De Sanctis-Cacchione Syndrome

This syndrome is the most severe form of xeroderma pigmentosum (XP) (Atlas ID #10004).

Autosomal recessive

ERCC6 , ERCC2 , XPA , XPC

278800

De Sanctis-Cacchione syndrome is characterized by the skin and eye symptoms of XP along with neurological symptoms and growth delays. The severity of the clinical presentations varies depending on the nature of the mutation and amount of sun exposure. The earliest skin conditions include persistent erythema, increased freckling and blistering that occur after exposure to sunlight. In most cases, onset of these symptoms is often during infancy, although symptoms may not be apparent until later in childhood in rare cases. Additional skin symptoms include hyperpigmentation, hypopigmentation, or complete depigmentation. Some patients may develop premalignant lesions such as actinic keratoses. These patients may experience an early onset of skin cancer. For example, skin cancers such as malignant melanoma, basal cell carcinoma, and squamous cell carcinoma often occur, and the most commonly affected areas are the head, neck, and face.
In De Sanctis-Cacchione syndrome, some of the eye symptoms associated with XP may be present, such as photophobia, keratitis, or conjunctivitis. The severity of symptoms related to the skin and eyes may depend on the amount of exposure to ultraviolet light.
Most patients with De Sanctis-Cacchione syndrome usually have one or more neurological abnormalities with the most frequent being mental retardation. Other abnormalities may include microcephaly, sensorineural deafness, dysarthria, areflexia, hyporeflexia, or spasticity. Affected individuals may also demonstrate ataxia or choreoathetosis. Shortening of the Achilles tendon can lead to quadriparesis.
Individuals with De Sanctis-Cacchione syndrome will also exhibit unusually slow development, profound growth delays resulting in dwarfism and hypogonadism.

Xeroderma pigmentosum: Typically, XP patients have a similar skin presentation as noted above. However, De Sanctis-Cacchione syndrome is the rarest manifestations of XP with the most severe DNA repair impairment. XP can also present with some neurologic manifestations; however, short stature and delayed gonadal maturation are more typical of De Sanctis-Cacchione syndrome. The presence of progressive neurologic involvement and age at symptom onset correlate with the degree of DNA repair impairment present (Rahbar 2015).
Cockayne syndrome: Patients have a typical face phenotype (microcephaly, wizened face, deep-set eyes, mandible prognathism, hypoplastic teeth, and malformed ears) and develop dwarfism, hypogonadism, and neurological abnormalities similar to De Sanctis-Cacchione syndrome that include progressive impairment of vision, hearing and speech, behavioral changes, intellectual disability, and ataxia, leading to severe disability (Uribe-Bojanini 2017). However, cases of De Sanctis-Cacchione syndrome can be distinguished from Cockayne syndrome since patients with Cockayne syndrome do not show XP-type skin findings or have increased risk of skin cancer. Conversely, patients with Cockayne syndrome tend to have normal or increased deep tendon reflexes or signs of primary demyelination (Moriwaki 1996).
Although the diagnosis of De Sanctis-Cacchione syndrome can be suspected by the patients clinical presentation, molecular genetic testing is recommended for confirmation of the patients mutation and complementation group characterization. The nucleotide excision repair (NER) system includes seven complementation groups XP-A to XP-G in addition to the XP variant group. NER is responsible for repairing UV-induced photoproducts inside DNA. If a mutation is present in any of the components of the pathway, then the entire pathway fails to function normally. Thus, identification of the patients mutation and complementation group characterization plays an important role in genetic counseling, antenatal diagnosis, discussion of etiology, and the probability of occurrence in future generations (Uribe-Bojanini 2017).

Patients have a 10,000-fold increase in the risk of developing skin basal cell carcinoma and squamous cell carcinoma and a 2,000-fold increased risk of melanoma (Uribe-Bojanini 2017).

Total protection of the skin from sunlight is important to prevent the development of skin lesions. Protective methods include use of topical sunscreens, sunglasses, and photoprotective layers of clothing. For the treatment of established skin lesions, chemotherapeutic agents, such as 5-fluorouracil, immunomodulators and retinoids, can be used depending on the location, severity and extension of the lesion (Caldas 2013).
Vitamin D supplementation may be necessary due to deficiency from rigorous sun protection. Psychological advisory and support groups are very important for patients and their families. The management of patients with neurological abnormalities includes the use of hearing aid devices, along with physical, occupational, and speech therapy. Genetic counseling should be offered for families at risk. (Uribe-Bojanini 2017).

The prognosis of the disease is poor overall.

