*3.3.3 Diagnosis*

CN diagnosis is often made based upon detailed history taking followed by careful clinical examination and thorough evaluation of all information collected. Then the diagnosis may be confirmed by 2–3 times/week neutrophil count monitoring over six weeks. Individuals with CN should preferably be genetically confirmed by assaying corresponding mutations in the *ELANE* gene [50, 59].

Typical CN diagnostic flow includes:


#### *3.3.4 Treatment*

Prompt, appropriate treatment of the infections associated with CN is important, including symptomatic and supportive treatment. Careful oral and dental care is also required. In addition, individuals with CN should avoid activities that may cause minor injuries [50, 59].

**Figure 13.**

*Diagnostic monitoring the changes in white blood cells (WBC), neutrophils, lymphocytes, and monocytes over a course of three months concerning the CN patient (Figure 10).*

Treatment with granulocyte colony-stimulating factor (G-CSF), also called Neupogen, is effective in raising blood neutrophil counts in CN patients. G-CSF treatment with G-CSF in patients with CN does not abrogate cycling, but increases the ANC, shortens the cycle periodicity from the usual 21 days to about 14 days, and prevents serious infections, reduces the symptoms and problems of infections in almost all patients [60].

Professional removal of dental plaque and calculus should be recommended monthly and during the neutropenic episodes, antibiotics may be given in order to prevent oral infection.

#### *3.3.5 Genetic counseling*

Genetic counseling is recommended for individuals with inherited forms of CN and their families, in particular the fact regarding 50% chance for CN offsprings from affected individual need to be discussed.

#### *3.3.6 Prognosis*

The development of CN is usually benign compared to autoimmune, congenital or idiopathic neutropenia. CN systemic symptoms e.g. recurrent fevers often diminish post adolescence but CN adults remained prone to oral ulcers, gingivitis, periodontitis, and various oral/facial infections [50–52].

#### **3.4 Periodontal Ehlers-Danlos syndrome**

Ehlers–Danlos syndromes (EDS) are clinically and genetically heterogeneous rare hereditary disorders categorized by varying degrees of connective tissue fragility, principally affecting skin, ligaments, blood vessels, and internal organs [61, 62]. Main clinical features comprise tissue fragility, skin extensibility, and joint hypermobility.

EDS was named by dermatologists Edvard Ehlers in 1901 and Henri-Alexandre Danlos in 1908. In 2017, the international EDS consortium published a revised EDS classification system with specific emphasis on molecular diagnosis as well as identification of causative genetic variants. The new classification recognizes 13 subtypes and periodontal manifestations are commonly observed in patients with periodontal Ehlers-Danlos syndrome (pEDS), also known as EDS type VIII, Ehlers-Danlos Syndrome, Periodontitis Type or Ehlers-Danlos Syndrome Periodontal Type [63, 64].

pEDS was considered a distinct EDS subtype [65] characterized by severe periodontitis with early disease onset with premature tooth loss, extra-orally includes pretibial hyperpigmented scarring, easy bruising and joint hypermobility. pEDS is an extremely rare EDS subtype with autosomal dominant inheritance. pEDS affects males and females in equal numbers, and the prevalence is unknown, more than 100 pEDS patients were reported [63, 64, 66].
