Temple-Baraitser Syndrome and Zimmermann-Laband Syndrome: one clinical entity?

Temple-Baraitser syndrome (TMBTS; MIM: 611816) and Zimmerman-Laband syndrome (ZLS; MIM: 135500) are rare developmental disorders with hypoplasia/aplasia of nails. These syndromes are considered to be distinct entities, with TMBTS defined as a disorder characterized by severe intellectual disability (ID), epilepsy, hypoplasia/aplasia of the nails of the thumb and great toe, a pseudo-myopathic appearance, and marked hypotonia in infancy [1‐6], and ZLS charatacterized by ID, gingival fibromatosis, associated with absence or dysplasia of all nails, hypoplasia of the distal phalanges, scoliosis, hepato-splenomegaly, coarse face, and hirsutism [7].

KCNH1 encodes a voltage-gated potassium channel that is predominantly expressed in the central nervous system, and mutations in this gene have been linked to both syndromes [6, 7].

Whole Genome Sequencing identified 3 missense mutations in TMBTS patient (Table 1). We validated and confirmed the de novo origin of these variants by Sanger sequencing.

The mutation in KCNH1 (c.1042G > A) has a damaging effect according to all different effect predictors tested. STK36 has a missense mutation (c.2131 T > C), which also has damaging effects according to half of the effect predictors tested. ZNF517 has a missense mutation (c.726C > A) predicted as disease causing by one of the effect predictors.

The KCNH1 mutation results in a substitution of Glycine by Arginine. Same mutation is found in both isoforms of this protein: p.(Gly348Arg) in short isoform (NM_002238.3) and p.(Gly348Arg) in long isoform (NM_172362) in the ion transport domain. The p.(Gly348Arg) mutation maps to the connecting loop between helices S4-S5 as reported by Kortum et al., and exerts a strong impact on function [18].

We report on a male Lebanese patient in which a de novo missense heterozygous mutation c.1042G > A in the KCNH1 gene led to TMBTS.

KCNH1 is a member of voltage-gated potassium channel proteins. It is recognized as an important regulator of cell proliferation in bone-marrow derived mesenchymal stem cells, and is involved in fundamental cellular and developmental processes [15, 16].

Mutations in KCNH1 have been recently associated with TMBTS [6]. Moreover, de novo gain-of-function mutations in KCNH1 have also been reported in individuals with ZLS [7].

Generally, TMBTS and ZLS can be distinguished by their characteristic phenotypic features, which include absence or dyplasia of all nails and hypertrichosis in ZLS vs hypoplasia or aplasia of only the great toe and thumb’s nails in TMBTS (Table 2). With this in mind, we considered that our patient had TMBTS. These syndromes are currently considered to be two separate entities, but their common characteristics suggest that these two syndromes may be different presentations of the same disorder. In fact, many common characteristics of patients with TMBTS and ZLS have been noted, such as, seizures, hypertrichosis, hypotonia, aplasia of nails, etc., which sometimes occur in some but not all patients (Table 2). It is noteworthy to mention that many clinical databases do not even mention TMBTS as a differential diagnosis for ZLS because of the absence of hypertrichosis, even though not all reported patients with ZLS present this characteristic.

Interestingly, the same mutation (c.1042G > A) identified in our patient has never been reported with TMBTS, but was previously detected in patients with ZLS (patient 7 in Abo-Dalo et al. or subject 3 in Kortüm et al.) [17, 18]. This substitution leads to a gain of function effect and mutants carrying this mutation exhibit an accelerated channel activation and a slower deactivation [18]. Along with the previously identified p.(Ile494Val) misense variant in KCNH1, which was shared among individuals with TMBTS and ZLS, the genetic defect identified in our patient, i.e., p.(Gly348Arg) was found in patients bearing different phenotypes and thus supposedly different syndromes. This provides stronger evidence that both syndromes clearly overlap and could be a phenotypic continuum. In fact, the mutation c.1042G > A was found in a patient with ZLS who does not present with hypertrichosis, similar to the patient reported herein. However, the patient had in addition, aplasia of all nails of hands and feet, thoracic scoliosis, and infrequent seizures, which were not present in our patient who had a delay in epiphyseal maturation, (Table 3) a feature never reported before in both entities, and gingival enlargement. The latter is a characteristic not reported previously in TMBTS affected individuals, however it is a frequent feature in patients with mutations of KCNH1 (Bramswig et al.). Genetic modifiers, possibly involving the Na⁺ and Ca²⁺ channels, might block the KCNH1 channels and result in the gingival enlargement as it is observed in individuals treated with Na⁺ blocker phenytoin or Ca²⁺ channel blocker nifedipine [18].

On the other hand, the patient reported by Kortum et al., developed seizures in adolescence, therefore one could speculate a late occurence of epilepsy in the patient described here with the same mutation. Yet, Bramswig et al. described 3 individuals presenting with an identical KCNH1 variant but with different clinical features with regard to epilepsy [19]. Consequently, the presence of a pathogenic KCNH1 variant alone could not allow for a prediction of occurence of epileptic seizure.

Other genetic modifiers could be responsible for the observed differences in clinical phenotype. We looked deeper at the results of the WGS and noticed mutations in two other genes STK36 and ZNF517, which were classified in some databases as possibly damaging. However, their significance remains to be elucidated. Recently, de novo mutations in STK36 have been identified in patients with epileptic encephalopathies [20]. Although our patient who has missense mutation in STK36 does not present with epilepsy at present, he might develop it in adolescence as in patient 3 in Kortum et al. Thus, concordant to previous reports, our data supports the evidence that the mutated KCNH1 is a major cause of TMBTS and ZLS, while other genes can act as disease modifying roles. Understanding the molecular mechanisms by which these genes exert disease modifying roles might help in the better understanding of the pathogenesis of these syndromes.

Finally, both ZLS and TMBTS patients with KCNH1 mutations show similar phenotypes. Nevertheless, two other ZLS patients were also described with mutations in the ATP6V1B2 gene that encodes a component of the vacuolar ATPase (V-ATPase). These mutations present a more pronounced phenotype characterized mostly by hypertrichosis and a coarser facial phenotype (Table 2). But due to the limited number of individuals described, a conclusion about whether probands with mutations involving ATP6V1B2 lead to a more severe syndrome might not be accurate. On the other hand, Kortüm et al. screened a cohort of 24 ZLS patients, of which only 8 had mutations in KCNH1 and ATP6V1B2 suggesting further the genetic heterogeneity in the ZLS disorder [18].

In summary, this study shows that the same KCNH1 mutation can lead to both ZLS and TMBTS. The phenotypic variability could be the result of a modifier gene or genes, and identification of such genes would be of great importance. A careful analysis of genetic polymorphisms in various loci should be taken into consideration for clinical diagnosis. Further investigations are needed to confirm if ATP6V1B2 mutations lead to a more severe phenotype.

ID, intellectual disability; TMBTS, Temple-Baraitser syndrome; WGS, whole genome sequencing; ZLS, Zimmermann-Laband syndrome.