Zimmermann-Laband syndrome (ORPHA:3473)
A rare genetic multiple congenital anomalies syndrome characterized by gingival fibromatosis, coarse facial appearance, and absence or hypoplasia of nails or terminal phalanges of hands and feet.
Epidemiology
About 50 patients have been reported to date.
Clinical description
Zimmermann Laband (ZLS) is characterized by the presence of a progressive, diffuse, gingival hypertrophy, often with multiple unerupted teeth and skeletal deformities of maxillary arches; a coarse facial appearance which includes a bulbous, soft nose, thickened lips, thick and floppy ears; and absence or hypoplasia of the terminal phalanges and nails of hands and feet. More variable features include hyperextensibility of joints, hepatosplenomegaly, mild hirsutism, and hearing loss. Intellectual disability is occasional and usually mild to moderate. The overgrown gingival tissues can affect the ability to speak.
Etiology
ZLS is genetically heterogeneous. Heterozygous gain of function missense variants in KCNH1 (1q32.2), and KCNN3 (1q21.3) genes have been described and, more rarely, recurrent missense variants in the ATP6V1B2 (8p21.3) gene. Zimmermann-Laband syndrome is allelic to Temple Baraitser syndrome (TBS) which is also caused by gain-of-function mutations in the KCNH1 gene, and is characterized by global developmental delay and severe intellectual disability, epilepsy, hypoplasia/aplasia of the nails of the thumb and great toe, and facial dysmorphism. As both syndromes have been described with the same variant, and some patients with KCNH1 variants are reported without full-blown TBS or ZLS, it is likely that TBS, and ZLS are part of a broader KCNH1-related disorder.
Diagnostic methods
Confirmation of the clinical diagnosis is based on KCNH1, KCNN3, and ATP6V1B2 sequencing by targeted sanger sequencing, or via NGS (next generation sequencing) multigene panel including KCNH1, KCNN3, and ATP6V1B2, as well as other genes that may be part of the differential diagnosis.
Differential diagnosis
ZLS has overlapping features with a few different diseases which include : FHEIG syndrome (characterized by facial dysmorphism, hypertrichosis, epilepsy, intellectual disability/developmental delay, and gingival overgrowth) resulting from gain-of-function KCNK4 variants, Cantú syndrome, and DOORS syndrome as well as other defined syndromes of hirsutism and coarsening of the face. Some ATP6V1B2 variants are responsible for autosomal dominant deafness-onychodystrophy (DDOD) syndrome, a syndromic form of deafness which shares features with ZLS, such as anomalies of digits, nails, and teeth. Variants in ATP6V1B2 have also been reported in patients with epilepsy, intellectual disability and mild gingival and nail abnormalities. Some patients with ABCC9 variants also have gingival hypertrophy and, rarely, hypoplasia of terminal phalanges. Isolated gingival fibromatosis has been documented as a dominantly transmissible trait.
Antenatal diagnosis
For parents of an index individual, prenatal diagnosis in subsequent pregnancies should be discussed.
Genetic counseling
Although familial aggregation with different inheritance patterns has been reported, all genetically confirmed ZLS to date follow an autosomal dominant mode of in inheritance, most cases resulting from a de novo mutation.
Management and treatment
Management and treatment are based on the phenotype. Orthodontic treatment may be needed.
Prognosis
Prognosis depends on the phenotype. The syndrome is not life-threatening.

                            Last update: 
                            April 2021


                            - Expert reviewer(s): 
                            Pr Catheline VILAIN | ITHACA*


                                * European Reference Network