Eliciting History

There is pertinent content in a pediatric medical history that is not required for an adult. In addition, the value of certain aspects of the history changes in significance as the child transitions through the various developmental stages. For instance, prenatal history is an essential component of the history in an infant, but diminishes in importance in older children and adolescents.

History‐taking is another aspect that is different in children and adolescents. For an infant and toddler, the history is obtained exclusively from the parent/caregiver; while for older children, the history is usually elicited from both the parent and the patient. The history‐taker should be cognizant that parents and caregivers may be influenced by their frame of mind, emotional state, presumptions, and expectations, which may compromise the reliability of the history. Children above the age of 4 years are often able to supplement their parent’s description with their own account. School‐age children and adolescents can assume a larger role in being the main historian and the reliance on parents is further reduced. This is potentially a delicate situation and the history‐taker needs to negotiate the process tactfully to avoid offending the parents or embarrassing older children/adolescents when sensitive topics are being discussed. Involving the child/adolescent in the interview process builds rapport and is the foundation for a successful and long‐term patient–doctor relationship.

Patient Examination

It is recommended to gather as much information as possible from the parent, and through observation and interaction with the child prior to the examination. The factors that influence the child’s compliance include past experiences, temperament, approachability, adaptability to the environment, and stage of cognitive development. There are several theories on how children evolve as they mature; the best known is Piaget’s theory of cognitive development. The four stages of Piaget’s theory correspond with age: sensorimotor (0–2 years), preoperational (2–7 years), concrete operational (7–11 years), and formal operational stage (11 years to adulthood). Behavioral management strategies are generally based on these theories. To maximize compliance for an examination, the practitioner should utilize the most appropriate behavioral management technique (Table 25‐1) based on the child’s developmental age, temperament, and past experiences.

Generally, children under the age of 3 years are pre‐cooperative and behavioral management strategies have limited benefit. The goal then is to perform an examination in a gentle and time‐efficient manner. For newborns and infants, clinical examination may be done on a flat surface or in the parent’s arms. For older infants and toddlers, a “knee to knee” examination is commonly performed. The infant/toddler lays flat on both the examiner’s and parent’s laps, with the head on the examiner’s lap and the lower half of the body on the parent. The child’s legs hang loose or looped around the parent’s waist. Children between the ages of 3 and 7 years are potentially cooperative and behavioral management strategies should always be employed. Children of these ages may be able to sit on the dental operatory chair independently for an examination. If the child is apprehensive, the parent may be invited to sit with the child on the dental chair.

Diagnostic Investigations

Ordering of diagnostic investigations is less straightforward in younger children for numerous reasons. In general, any investigation that rely on subjective response (e.g., pain on palpation or percussion) is less reliable in children. The ability to comply with an investigation is another consideration unique to this population. If a young child is unable to remain still for a radiographic imaging or will not allow blood to be drawn for a hematologic test, the practitioner then needs to decide whether the investigation is sufficiently critical to justify sedating the child (and exposing the child to the risk of sedation or general anesthesia) to complete the investigation. Another frequent parental concern is the risk of radiation exposure. The radiation exposure from dental radiographs is small and dental radiographs should be taken if the image finding will impact treatment. Although the radiation doses are higher with medical‐grade imaging, the same principle will apply.

Treatment

As with adults, symptomatic, aggressive, potentially malignant, or malignant conditions in children should be managed immediately. The decision to treat asymptomatic, slow‐growing, and likely benign lesions is less clear in a young child, especially when sedation or general anesthesia is needed. With a recent flurry of reports of potentially negative impact of repeated general anesthetics on the brain development of children under the age of 3 years,² the practitioner needs to weigh the pros and cons of performing the procedure under sedation, versus monitoring and delaying intervention until the child is able to comply for the procedure under local anesthesia.

Medications for oral medicine conditions are often prescribed “off‐label” due to a lack of clinical trials.³ Of the limited studies available, most are in the adult population. The effectiveness, safety, and adverse reactions of a particular drug in an adult may differ in a child, especially in those under the age of 2 years. As such, practitioners must exercise caution when prescribing a medication for a child, even if the same medication may have been found beneficial in an adult. Other considerations include the impact of the medication on growth and development, the need for dose adjustments in overweight and obese children as well as in newborns and infants due to immature metabolic processes, the potential for miscalculated doses, as well as the ability and the compliance of the child to adhere to the route and frequency of the prescribed regimen. A general guide to ascertain whether an off‐label medication should be used in a child may be guided by these principles: (1) moderate‐ or high‐quality evidence supporting the off‐label use; and (2) obtaining informed consent whereby the rationale of using the medication, side effects, and alternative treatments are explained to the parent and the patient.

