What Is Zimmermann–Laband Syndrome (ZLS)?

healthinfi.png308o

Zimmermann–Laband Syndrome (ZLS)

Zimmermann–Laband syndrome (ZLS), also known as Laband–Zimmermann syndrome, and Laband’s syndrome, is an extremely rare. autosomal dominant congenital disorder. 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.

Zimmermann-Laband syndrome is a rare disorder characterized by gingival fibromatosis, dysplastic or absent nails, hypoplasia of the distal phalanges, scoliosis, hepatosplenomegaly, hirsutism, and abnormalities of the cartilage of the nose and/or ears (summary by Balasubramanian and Parker, 2010).

Gingival fibromatosis can be present as an isolated form or be part of a genetic disease. The Zimmermann-Laband syndrome (ZLS) is a rare disorder inherited as an autosomal dominant fashion, clinically characterized by gingival fibromatosis, bulbous soft nose, thick floppy ears, nail dysplasia, joint hyperextensibility, hepatosplenomegaly, skeletal anomalies and occasional mental retardation.

We studied a girl aged five years with clinical and radiological features of the ZLS, additionally she presented deafness not previously described in the ZLS, as only partial hearing loss was reported in some patients.

The father presented some facial features suggestive of ZLS, nevertheless he did not have gingival fibromatosis or hypertrichosis. We suggest that this case supports that ZLS can be part a contiguous genes syndrome or be consequence ofa gene mutation with wide variable expression. The present report supports that ZLS has a wide clinical spectrum.

Symptoms

This table lists symptoms that people with this disease may have. For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. This information comes from a database called the Human Phenotype Ontology (HPO) . The HPO collects information on symptoms that have been described in medical resources. The HPO is updated regularly.

Symptoms include gingival fibromatosis, associated with hypoplasia of the distal phalanges, nail dysplasia, joint hypermobility, and sometimes hepatosplenomegaly. The nose and pinnae are usually large and poorly developed, which gives the individuals with the syndrome abnormal facial characteristics. Mental retardation may also occur.Both males and females are equally affected. Gingival fibromatosis is usually present at birth or appears short after. The term Zimmermann–Laband was coined by Carl Jacob Witkop in 1971.

Synonyms

  • Zimmermann-Laband Syndrome
  • Gingival Fibromatosis, Abnormal Fingers, Nails, Nose, Ear, Splenomegaly
  • ZLS

General Discussion

Laband syndrome, also known as Zimmerman-Laband syndrome, is an extremely rare genetic disorder characterized by abnormalities of the head and facial (craniofacial) area and the hands and feet. Most children with this disorder have abnormally large gums (gingival fibromatosis). Overgrown gums may affect the ability to chew, swallow, and/or speak.

In addition, affected infants may exhibit abnormally long, thin fingers and toes and/or deformed (dysplastic) or absent nails at birth. In some cases, mental retardation may also be present. In most cases, Laband syndrome is believed to be inherited as an autosomal dominant trait. However, evidence of autosomal recessive inheritance has also been reported.

Zimmermann-Laband syndrome is a very rare entity with autosomal dominant mode of inheritance. Both the sexes may be affected in equal ratio. Eleven cases from two families in the literature were well documented with evidence of autosomal dominant inheritance. A total of forty cases have been reported till 2010. This syndrome is coded with phenotype MIM number 135500.

The gene responsible for Zimmermann-Laband syndrome is located in 3p14.3 and implicates four likely candidate genes in this region. CACNA2D3 gene encoding a voltage dependent calcium channel, LRTM1 gene of unknown function, WTN5A gene encoding a secreted signalling protein, and ERC2 gene, which encodes for a synapse protein. Gingival hyperplasia is reported to be present in patients treated with calcium channel blockers that affect intracellular calcium metabolism or transport.

This syndrome is not a life-threatening disorder. The most consistent feature of the syndrome is gingival fibromatosis appearing in early childhood. It may exist as an isolated finding or as part of a genetic syndrome. In the diagnosis, generalized gingival enlargement, a detailed medical history, and systemic evaluation is necessary to differentiate gingival fibromatosis from various other types of acquired generalized gingival enlargement that can occur as a result of inflammation, pregnancy, leukemia, and in response to certain drugs such as phenytoin, diltiazem, cyclosporine, verapamil, and nifedipine.

