristics of the syndrome are highly variable and complicated. This paper reports a case of ZLS and the clinical manifestations encountered in relation to the current available literature. The comprehensive management of the patient's dentition is described, focusing on the orthodontic and surgical considerations clinicians should be aware of when treating patients with the syndrome.

Zimmermann-Laband Syndrome

Zimmermann–Laband syndrome is a very rare disorder characterized by gingival fibromatosis, abnormalities of soft cartilages of the nose and/or ears, hypoplastic or absent nails and terminal phalanges, joint hypermobility, hypatoslenomegaly, mild hirsutism and learning difficulties. Early presentation of Zimmer–mann–Laband syndrome in a newborn has rarely been described. This paper describes a newborn patient with Zimmermann–Laband syndrome.

Expanding the phenotype of gingival fibromatosis–mental retardation–hypertrichosis (Zimmermann–Laband) syndrome

Zimmermann-Laband syndrome (ZLS) is a rare disorder characterized by gingival fibromatosis, hypertrichosis, intellectual disability, and absence and/or hypoplasia of the nails or terminal phalanges of the hands and feet. The syndromic features of ZLS are highly variable and can overlap with other entities featuring gingival fibrosis. This study describes a patient with ZLS with novel findings, including colpocephaly, hemivertebra, polydactyly, hyperpigmentation, and hemihyperplasia. Thus, the present report expands the phenotypic spectrum of this uncommon syndrome.

Current concepts on gingival fibromatosis-related syndromes.

Gingival fibromatosis is a rare, benign, slowly-growing fibrous overgrowth of the gingiva, with great genetic and clinical heterogeneity. Gingival fibromatosis/overgrowth can be inherited as an isolated trait (hereditary gingival fibromatosis) and/or as a component of a syndrome, or it can be drug induced. As a clinical manifestation of a syndrome, gingival fibromatosis is usually associated with generalized hypertrichosis, mental retardation, or epilepsy. Gingival fibromatosis and its related syndromes are mainly inherited in an autosomal-dominant manner, but autosomal-recessive inheritance has also been reported. Clinical syndromic presentation includes Zimmermann-Laband syndrome, Ramon syndrome, Rutherford syndrome, Cowden syndrome, Cross syndrome, Göhlich-Ratmann syndrome, Avani syndrome, and I-cell disease. However, a phenotypic overlap has been suggested, as many combinations of their systemic manifestations have been reported. Treatment of choice is usually gingivectomy with gingivoplasty. Before any therapy, clinical practitioners must take into consideration the clinical course of a particular syndrome and every possible functional and esthetic disorder.

Zimmermann-Laband Syndrome in a Six-year-old Girl: A Case Report

Zimmermann-Laband syndrome is an inherited disease characterized by extensive gingival enlargement and abnormalities of the head, face, hands, feet, nose, and ears. Hypoplastic or absent nails, mild hair loss, and mental retardation are seen in some cases. The present paper describes a patient, aged six and half years, with typical features of Zimmermann-Laband syndrome.

Zimmermann-Laband Syndrome: Report of a Case with Early Cardiac Complications

Zimmermann-Laband Syndrome: Report of a Case with Early Cardiac Complications 1Atul P Sattur, 1Krishna N Burde, 2Venkatesh G Naikmasur, 3Megha Goyal 1Professor, Department of Oral Medicine and Radiology, SDM College of Dental Sciences and Hospital, Dharwar Karnataka, India 2Professor and Head, Department of Oral Medicine and Radiology, SDM College of Dental Sciences and Hospital, Dharwar Karnataka, India 3Postgraduate Student, Department of Oral Medicine and Radiology, SDM College of Dental Sciences and Hospital, Dharwar Karnataka, India

Report of a case of Zimmermann–Laband syndrome with new manifestations

Zimmermann-Laband syndrome is a rare disorder characterized by gingival fibromatosis, abnormalities of the nose and/or ears, absence and/or hyperplasia of the nails or terminal phalanges of the hands and feet, hyperextensibility of joints, hepatosplenomegaly, mild hirsutism and mental retardation. The syndromic characteristics of Zimmermann-Laband syndrome are highly variable and complicated. This paper described a patient with Zimmermann-Laband syndrome with new manifestations and discusses the possible underlying genetic mechanisms.

Zimmermann–Laband syndrome in a child previously described with brachydactyly, extrahepatic biliary atresia, patent ductus arteriosus and seizures

Zimmerman–Laband syndrome is a rare genetic disorder characterized by gingival fibromatosis, dysplastic or absent nails, hypoplasia of the distal phalanges, scoliosis, hepatosplenomegaly, hirsutism and abnormalities of the cartilage of nose and/or ears. We would like to give an update on the progres

Zimmermann-Laband Syndrome: Report of a Case with Early Cardiac Complications

Zimmermann-Laband Syndrome: Report of a Case with Early Cardiac Complications

Gingival overgrowth, congenital generalized hypertrichosis, mental retardation and epilepsy: case report and overview

We report on a patient with congenital generalized hypertrichosis, mental retardation, tonic-clonic seizures with onset during the first year of life and gingival overgrowth, unrelated to antiepileptic treatment. This phenotype represents a unique combination of features, bridging the variable association of gingival overgrowth, generalized hypertrichosis, mental retardation or epilepsy. This may occur in combination with nail and/or digital anomalies, as in Zimmermann-Laband syndrome, and the broader phenotypes of the Anavi, Göhlich-Ratmann and Ramon syndromes. On the basis of the clinical overlap between our patient and these disorders inherited either as autosomal dominant or recessive traits and unknown molecular defects, a recurrence risk of one in four was considered appropriate.

