Zimmermann-Laband Syndrome 1

A number sign (#) is used with this entry because of evidence that Zimmermann-Laband syndrome-1 (ZLS1) is caused by heterozygous mutation in the KCNH1 gene (603305) on chromosome 1q32.

Description

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).

Genetic Heterogeneity of Zimmermann-Laband Syndrome

Zimmermann-Laband syndrome-2 (ZLS2; 616455) is caused by mutation in the ATP6V1B2 gene (606939) on chromosome 8p21.

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.

Inheritance

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.

Population Genetics

Kim et al. (2007) stated that 39 patients with ZLS had been reported worldwide.

Cytogenetics

Stefanova et al. (2003) described an apparently balanced reciprocal t(3;8)(p21.2;q24.3) 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.

Molecular Genetics

By whole-exome sequencing in 5 unrelated patients with core features of ZLS, Kortum et al. (2015) identified heterozygosity for de novo missense mutations in the KCNH1 gene in 3 individuals (603305.0005-603305.0007), including an Italian boy originally reported by Castori et al. (2013). The remaining 2 patients carried the same missense mutation in the ATP6V1B2 gene (see 606939.0002 and ZLS2, 616455). Sequencing of the KCNH1 gene in an additional cohort of 19 patients exhibiting clinical features consistent with ZLS revealed 3 more individuals with missense mutations, including 2 Australian patients originally reported by Abo-Dalo et al. (2008) as patient 7 (603305.0008) and patient 9 (603305.0009). Kortum et al. (2015) noted that finding a KCNH1 or ATP6V1B2 mutation in 8 of 24 patients indicated further genetic heterogeneity in ZLS.

Exclusion Studies

In 7 patients clinically diagnosed with ZLS, including patients previously reported by Koch et al. (1992), Pfeiffer et al. (1992), and Robertson et al. (1998), as well as 9 patients with a phenotype sharing some ZLS-specific features, including patients originally reported by Gohlich-Ratmann et al. (2000), Steiner and Marques (2000), Stewart et al. (2000), and Canun et al. (2003), Abo-Dalo et al. (2008) analyzed 9 genes involved in the WNT (see 164820) signaling pathway but did not find any disease-causing mutations.

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.