In such cases, the gingiva is usually not as enlarged or as fibrotic as in hereditary gingival fibromatosis. Shah and Gupta reported a case of Zimmermann-Laband syndrome in a young child of age 3½ years associated with bilateral developmental cataract. Lin et al., presented with new manifestations of thymic hyperplasia evident as a soft tissue mass in front of the aorta without enlargement of lymph nodes. Other manifestations such as left ventricular hypertrophy and aortic root dilation were reported.

Sawaki et al., stated that the major clinical findings of Zimmermann-Laband syndrome would be gingival fibromatosis, hyperplasia or absence of the terminal phalynx or nails of hand and feet, bulbous soft nose, thick lips, large ears, and enlargement of soft tissues of the face. Syndromes such as Murray-Puretic-Drescher (juvenile hyaline fibromatosis) present with multiple hyaline fibromas, osteolysis of terminal phalanges, recurrent infection, stunted growth, and premature death.

Cross syndrome presents with microphthalmia mental retardation, athetosis, and hypopigmentation. Jones syndrome presents with progressive deafness. When gingival fibromatosis is associated with nose, bone, and nail defects it may characterize the presence of Zimmermann-Laband syndrome.

Surgical correction of gingival fibromatosis is recommended, although there is no information on the permanence of the results of this treatment in the literature. Extraction of the deciduous teeth followed by internal bevel gingivectomy with osseous recontouring in our case will establish the necessary conditions for an effective orthodontic treatment, which may improve the facial esthetics.

Clinical Features

Zimmermann (1928) is credited with the first description of this disorder in 2 patients (Kim et al., 2007).

Laband et al. (1964) and Alavandar (1965) reported 2 Asiatic Indian families (one living in the Caribbean and one in India) in which gingival fibromatosis occurred in association with ‘whittling’ of the terminal phalanges and absence or dysplasia of the fingernails. The report by Laband et al. (1964) described the disorder in a 38-year-old Trinidad woman and 5 of her 7 children.

The mother showed large, soft ears, hypertension, hyperextensibility of metacarpophalangeal joints, and splenomegaly. The affected children had soft tissue enlargement of the nose and ears, splenomegaly, skeletal abnormalities, obscure or reduced size of toenails and thumbnails, short terminal phalanges, and hypermobility of several joints. The report by Alavandar (1965) described 5 affected persons in 3 generations with associated features of thickening of the soft tissues of the nose and ear with softness of the cartilages, hyperextensible joints, and hepatomegaly.

Chodirker et al. (1986) reported a case of this syndrome, which they called Zimmermann-Laband syndrome, with profound mental retardation. Pina-Neto et al. (1988) also reported a case with mental retardation. Van Buggenhout et al. (1995) stated that 23 patients, including 11 patients from 2 families, had been reported with Zimmermann-Laband syndrome. Most patients had normal intelligence, although some were mildly retarded. They reported a patient with ZLS and severe mental retardation and concluded that severe mental retardation can be a feature of the syndrome.

Robertson et al. (1998) reported on a 4-decade follow-up of a male with ZLS who developed a cardiomyopathy and dilatation of the aortic root and arch, anomalies previously undescribed in this disorder. From birth he had had a coarse face, protruding tongue, hirsutism, dry thick skin, hypotonia, umbilical hernia, and hepatosplenomegaly. Congestive heart failure due to patent ductus arteriosus (see 607411) resolved after spontaneous closure of the duct. At the age of 8 years, myopia and poorly developed teeth with hypertrophic gingival margins were additional features. Extensive areas of long downy body hair had required shaving from age 4 years.

Liver, skin, and skeletal muscle histologic findings were all normal after extensive attempts to demonstrate storage material. He progressed to manual employment in a sheltered position, but did not achieve skills sufficient for independent living. A pericardial effusion of uncertain cause was detected during the second decade of life, and increasing dyspnea and reduced exercise tolerance necessitated the formation of a pleuropericardial window at age 24 years.