Consent

The consent process varies between countries. Practitioners should be familiar with and must abide by the local laws and regulations where they practice. In the United States, both the 1976 and 1995 AAP policies on informed consent stipulate that permission must be obtained from the parent or legal guardian prior to medical interventions for patients under 18 years of age.⁴ The 1995 policy also states that older children and adolescents should participate in the medical decision‐making process and provide assent to their care whenever reasonable.⁵ Although assent is only mandatory for enrollment in research studies, the value of involving young patients in their own medical decision‐making is increasingly being acknowledged. Assent may be obtained from children as young as 6–7 years of age. Assent involves explaining to the child in a language that they can understand as to what to expect with investigations and treatment, and encouraging questions to ensure that the child understands the situation. This process will help them become more involved in their medical care. While involving children and adolescents in medical decision‐making is desired, they are vulnerable decision‐makers. This is attributed to their neuropsychologic immaturity (e.g., adolescent behaviors such as sensation‐seeking and risk‐taking), influences from peers, and inexperience with decision‐making, especially in complex and stressful situations. Thus, it is imperative that the parent/legal guardian remains the final decision‐maker. When a treatment or intervention is deemed essential, assent should not be sought. Instead, the pediatric patient should be informed of the decision. Dissent by the pediatric patient will carry more weight for elective interventions or interventions that can be deferred without substantial risks or complications.

Developmental Oral Cysts of the Newborn

Developmental oral cysts are common in newborns, with no gender predisposition. It is difficult to provide an estimate of the prevalence because of reporting bias as well as differences in study design, diagnostic criteria, and sample population between studies. Fromm classified developmental oral cysts based on their etiology and location.⁶ Epstein pearls are located on the mid‐palatal raphe, Bohn’s nodules may be found at the junction of the hard and soft palate or at the vestibular region (rare), and dental lamina (gingival) cysts are found on the alveolar ridge crest. An Epstein pearl is thought to be a result of epithelium entrapment between the palatal shelves when they fuse in the midline in utero to form the secondary palate. Bohn’s nodule is thought to be derived from the epithelial remnants of minor salivary glands.⁷ Unlike Epstein pearl and Bohn’s nodule, dental lamina (gingival) cyst (Figure 25‐1) is odontogenic in origin and arises from the cell rests of Serres (remnants of dental lamina epithelium).⁸ Of note is that these three terms are often used interchangeably, although the term “developmental oral cyst of the newborn” is preferable. Regardless of the origin and location, developmental oral cysts typically present as a single or multiple painless, small nodules filled with keratin, which imparts a white/yellowish appearance. The diagnosis is made clinically based on the presentation, location, and age. Developmental oral cysts of the newborn are benign and resolve spontaneously within the first few months of life, thus no treatment is needed.

Lymphangioma of the Alveolar Ridge

Lymphangiomas of the alveolar ridges (Figure 25‐2) in infants were first described in 1976 and present as a single or multiple, fluid‐filled, sessile, dome‐shaped, bluish lesions on the maxillary or mandibular posterior dentoalveolar ridges.⁹ The condition usually occurs bilaterally.¹⁰ Lymphangiomas of the alveolar ridges have only been reported in infants of African descent, with a male predilection. The histologic examination reveals a proliferation of endothelial‐lined lymphatic spaces. The diagnosis is often made clinically based on the presentation and ethnic predilection. No treatment is needed, as the lesions are benign and all cases have been reported to resolve spontaneously.¹¹

Eruption Cyst

An eruption cyst is a benign odontogenic cyst that is considered to be a soft tissue variant of the dentigerous cyst. It is recognized as a separate clinical entity from a dentigerous cyst and is proposed to develop from the separation of the reduced enamel epithelium from the crown of the tooth.¹² The eruption cyst usually presents in the first decade of life and is commonly associated with the eruption of the permanent first molars and maxillary incisors. Clinically, the cyst appears as a soft, fluctuant, sessile, dome‐shaped, translucent swelling overlying the crown of an erupting tooth. Occasionally, the swelling may appear blue or blue‐black when it is filled with blood (eruption hematoma), likely attributed to trauma during function. The diagnosis is made clinically based on the presentation and temporal relationship with the eruption of a tooth. Radiographs are generally not necessary, as there are no characteristic findings. Furthermore, the cystic space cannot be visualized, as the cyst is entirely in soft tissue. The majority of eruption cysts are asymptomatic and rarely require intervention. The cyst naturally marsupializes as the tooth erupts into the cystic space and through the gingiva. In individuals who complain of discomfort during mastication and in situations whereby the cyst continues to enlarge to cause discomfort, simple surgical removal of the roof of the cyst to expose the crown of the tooth under local anesthesia may be performed.

Congenital Epulis of the Newborn (Congenital Granular Cell Tumor)

The congenital epulis (CE) is a rare, soft tissue benign tumor (0.0006%) that occurs almost exclusively in newborns (Figure 25‐3). The tumor occurs 8–10 times more often in females than in males.¹³ The etiology is unknown, but there are several hypotheses regarding the origin of CE. The most popular ones are those that favor gingival and odontogenic epithelial origins.¹⁴ Clinically, CE appears as a single, firm, smooth‐surfaced, sessile or pedunculated, round, pink or reddish mass commonly occurring on the anterior maxillary alveolar ridge. Multiple tumors have been reported in a minority of cases.¹⁵ CE does not appear to grow after birth and the majority are less than 2 cm, though tumors as large as 10 cm have been reported.¹⁶ Large CE may interfere with feeding and cause airway obstruction. The granular cells in CE resemble the cells in granular cell tumor histologically (i.e., large round cells with abundant granular, eosinophilic cytoplasm, and round basophilic nuclei) and thus it is also known as congenital granular cell tumor. However, unlike granular cell tumor, CE does not display a strong reactivity to S100 protein.^17,18 A clinical diagnosis of CE is not difficult to make because of its presence at birth, appearance, and location. Nevertheless, histology is needed to confirm diagnosis. Spontaneous regression is rare.¹⁷ Surgical excision is the treatment of choice and recurrence is unlikely even when the removal is incomplete.

Lingual Thyroid

Lingual thyroid is an ectopic thyroid gland found at the base of the tongue. This occurs as a result of the thyroid gland failing to descend to its normal anatomic site in utero. The incidence is approximately 1 in 100,000 to 1 in 300,000 live births and is 4–7 times more common in females.¹⁹ Lingual thyroid may present as small asymptomatic nodules or a single large mass. The diagnosis is made by radionuclide imaging, ultrasonography, computed tomography, and magnetic resonance imaging. Most affected individuals do not require treatment.¹⁹ Some individuals may be hypothyroid and require thyroid hormone replacement.²⁰ Over 70% of cases have no other functional thyroid tissue, thus surgical removal is contraindicated unless the structure is causing airway obstruction, bleeding, or shows cystic degeneration. The potential for malignant change appears to be similar to that of orthotropic thyroid tissues.²¹

Melanotic Neuroectodermal Tumor of Infancy

Melanotic neuroectodermal tumor of infancy (MNTI) is rare and only about 350 cases have been reported in the literature.²² The tumor commonly occurs in children under 1 year of age. The majority of MNTI are benign, but a few malignant cases have been reported.^23,24 The high urinary levels of vanillylmandelic acid in individuals with MNTI support the neural crest origin of MNTI. Clinically, the tumor typically presents as a painless, nonulcerative, firm, smooth‐surfaced, sessile swelling on the anterior maxillary alveolar ridge. The color varies greatly, ranging from mucosal colored with a bluish hue to a reddish‐brown lesion. Although benign, MNTI grows rapidly and can infiltrate and destroy the adjacent bone and soft tissue. The histologic examination reveals two distinct cell types that form sheets, nests, or cords within a dense collagenous stroma.²⁵ The first cell type is a larger, cuboidal epithelioid cell containing melanin granules, generally found at the periphery of the tumor. The other cell type is smaller and round, with a hyperchromatic nuclei and scant cytoplasm. These cells tend to grow in nests and are surrounded by the larger cuboidal cells. The diagnosis is made based on the clinical presentation, high urinary vanillylmandelic acid, and histology. Surgical intervention is the treatment of choice. Recurrence ranges greatly, between 10% to 60%.^22,26 Younger age and surgical curettage were associated with the highest recurrence, while segmental resection was associated with the lowest recurrence.²⁶

Vascular Anomalies

Vascular anomalies are common in newborns and the majority are benign and self‐limiting. They are broadly categorized into vascular tumors and malformations. Vascular tumors are true neoplasms of endothelial cells, while vascular malformations are abnormalities of the vessel structure. Historically, the term “hemangioma” was used to describe any vascular tumor‐like lesion; however, this definition should not be used when referring to vascular malformations.

Vascular Malformations

Vascular malformations (VMs) are categorized by the International Society for the Study of Vascular Anomalies into (1) simple malformation consisting of only one type of vessel; (2) combined malformation defined as ≥2 VMs in a single lesion; (3) anomalies of major named vessels; and (4) VM associated with other anomalies (Table 25‐2).³⁹ VMs are further divided based on the type of involved vessels and flow characteristics: low flow (capillary, venous, lymphatic, or combination) and high flow (arterial, arteriovenous). The diagnosis for small localized or superficial lesions is often based on history and clinical presentation. The use of imaging such as Doppler ultrasonography and magnetic resonance imaging may be needed to confirm the diagnosis of extensive and deeper lesions.

Vascular Malformations
Simple	Combined	Anomalies of Major Named Vessels	Associated with Other Anomalies (Not Exhaustive)
Low flow Lymphatic malformation Capillary malformation Venous malformation High flow Arteriovenous malformation (development)* Arteriovenous fistula (acquired)*	Any combination of the four types of vessels (lymphatic, capillary, venous, or arteriovenous) or ≥2 vascular malformations in a single lesion, e.g., capillary–venous malformation, capillary–arteriovenous malformations	Affecting veins, arteries, or lymphatics of large caliber	Sturge–Weber syndrome Klippel–Trenaunay syndrome Capillary malformation–arteriovenous malformation syndrome Cutis marmorata telangiectatica congenita Macrocephaly–capillary malformation syndrome Maffucci syndrome Phakomatosis pigmentovascularis Proteus syndrome CLOVES (congenital lipomatous overgrowth, vascular malformations, epidermal nevi and scoliosis/skeletal/spinal anomalies) syndrome

^* Although arteriovenous malformations/fistulas contain arteries, veins, and capillaries, they are not considered a combined venous malformation with an arterial malformation, but an entity involving several types of vessels.

Approximately 50% of VMs occur in the head and neck region, with a slight female predisposition.⁴⁰ All VMs are present at birth, but may be clinically subtle. They become more apparent over time and grow proportionately with the infant’s overall growth. VMs generally do not involute (with the exception of nevus simplex), and their growth may be influenced by trauma, infection, and hormonal changes.

Lymphatic Malformations

Lymphatic malformations (traditionally known as “lymphangiomas”) are benign, low‐flow lesions consisting of malformed, dilated lymphatic channels or cysts of varying sizes. These abnormal structures do not communicate with the rest of the lymphatic or venous systems, resulting in lymphedema, lymphangiectasia, and proliferation in the affected area. The majority of the lymphatic malformations are congenital and are due to the abnormal development of lymphatic jugular sacs. Acquired lesions are thought to arise as a result of trauma or respiratory infection. The reported incidence ranges from 1 in 500 to 1 in 4000 live births.⁴¹ Lymphatic malformations are usually diagnosed at birth or before 2 years of age.⁴² Two‐thirds of the cases occur in the head and neck region.^43,44

Lymphatic malformations are classified into three types: microcystic, macrocystic (cysts >2 cm, formerly known as cystic hygroma), and mixed type. Microcystic lesions are commonly found above the level of the mylohyoid muscle, while macrocystic lesions are typically located below the level of the mylohyoid muscle and involve the anterior and posterior cervical triangles.^43,44 An intraoral lymphatic malformation is usually of the microcystic type and commonly presents on the anterior portion of the tongue. The condition presents as a cluster of multiple, small, firm, clear vesicles (“pebbly” or “frog’s eggs” appearance) that may infiltrate the underlying subcutaneous tissues and muscles (Figure 25‐4A). The vesicles sometimes appear red or purplish due to secondary bleeding from trauma. A macrocystic lymphatic malformation appears as a smooth, compressible swelling under normal or bluish skin (Figure 25‐4B). The symptoms and the severity of complications vary based on the type, size, depth, and location(s) of the malformation. Fortunately, medically significant lymphatic malformations are rare. The main treatment objectives are restoration and preservation of function and esthetics. The treatment modalities range from observation, drug therapy (e.g., sirolimus), sclerotherapy, laser therapy, and radiofrequency ablation to surgical excision.^45,46 Small lesions that do not affect function and do not cause cosmetic disfigurement are managed conservatively. Large head and neck lymphatic malformations often require intervention, as they may obstruct the airway. Such lesions are extremely difficult to manage (e.g., high risk of complications, incomplete resection) due to their close proximity with adjacent vital structures.

Capillary Malformations

Capillary malformations are low‐flow malformations of the dermal capillaries and postcapillary venules. There are two types of capillary malformations: nevus simplex (macular stain) and nevus flammeus (port‐wine stain).⁴⁷

Nevus simplex is a common condition affecting 40%–60% of newborns and presents as single or multiple, blanchable, pale pink to red patches with indistinct borders. The patch becomes more visible when the infant is crying. Nevus simplex typically occurs on the midline, commonly affecting the eyelid, glabella, and midline of the nape of the neck. Nevus simplex generally fades without treatment within 1–2 years.

Nevus flammeus affects 0.1%–0.3% of newborns and presents as a flat, pink or purple macule with variable blanchability that is most common on the face. The affected area typically has a unilateral distribution that does not cross the midline and frequently follows the distribution of the trigeminal nerve. Nevus flammeus does not regress and grows in proportion to the infant’s growth, becoming darker and nodular (“cobblestone” appearance) with age. Nevus flammeus is usually an isolated condition, but may be associated with other abnormalities (e.g., glaucoma, central nervous system [CNS] involvement) or be part of a syndrome such as in Sturge–Weber syndrome. There are several reports of accompanying oral findings in individuals with facial port‐wine stains and Sturge–Weber syndrome.^48,49 These manifest as unilateral hemangiomatous lesions occurring on the gingiva, lips, tongue, and palate. In a case series of 30 individuals with facial port‐wine stains and corresponding oral lesions, hemorrhage after dental procedures appeared to be low.⁵⁰ The treatment objectives are esthetic improvement and prevention of complications. Pulsed dye laser is considered to be the standard of care for the treatment of nevus flammeus.

Venous Malformations

Venous malformations are the most common low‐flow VMs. The malformation can affect any tissue, but primarily develops in cutaneous, subcutaneous, or mucosal tissues. Approximately 40% occur in the head and neck region. Intraoral venous malformation appears as a slow‐growing, soft, compressible, bluish lesion that may swell with the Valsalva maneuver (Figure 25‐5). Occasionally, phlebolith formation within a venous malformation may occur, thought to be due to trauma or venous stasis.^51,52 Intraoral venous malformations may cause speech and masticatory difficulties if they are on the tongue. Some may be life‐threatening if they are close to vital structures. Venous malformation is frequently misdiagnosed as IH; a detailed history of the presentation at birth and the behavior in the first few months of life will help distinguish the two entities. The treatment modalities include sclerotherapy, laser therapy, compression therapy, and surgical resection.⁵³ The choice of treatment is based on the location and extent of the malformation as well as the individual’s preference.

Arteriovenous Malformations

Arteriovenous malformations (AVMs) are high‐flow VMs that occur due to the abnormal connections of arteries, veins, and capillaries, resulting in a direct arterial and venous communication. AVMs commonly occur in the head and neck region, but overall they are rare.⁵⁴ They are the most dangerous among all the vascular anomalies because they are associated with life‐threatening complications. In the oral cavity, AVMs have been reported to occur on the tongue (most common), floor of the mouth, and palate, as well as the gingival and buccal mucosa.^55,56 An intraoral AVM appears as a soft, blanchable, red to bluish swelling, usually with a palpable thrill or audible bruit. Other oral findings include warmth, tissue expansion and destruction, ulceration, disfigurement, bleeding and pain. Clinically, AVM may be differentiated from IH by the continuous expansile growth after birth and from capillary malformation by the high‐flow rate. The treatment objectives are to control the shunting effect and minimize clinical manifestations and complications. The treatment modalities include embolization and surgical management.⁵⁷

Intraosseous Vascular Malformations

Intraosseous VMs are extremely rare. Fortunately, the majority of intraosseous VMs are predominantly venous malformations and AVMs are uncommon.^58–60 Intraosseous AVM is the more serious condition because of the risk for catastrophic hemorrhage after a dental extraction or a routine biopsy.^61–63 Affected individuals frequently present with pain, facial swelling and asymmetry, skin discoloration, loose teeth, bleeding from the gingival sulcus or associated with erupting teeth, and audible or palpable pulsations. Intraosseous venous malformation is a slow‐growing, indolent mass with variable intraoral presentations depending on the location and extent. The condition may be totally asymptomatic or present with signs and symptoms similar but milder than that observed in an intraosseous AVM. Radiographically, intraosseous VM commonly appears as a unilocular or multilocular radiolucency, with each locule having a “soap bubble” or “honeycomb” appearance. A “sunburst” radiographic pattern may be observed with larger malformations. Teeth in the affected area may show root resorption. In addition to the treatment modalities for mucosal VMs, partial or total jaw resections may be indicated.^63,64

Lip Anomalies

Tongue Anomalies

Ankyloglossia

Ankyloglossia or tongue tie is a developmental abnormality characterized by a short lingual frenum or a frenum attachment at or near the tongue tip, resulting in restricted tongue movement. Posterior ankyloglossia is a widely used term to specifically refer to a frenulum attachment at the middle to posterior aspect of the undersurface of the tongue. The use of the term “posterior ankyloglossia” is discouraged, because the frenulum attachment may be normal in these cases and the associated feeding difficulties are likely caused by other factors. The term “symptomatic ankyloglossia” is thus more appropriate. The reported prevalence of ankyloglossia ranges widely from <1% to 12%, with a male predilection.^68,69 The diagnosis has increased significantly in the past two decades due to the increased advocacy of breastfeeding coupled with the awareness of the impact of ankyloglossia on breastfeeding.⁷⁰

There are generally two classification systems used to grade ankyloglossia severity: those that utilize anatomic criteria such as point of tongue attachment and length of frenulum (e.g., Coryllos system, Kotlow system) and those that incorporate function in addition to anatomic criteria (e.g., Hazelbaker Assessment Tool for Lingual Frenulum Function, Bristol Tongue Assessment Tool).⁶⁸ Classification systems that incorporate function are generally preferred, but so far none is universally accepted. The clinical examination often reveals the presence of a heart‐shaped tongue on protrusion or the inability of the tongue to touch or protrude beyond the vermillion border. Infants with ankyloglossia are reported to experience more difficulty with breastfeeding. In such cases, frenotomy, which involves elevating the tongue, isolating the frenulum with a retractor/gloved fingers, and cutting of the frenulum with scissors, may be performed. Hemostasis is easily achieved with the application of pressure with gauze. Frenotomy may also be carried out with a laser or electrocautery. A randomized clinical trial concluded that topical anesthesia is not beneficial for pain relief. Instead, 24% sucrose solution given orally before the procedure accompanied by postprocedure nonnutritive sucking can help reduce discomfort.⁷¹ Complications are rare, but may include bleeding (most common), pain, injury to the Wharton ducts, infection, and recurrence. The association between ankyloglossia and articulation problems, malocclusion, gingival recession, and mandibular growth is not clearly defined. A recent systematic review concluded that there was insufficient evidence to support frenotomy for these conditions.^72,73

Retrocuspid Papillae

The retrocuspid papilla is a small (2–3 mm), moderately firm, smooth‐surfaced, sessile, round, pink (normal gingival color) to red papule located on the attached lingual gingiva of the mandibular canine. They often occur bilaterally and are observed more frequently in children and females. The reported prevalence ranges from 25% to 80%. The histologic examination reveals large, stellate‐shaped, multinucleated fibroblasts that are similar to those observed in giant cell fibroma.⁸⁰ The diagnosis is made clinically based on the bilateral presentation and location. Retrocuspid papillae are asymptomatic and spontaneously resolve with age. No treatment is needed.

Café‐au‐Lait Pigmentation

Café‐au‐lait pigmentation appears as well‐circumscribed, uniformly light to dark brown skin macules that are typically two to three shades darker than the normal skin color. They vary from a few millimeters to ≥10 cm and can occur anywhere on the body. Café‐au‐lait pigmentation is often present at birth or appears in the first months of life. Isolated macules are common and usually have no clinical significance. However, multiple café‐au‐lait spots or macules should prompt evaluation for underlying genetic disorders such as Peutz–Jeghers syndrome, McCune–Albright syndrome, or neurofibromatosis type 1.^81,82 The outline of the café‐au‐lait spots may provide a clue as to the underlying genetic disorder. Café‐au‐lait spots in McCune–Albright syndrome have characteristic irregular borders analogous to the coast of Maine, unlike the smooth borders of the hyperpigmentation in neurofibromatosis, which is analogous to the coast of California. Multiple mucosal pigmentations on the lips and buccal mucosa have also been observed in these genetic disorders.⁸³ Of these disorders, perioral pigmentation is a prominent feature in Peutz–Jeghers syndrome. The intraoral pigmentation associated with genetic conditions, especially those on the buccal mucosa, do not fade and tend to persist with age.⁸¹ Another case report suggested that intraoral pigmentations associated with genetic disorders appeared to develop later in life compared to the cutaneous café‐au‐lait pigmentation.⁸⁴

Congenital Lingual Melanotic Macule

Congenital lingual melanotic macule (CLMM) is a rare benign condition that was first described in 2003.⁸⁵ The prevalence is unknown. CLMM (Figure 25‐7) is present at birth and appears as a homogeneous or heterogeneous, 2–5 mm brown or black macule on the midline or the lateral border of the tongue. The size appears to increase with the infant’s growth. The histologic examination reveals increased melanin deposition in the basal cell layer and varying degrees of hyperkeratosis.⁸⁶ The diagnosis is often made clinically based on the characteristic appearance and the presence at birth. No treatment is required other than routine reviews to ensure that the macule has not rapidly increased in size or demonstrated any signs of induration or ulceration. A biopsy is indicated if the macule displays these signs and symptoms.

Physiologic Pigmentation

Physiologic pigmentation is common among darker‐skinned individuals and results from an increase in melanin production. The attached gingiva is the most common location, where it appears as a homogeneous, ribbon‐like band of light brown to almost black pigmentation. Physiologic pigmentation may be observed elsewhere in the oral cavity, including the tips of the fungiform papillae. The color appears to darken with age. The diagnosis is made clinically and no treatment is required.

Genetic Disorders with Significant Oral Mucosal Findings

Hereditary Gingival Fibromatosis

Hereditary gingival fibromatosis (HGF) is a rare condition characterized by a slow, progressive gingival enlargement due to the collagenous overgrowth of connective tissue. The incidence ranges greatly between 1 in 175,000 to 1 in 750,000 live births. HGF may be an isolated disorder with an autosomal dominant or recessive mode of inheritance (less common), or may occur as part of a syndrome (Table 25‐4).⁸⁷ The gingival enlargement is asymptomatic and the enlarged gingival tissue is firm, fibrotic, and pink in color (normal mucosal color). There is minimal inflammation. The location of the gingival enlargement may be generalized or localized to either a quadrant or the interdental papillary area. The condition is rarely present at birth and the onset appears to correlate with the eruption of the permanent dentition, though there have been reports of earlier onset coinciding with the eruption of the deciduous dentition. The gingival enlargement worsens during adolescence, suggesting a hormonal influence. The complications include mastication and speech difficulties as well as teeth displacement. The diagnosis is usually made clinically based on presentation, family history, and exclusion of drug‐induced causes of gingival enlargement. For minimal gingival enlargement, regular professional dental cleaning and a good oral hygiene home‐care program are often adequate. Gingivectomy may be carried out for more extensive involvement, but repeated interventions are needed due to recurrence.

Multiple Neuroendocrine Neoplasia Type 2B

Multiple endocrine neoplasia syndromes (MENs) are a group of rare autosomal dominant disorders classified into types 1, 2A, 2B (formerly type 3), and 4 based on the genetic mutations and phenotypic features. The estimated prevalence of MEN type 2 is 1 in 30,000 and the disorder is due to a mutation in the RET proto‐oncogene. This mutation causes a gain of function, resulting in increased cell proliferation and abnormal division in tissues where the RET proto‐oncogene is expressed (i.e., thyroid, parathyroid, adrenal glands). Oral findings are prominent features in MEN type 2B, typically occurring in the first decade of life, and are often the first signs of the syndrome. The oral findings present as multiple asymptomatic, pink or mucosal‐colored nodules or papules (“oral neuromas”).⁹² They are frequently located on the labial mucosa or anterior tongue,^93,94 but may also be observed on the buccal mucosa, gingiva, or palate. The presence of bilateral neuromas on the commissures of the lips is characteristic for MEN type 2B.⁹⁵ The histologic examination of the neuroma reveals an encapsulated mass of myelinated and unmyelinated nerves in a connective tissue background.⁹⁶ Other clinical features include full lips, thickened eyelids, high‐arched palate, and a marfanoid body habitus. A serious complication in all individuals with MEN type 2B is the early development of aggressive medullary thyroid carcinoma (MTC).⁹⁷ Approximately 50% will also develop pheochromocytoma. A preliminary diagnosis of MEN type 2B is made based on the clinical presentation and confirmed with genetic testing. The treatment objectives are early diagnosis and prophylactic thyroidectomy at an early age (usually during the first year of life). Those who do not undergo thyroidectomy are likely to develop metastatic MTC. No treatment is necessitated for the oral neuromas as they are benign. They may be surgically excised if they interfere with function or for esthetic reasons.

Syndrome87	Inheritance	Features Apart from Gingival Enlargement
Costello syndrome88	Autosomal dominant	Coarse facial features including relative macrocephaly, high forehead, bi‐temporal narrowing, hypertelorism, short nose with depressed nasal bridge, large mouth with thick upper lip vermillion, low‐set ears Nasal and perioral papillomas Redundant skin on neck, hands, and feet Short stature
Cross syndrome	Autosomal recessive	Athetosis Hypopigmentation Intellectual disability
Amelogenesis imperfecta, type Ig (Enamel–renal–gingival syndrome)89	Autosomal recessive	Amelogenesis imperfecta Nephrocalcinosis
Gingival fibromatosis with hypertrichosis	Autosomal dominant	Hypertrichosis Intellectual disability
Hyaline fibromatosis syndrome90 (Figure 25‐8)	Autosomal recessive	Joint stiffness and contractures Osteopenia Pink papules on chin, nasolabial folds, forehead, ears, and back of neck Subcutaneous nodules Systemic manifestations, e.g., failure to thrive, persistent diarrhea, recurrent infections
Jones syndrome	Autosomal dominant	Progressive sensorineural hearing loss
Ramon syndrome	Autosomal recessive	Cherubism Epilepsy Hypertrichosis Intellectual disability Juvenile rheumatoid arthritis Ocular abnormalities Stunted growth
Rutherford syndrome	Autosomal dominant	Corneal dystrophy Delayed tooth eruption
Zimmermann–Laband syndrome91	Autosomal dominant	Dysplastic or absent nails Ear and nose defects Hepatosplenomegaly Hirsutism Hypoplasia of distal phalanges Joint hyperextensibility Scoliosis

Genodermatoses

Genodermatoses are a large group of inherited skin disorders. Many of these disorders have accompanying oral findings, which are discussed in this section.

Cowden Syndrome (Multiple Hamartoma Syndrome)

Cowden syndrome is an autosomal dominant disorder characterized by the distinctive mucocutaneous findings of trichilemmomas, acral keratosis, as well as facial and oral papillomatous papules. The estimated prevalence is 1 in 200,000 to 1 in 250,000. The majority of cases are due to a mutation in the PTEN gene. The PTEN gene is considered to be a tumor suppressor gene and the loss of function results in uncontrolled cell proliferation. The age of onset of the skin and oral findings ranges from 4 to 75 years of age, but is most commonly noticed in the second decade of life. The oral findings present as multiple asymptomatic papules on the gingiva, buccal mucosa, and tongue in up to 80% of affected individuals and impart a “cobblestone” appearance to the affected surfaces. This oral presentation has been termed “oral papillomatosis” or “fibropapillomatosis.”^83,98 A recent study suggested that the etiology of the oral papillomatous papules may be related to the human papilloma virus.⁹⁹ Other dental findings include high‐arched palate, increased risk of periodontal disease, and dental caries.¹⁰⁰ The systemic presentations include hamartomas in multiple organ systems, gastric and intestinal polyps, increased risk for breast (most common), thyroid, endometrial, and renal carcinomas, macrocephaly, and cognitive delay. The National Comprehensive Cancer Network clinical criteria are often used to obtain a preliminary diagnosis of Cowden syndrome.^101,102 Follow‐up genetic testing should be performed to confirm diagnosis if the individual fulfills the criteria. The treatment objectives include close cancer surveillance and genetic counseling. No treatment is usually needed for the mucocutaneous lesions as they are benign. Surgical excision may be carried out for esthetic reasons or if the lesions interfere with function.

Dyskeratosis Congenita (Zinsser–Engman–Cole Syndrome)

Dyskeratosis congenita (DC) is a rare inherited disorder characterized by the classic triad of mucocutaneous features: dystrophic nails, oral leukoplakias, and reticular skin hyperpigmentation. Three modes of inheritance are recognized: X‐linked recessive, autosomal dominant, and autosomal recessive. The estimated incidence is 1 in 1,000,000 live births. DC is caused by a defect in the telomere complex resulting in genomic instability and premature cell death. Several genetic mutations have been reported, including ACD, CTC1, DKC1, NHP2, NOP10, PARN, RTEL1, TERC, TERT, TINF2, and WRAP53.¹⁰³ The oral lesions in DC present as bullae on the tongue or buccal mucosa that rupture to form erosions or ulcers (Figure 25‐9). The chronic cycle of mucosal breakdown and healing eventually results in the development of generalized intraoral white plaques (oral leukoplakia).^83,104 The tongue is the most frequently affected site. Oral leukoplakias are present in 65%–80% of individuals with DC, including those younger than 15 years of age. One‐third of the oral leukoplakias will become malignant within a 10–30‐year period.⁸³ In addition to the increased risk for head and neck squamous cell carcinoma, individuals with DC are at an increased risk for hematologic (e.g., leukemia, myelodysplastic syndrome)¹⁰⁵ and solid organ malignancies (e.g., lung, stomach). Other reported oral/dental findings include complete loss of papillae on the tongue, spontaneous oral bleeding, intraoral pigmentation, oral lichenoid changes, aggressive periodontitis, decreased crown‐to‐root ratio, increased risk of dental caries, hypodontia, and taurodontism.^106–108 DC is usually diagnosed between the ages of 5 and 12 years and is made based on the classic mucocutaneous features. Reticulate hypopigmentation involving the chest and neck, and small thin nails with longitudinal ridges that fade with age, are the typical initial findings. The management of DC is based on the involved organ systems. Early diagnosis and referral to a hematologist are essential because of the risk of bone marrow failure. Hematopoietic cell transplantation is the definitive treatment for bone marrow failure associated with DC, but this does not resolve the oral lesions. The use of topical corticosteroids and thalidomide for oral ulcers in both children and adults has been reported with variable effectiveness.¹⁰⁵ As the oral leukoplakias in individuals with DC have a 1000‐fold increased risk of malignant transformation compared to the general population, a comprehensive oral mucosal examination should be performed every 6 months.¹⁰⁹ Biopsy is indicated if the oral leukoplakic areas demonstrate clinical features suspicious for malignant changes (i.e., thickening surface, granular or verruciform surface, erythroplakia).

Epidermolysis Bullosa

Epidermolysis bullosa (EB) is a genetically diverse group of disorders characterized by epithelial fragility resulting in blisters and ulcers after minor trauma. The estimated incidence is 1 in 50,000 live births. EB is classified into four main types based on the level of blister formation: EB simplex (most common; Figure 25‐10), junctional EB, dystrophic EB, and Kindler syndrome.¹¹⁰ Within each type, there are various subtypes that are further classified based on the inheritance pattern, the defective protein, and phenotypic features.¹¹¹ Table 25‐ 5 summarizes the key findings of the various EB subtypes. The diagnosis of EB is confirmed by skin biopsy with immunofluorescence microscopy. Some cases may require transmission electron microscopy or mutational analysis to identify the level of cleavage and subtype. There is no cure for EB and the treatment strategies are largely supportive (e.g., pain control, wound care, prevention of secondary infections). