Uncombable Hair Syndrome 1
Uncombable Hair Syndrome 1 is caused by a defect in the Trichohyalin gene (TCHH) found in hair follicles and some parts of hair strands. It serves as a scaffold protein, with involucrin, in cell envelope organization. The trichohyalin gene is produced and changed by other proteins and to molecules such as keratin intermediate filaments to form organized cross-links. These networks provide the hair shaft with its cylindrical form. This, in turn, leads to frizzy hair, resulting in uncombable hair. The chromosomal location for this TCHH gene is located on chromosome 1. The condition usually improves over time, and will have better hair structure once it reaches adolescence.It is still being decided whether TCHH is autosomal dominant, or autosomal recessive. In an experiment, they identified the causative mutations of UHS in 3 genes; PADI3, TGM3, and TCHH in 11 children. These children carried homozygous/heterozygous mutations in those 3 genes, which resulted in autosomal recessive inheritance. Because it was identified as autosomal recessive inheritance, scanning electron microscopy was performed in order to rule out autosomal dominance since this type of gene can also be autosomal dominant to a certain extent. Uncombable Hair Syndrome 2
Uncombable Hair Syndrome 2 is caused by a defect in Transglutaminase 3 (TGM3) gene. This gene helps provide instructions for creating an enzyme known as Transglutaminase 3. This gene is found in skin cells known as keratinocytes and corneocytes. This helps frame the scalp, root, and strands of hair. It helps the molecules bind 
proteins.
With this experiment, they performed a process called immunoblotting and immunofluorescence. With immunoblotting, it appeared that the transfected cells had a marginally lower expression of the mutant compared to the wild-type. With immunofluorescence it resulted in an irregular intracellular location of the protein. Therefore, it helped conclude that there was a reduction in enzymatic action that encodes a protein to hair shaft arrangement, which relates to central centrifugal cicatricial alopecia(CCCA). Diagnosis
Differential diagnosis
Other syndromes with hair abnormalities may also show features of uncombable hair syndrome such as Rapp–Hodgkin ectodermal dysplasia syndrome, loose anagen syndrome, EEC syndrome (ectodermal dysplasia, ectrodactyly and cleft lip/palate) and familial tricho-odonto-onychial ectodermal dysplasia with syndactyly. However, unlike these conditions, uncombable hair syndrome alone is not associated with physical, neurologic, or mental abnormalities.According to the U.S. National Institute of Health, the condition tends to develop in childhood (age 3-12) and resolve by adolescence.Another observation that can be made when detecting uncombable hair syndrome in individuals is by observing the hair shaft under a special microscope. When individual hair strands are being viewed, the hair is triangular or kidney-shaped and has a longitudinal groove on one or two faces.Clinical diagnosis of UHS can be confirmed molecularly by performing high-resolution microscopy on hair shafts using scanning electron microscopy (SEM). SEM allows for the visualization of hair shaft cross-sections, which can appear triangular, heart-shaped, kidney-shaped, flat, or longitudinally grooved. Interestingly, multiple different cross sections can appear on a single shaft of hair.