Histologic findings of the pericardium were normal; no evidence for tuberculosis was found. Echocardiography demonstrated left atrial dilatation and progressive dilatation of the aortic arch from the aortic root to the descending aorta. At the age of 37 years his height was 167 cm and head circumference was 60 cm. Gingival fibromatosis was encroaching on the dental crowns and extending posteriorly along the palatal shelves. The thumbs and great toes were small and the toenails and fingernails hypoplastic.

In the report of a balanced reciprocal translocation in mother and daughter by Stefanova et al. (2003), the 40-year-old proposita had been referred to the dental clinic at age 16 years because of excessive gingival hypertrophy that completely covered the tooth crowns. She and her daughter, aged 5 years, showed gingival hyperplasia, large fleshy nose, macrostomia, full lips, large tongue, large thick eyelashes, and normal intelligence. The mother showed dystrophic fingernails and aplasia of the toenails, whereas the daughter had aplasia of both the fingernails and toenails, prominent ears, and generalized hirsutism.

Davalos et al. (2005) reported 2 unrelated children, a 9-year-old girl and an 11-month-old boy, with clinically and radiologically diagnosed ZLS who displayed previously unreported features: marked body overgrowth in both, cavernous hemangiomata in the frontal and left cerebellar regions in the boy, and unusual radiologic characteristics including broad medullary canals and metaphyses of the long bones, thin cortices, broad ribs, and accelerated skeletal maturation in the girl.

The boy had psychomotor delay, whereas the girl had high intelligence (full IQ of 123). The girl’s mother and 2 brothers also had mild hypertrichosis but no other features of ZLS; the boy’s father had soft tissue enlargement of the nose, ears, and lips. Davalos et al. (2005) suggested that upon close examination, family members may be found to have mild expression of ZLS.

Balasubramanian and Parker (2010) studied a 5-year-old boy previously reported by Roper et al. (2005) as having a novel syndrome of brachydactyly, extrahepatic biliary atresia, patent ductus arteriosus, and seizures, and suggested that the patient actually had Zimmermann-Laband syndrome. The boy also had renal calculi, nonautoimmune diabetes, and bilateral cataracts. Balasubramanian and Parker (2010) noted that the patient with ZLS reported by Shah et al. (2004) also had bilateral cataracts.

Chacon-Camacho et al. (2011) reported an 8-year-old girl who exhibited characteristic features of Zimmermann-Laband syndrome, including gingival overgrowth, facial dysmorphism, generalized hypertrichosis, intellectual disability, seizures, and hypoplasia of nails. In addition, she had colpocephaly, hemivertebra, polydactyly, segmental hyperpigmentation, and hemihyperplasia, thus expanding the phenotypic spectrum of the disease.

Davalos et al. (2011) reported a 9-year-old girl, born of healthy nonconsanguineous parents, with Zimmermann-Laband syndrome. The patient, who was born prematurely with polyhydramnios, had macrosomia, macrocephaly, generalized hypertrichosis, asymptomatic hepatomegaly, nail hypoplasia, and gingival hyperplasia.

Facial dysmorphism included a wide forehead, thick eyebrows, downslanting palpebral fissures, a thick bulbous nose, thick antihelices and auricles, and a large mouth with thick lower lip. She had severe bilateral sensorineural hearing loss but normal intelligence. Radiologic features included wide medullary canals and wide metaphyses of the long bones with thin cortices. Her father had a bulbous nose and thick lips and auricles. No other family members were affected. Davalos et al. (2011) reviewed the clinical and radiologic features of 30 reported patients with ZLS, including their own.

Castori et al. (2013) described an unrelated girl and boy with Zimmermann-Laband syndrome and reviewed 50 previously published reports. The combination of gingival hypertrophy and nail hypoplasia or aplasia represented the core phenotype and was reported in 100% of patients. The most typical craniofacial presentation, reported in more than 50% of patients, consisted of soft ears and nose, large and bulbous nose, and thick lips or macrostomia. Additional commonly reported features included joint hypermobility, hypertrichosis, and hepatomegaly, with or without splenomegaly. Approximately 40% of patients presented with some degree of intellectual disability, and approximately 13% also suffered seizures.