No mutation in genes of the WNT signaling pathway in patients with Zimmermann–Laband syndrome

Abo-Dalo, Benjamina; Roes, Melaniea; Canún, Soniae; Delatycki, Martinf; Gillessen-Kaesbach, Gabrieleb; Hrytsiuk, Ihori; Jung, Christinec; Kerr, Bronwynj; Mowat, Davidg; Seemanova, Eval; Steiner, Carlos E.m; Stewart, Helenk; Thierry, Patrickn; van Buggenhout, Grieto; White, Sueh; Zenker, Martind; Kutsche, Kerstina Author Information

Extensive molecular genetic analysis of the 3p14.3 region in patients with Zimmermann–Laband syndrome

Zimmermann-Laband syndrome (ZLS) is a rare autosomal dominant inherited disorder characterized by a coarse facial appearance, gingival fibromatosis, and absence or hypoplasia of the terminal phalanges and nails of hands and feet. Additional, more variable features include hyperextensibility of joints, hepatosplenomegaly, mild hirsutism, and mental retardation. Mapping of the translocation breakpoints of t(3;8) and t(3;17) found in patients with the typical clinical features of ZLS defined a common breakpoint region of approximately 280 kb located in 3p14.3, which includes the genes CACNA2D3 and WNT5A. Breakpoint cloning revealed that both translocations most likely occurred by non-homologous (illegitimate) recombination. Mutation analysis of nine genes located in 3p21.1-p14.3, including CACNA2D3, which is directly disrupted by one breakpoint of the t(3;17), identified no pathogenic mutation in eight sporadic patients with ZLS. Southern hybridization analysis and multiplex ligation-dependent probe amplification (MLPA) did not detect submicroscopic deletion or duplication in either CACNA2D3 or WNT5A in ZLS-affected individuals. Mutation analysis of nine conserved nongenic sequence elements (CNEs) in 3p21.1-p14.3, which were identified by interspecies comparison and may represent putative regulatory elements for spatiotemporally correct expression of nearby genes, did not show any sequence alteration associated with ZLS. Taken together, the lack of a specific coding-sequence lesion in the common region, defined by two translocation breakpoints, in sporadic patients with ZLS and an apparently normal karyotype suggests that either some other type of genetic defect in this vicinity or an alteration elsewhere in the genome could be responsible for ZLS.

Candidate loci for Zimmermann–Laband syndrome at 3p14.3

A male with 46,XY,t(3;17)(p14.3;q24.3) presented with gingival hyperplasia, hypertrichosis, unusually large ears and marked hypertrophy of the nose, characteristic of the Zimmermann-Laband syndrome (ZLS). Other features include large facial bones and mandibles, large protruding upper lip, enlarged fingers and toes, strabismus, and enlarged phallus. Knowledge of a 46,XX,t(3;8)(p21.2;q24.3) reported previously in a mother and daughter with ZLS suggests that the 3p14.3-p21.2 region may contain a gene responsible for ZLS. We have reassessed the chromosome 3 breakpoint region of the t(3;8) and revised its breakpoint location to 3p14.3, based upon an updated human genome sequence assembly. Using fluorescence in situ hybridization (FISH) with BAC clones, we have also identified a breakpoint spanning clone at 3p14.3 in our t(3;17) patient, thereby narrowing the breakpoint to a region of approximately 200 kb. These data suggest that the gene responsible for ZLS is located in 3p14.3 and implicates four likely candidate genes in this region: CACNA2D3, encoding a voltage-dependent calcium channel, LRTM1, a gene of unknown function embedded within CACNA2D3, WNT5A, encoding a secreted signaling protein of the WNT family, and ERC2, which codes for a synapse protein.

Fibromatose gingivale dans le cadre d’une atteinte syndromique

Gingival fibromatosis is an inherited disease of the gingival tissue causing proliferative fibrous lesions occurring alone or as one feature of a more widespread syndrome. A 26-year-old girl consulted the oral surgery department for a functional problem due to the presence of two tumor masses located in the palate. The histological diagnosis was gingival fibromatosis. The presence of skeletal disorders in this patient with gingival fibromatosis suggested the diagnosis of Zimmermann Laband syndrome. Gingival fibromatosis is a rare condition characterized by a gingival hypertrophy. It is transmitted by autosomal dominant or recessive inheritance. The oral examination and histology provides the diagnosis. The treatment consistes of surgical removal of the hyperplasic fibrous tissue. Prognosis is dominated by the risk of recurrence which is frequent. Generally, gingival fibromatosis is isolated. In rare cases, it can be associated with symptoms sugges-ting a syndromic diagnosis such as Zimmermann Laband syndrome. In addition to gingival hypertrophy, skeletal anomalies can involve the fingers, the toenails, the thorax or the vertebrae. Splenomegaly and joint hyperextensibility can also be found.