The nucleotide excision repair (NER) system includes seven complementation groups XP-A to XP-G in addition to the XP variant group. NER is responsible for repairing UV-induced photoproducts inside DNA. If a mutation is present in any of the components of the pathway, then the entire pathway fails to function normally. Patients with De Sanctis-Cacchione syndrome have been found to harbor mutations in ERCC6 (CSB), XPA, ERCC2 (XPD), and XPC genes.

CSB (Cockayne syndrome B), CKN2, ARMD5, RAD26

90 kbp; at least 21 exons

The ERCC6 gene encodes the CSB protein.

1493-amino acid protein has an N-terminal domain, followed by an acidic stretch, a glycine-rich region, a central helicase domain, and a nuclear localization signal (Troelstra et al. 1992).

Ubiquitous.

Nuclear.

Encodes a DNA-binding protein (CSB) that plays a role in transcription-coupled excision repair. The encoded protein has ATP-stimulated ATPase activity, interacts with several transcription and excision repair proteins, and may promote complex formation at DNA repair sites (Troelstra et al. 1992). CSB is essential for the NER system, which removes RNA polymerase blocking lesions. The CSB protein plays an important role in general nuclear transcription and stimulates RNA polymerase II progression beyond pause sites (Shehata 2014).

Biallelic mutations have been found in the ERCC6 genomic DNA (C2282T) of three patients with De Sanctis-Cacchione syndrome.

XP-A, xeroderma pigmentosum, complementation group A, XP1, XPA_HUMAN, XPAC

22448 bp; 6 exons.

273 amino acids, 31.4 kDa. DNA excision repair protein. The functional domain for damaged DNA recognition contains a zinc-finger motif with 4 cysteine residues: Cys-X2-Cys-X17-Cys-X2-Cys motif and a glutamic acid cluster encoded by Exon 2. The nuclear localization signal is located in Exon 1.

Ubiquitous.

Nuclear.

Initiates DNA repair by binding to damaged sites with various affinities, depending on the chemical structure of the lesion. Two proteins have been identified and implicated in one of the first steps of NER system to recognize lesions in DNA: the XPA gene product and the XPC gene product. In vitro the XPA protein binds preferentially to damaged DNA compared to non-damaged DNA. The XPA protein binds to replication protein A (RPA) which enhances the affinity of XPA for damaged DNA and is essential for NER. The XPA protein has been shown to bind to ERCC1 and TFIIH. It is possible that the complex XPA\/RPA may inform the repair machinery which strand contains the damage and be eliminated.

13 nucleotide substitutions and 5 small insertion\/deletion.

XPD, XP-D, xeroderma pigmentosum complementary group D

54336 bp; 23 exons

2400b mRNA

760 amino acids.

Ubiquitous.

Nuclear.

5-3 ATP-dependent helicase activity involved in DNA NER pathway and as a subunit of the basal transcription factor TFIIH. The ERCC2 (XPD) as the ERCC3 (XPB) protein are also found in the transcription factor TFIIH, a large complex involved in the initiation of transcription. TFIIH fulfills a dual role in transcription initiation and NER and the role of TFIIH in NER might closely mimic its role in the transcription initiation process. In transcription initiation, TFIIH is thought to be involved in unwinding of the promoter site and to allow promoter clearance. In the NER process, TFIIH causes unwinding of the damaged region that has been localized by XPC- RAD23B (HR23B) and XPA-RPA, enabling the accumulation of NER proteins around the damaged site.

17 mutated sites.

XP-C, XPCC, RAD4, xeroderma pigmentosum, complementation group C

17703 bp; 16 exons.

3558b mRNA.

939 amino acids.

Ubiquitous.

Nuclear.

Involved in the early recognition of DNA damage present in chromatin. Two proteins have been identified and implicated in (one of) the first steps of NER system to recognize lesions in DNA: the XPA gene product and the XPC gene product in complex with HR23B. The XPC-HR23B complex has been implicated in DNA damage recognition, especially the cyclobutane pyrimidine dimers induced by UV-light. XPC cells have low NER capacity, but the residual repair has been shown to occur specifically in transcribed genes. It is very likely that the XPC-HR23B complex is the principal damage recognition complex. Binding of XPC-HR23B to a DNA lesion causes local unwinding, so that the XPA protein can bind and the whole repair machinery can be loaded onto the damaged site. The XPC-HR23B complex is only required for global genome repair. In case of transcription coupled repair when an RNA polymerase is stalled at a lesion, the DNA is unwound by the transcription complex and XPA can bind independently of the XPC-HR23B complex.

A novel germline mutation in the XPC gene (c.547A>T) was identified in one case causing De Sanctis-Cacchione syndrome. This variant is predicted to result in premature protein termination (p.Lys183*) (Uribe-Bojanini 2017).