Clinical presentation

  • gingival hypertrophy
  • bulbous nose and thick ears
  • abnormal hands
    • clubbed fingers and toes
    • nail hypoplasia/dysplasia
    • hypoplasia of the terminal phalanges of the hands and feet.
  • mental retardation (variable severity)
  • seizures
  • hypetrichosis
  • other skeletal abnormalities

Radiographic features

  • skeletal abnormalities
  • hypoplasia of the terminal phalanges of the hands and feet
  • possible limb asymmetry
  • possible kyphosis
  • possible lumbar spondylodysplasia
  • possible mandibular hypertrophy

Inheritance

Zimmerman Laband syndrome is inherited in an autosomal dominant pattern. This means the defective gene is located on an autosome, and only one copy of the gene is sufficient to cause the disorder, when inherited from a parent who has the disorder.

The condition is caused by mutations in a potassium channel gene – KCNH1.

Castori et al. (2013) reviewed 50 previously published reports of Zimmermann-Laband syndrome and stated that an autosomal dominant mutation with high mutation rate and rare instances of germline mosaicism seemed to represent the most likely inheritance pattern.

Cytogenetics

Stefanova et al. (2003) described an apparently balanced reciprocal translocation in a mother and daughter with ZLS. Using FISH with BAC clones, the authors refined the breakpoints to chromosomes 3p21.2 and 8q24.3 and thereby narrowed both breakpoint regions to approximately 1.5 Mb. Thus the causative gene is located on 3p or 8q.

Kim et al. (2007) reported a boy with ZLS who had an apparently balanced de novo t(3;17)(p14.3;q24.3) translocation. FISH analysis localized the chromosome 3 breakpoint to a 200-kb region on chromosome 3p14.3. Kim et al. (2007) reassessed the chromosome 3p breakpoint described by Stefanova et al. (2003) and revised the breakpoint location to a 3.2-Mb region in chromosome 3p14.3 based upon an updated human genome sequence assembly. The results suggested that the gene responsible for ZLS is located at 3p14.3.

Genotype/Phenotype Correlations

Kortum et al. (2015) noted that all 6 ZLS patients with mutations in the KCNH1 gene had a history of seizures, whereas the 2 patients with mutations in the ATP6V1B2 gene did not; in contrast, the latter 2 patients exhibited coarser facial features. Other clinical features, such as hearing loss and hypertrichosis, were variably present in the 8 ZLS patients.

Summary

Epidemiology

Forty-four patients have been reported to date.

Clinical description

Coarse facial appearance includes bulbous soft nose, thickened lips, thick and floppy ears and gingival hypertrophy or fibromatosis. The syndrome has a highly variable clinical expression, and other possible features include hyperextensibility of joints, hepatosplenomegaly, hypertrichosis and hearing loss. Intellectual deficit is occasional and usually mild to moderate. The overgrown gingival tissues can affect the ability to speak.

Etiology

The genetic basis is unknown. Mapping of breakpoints of two translocations t(3;8) and t(3;17) found in two patients with the typical clinical features of Zimmermann-Laband syndrome defined a common breakpoint region located in 3p14.3 but the lack of a specific coding-sequence lesion in the common region suggests that either some other type of genetic defect in this vicinity, or an alteration elsewhere in the genome, could be responsible for ZLS. Autosomal dominant inheritance has been suggested.

Differential diagnosis

The differential diagnosis includes other defined syndromes of hirsutism and coarsening of the face. Isolated gingival fibromatosis has been documented as a dominantly transmissible trait.

Management and treatment

Treatment consists of surgical removal of the hyperplasic fibrous tissue and appropriate orthodontic treatment to improve esthetic appearance and eruption of the non-erupted teeth.

Prognosis

Prognosis is dominated by the risk of recurrence, which is high. Physical systemic evaluation is essential. The syndrome is not life-threatening.

For more information visit us our website: https://www.healthinfi.com

1 250

No Comments

    Leave a Reply