Sir,

Focal facial dermal dysplasia (FFDD) is a group of developmental syndromes characterized by bitemporal (FFDD types I–III) or peri-auricular (FFDD-IV) scar-like depressions resembling forceps marks or cutis aplasia [1].

A five-month-old female, originally from a non-consanguineous family from Guerrero, presented with a localized dermatosis on her head, specifically in the temporal region, characterized by bilateral and symmetrical scar-like lesions. She exhibited redundant facial soft tissues, sparse lateral and up-slanting eyebrows, upper distichiasis, the absence of eyelashes on the lower eyelid, periorbital puffiness, flattened nasal bridge, bulbous nasal tip, and prominent upper lip, micrognathia (Figs 1a and 1b). She had a history of congenital hypothyroidism. She was the only child of non-consanguineous parents, both without visible congenital defects upon physical examination. The approach was complemented with neurophysiology and it documented right superficial hypoacusis. An echocardiographic study showed an atrial septal defect, pulmonary valve stenosis, and pulmonary hypertension. A skin biopsy reported findings consistent with aplasia cutis. Exome sequencing was performed, which revealed a triplication in the region 1p36.23-p36.22 (3.04 Mb, 60 genes). These results led to the diagnosis of FFDD type III (Setleis syndrome)

Figure 1: (a) Frontal view (blue arrow): bitemporal scar-like lesions. Additionally, sparse lateral and up-slanting eyebrows, distichiasis, the absence of eyelashes on the lower eyelid, and epicanthal folds.(b) Lateral view: temporal scar-like lesion and low-set ears.

FFDD type III (OMIM #227260) presents with bitemporal scar-like lesions, along with other facial manifestations listed in Table 1 [1]. This disease is primarily caused by monogenic alterations, with biallelic variants in TWIST2 or CYP26C1 leading to a loss of function. The most described etiologies involve monogenic variants, while structural alterations in the chromosomes are less frequently observed. Chromosomal alterations, including duplications and triplications, are associated with more severe phenotypes, involving delayed neurodevelopment and cardiac abnormalities. Genetic heterogeneity is evident in FFDD-III, with some cases showing duplication in 1p36.22 without TWIST2 or CYP26C1 variants. One study contrasts triplications and duplications, identifying the smallest region of overlap (SRO) that includes morbid genes. The hypothesis suggests that a gene product may interfere with TWIST2 activity, contributing to the syndrome’s phenotype. DRAXIN, present in the smallest region of overlap (SRO), normally acts as an inhibitor of the WNT signaling pathway and influences neural crest cell delamination and epithelial-mesenchymal transition (EMT). Further research on DRAXIN is needed to understand its role in the development of facial dermal structures and EMT, which could clarify the mechanism behind 1p36.22 copy number variants in Setleis syndrome. In cases of duplication and triplication, the alterations converge at a locus with dosage-sensitive genes, potentially explaining the FFDD-III phenotype. However, the involvement of other genes cannot be excluded [1–3].

Table 1: Facial findings of FFDD type III.

This new case identified a previously undocumented structural alteration in the chromosomal region 1p36.23-p36.22 as a potential cause of FFDD type III. While its exact contribution to the syndrome’s etiology and pathogenesis is not fully understood, this finding helps to characterize the observed phenotype. These chromosomal alterations are associated with more severe phenotypes, including neurodevelopmental delay and cardiac anomalies, highlighting the complexity and severity of these focal facial dermal dysplasias.

REFERENCES

1. Rosti RO, Uyguner ZO, Nazarenko I, Bekerecioglu M, Cadilla CL, Ozgur H, et al. Setleis syndrome:Clinical, molecular and structural studies of the first TWIST2 missense mutation. Clin Genet. 2015;88:489-93.

2. Cervantes-Barragán DE, Villarroel CE, Medrano Hernández A, Durán McKinster C, Bosch Canto V, Del-Castillo V, et al. Setleis syndrome in Mexican-Nahua sibs due to a homozygous TWIST2 frameshift mutation and partial expression in heterozygotes:Review of the focal facial dermal dysplasias and subtype reclassification. J Med Genet. 2011;48:716-20.

3. Weaver DD, Norby AR, Rosenfeld JA, Proud VK, Spangler BE, Ming JE, et al. Chromosome 1p36.22p36.21 duplications/triplication causes Setleis syndrome (focal facial dermal dysplasia type III). Am J Med Genet A. 2015;167A:1061-70.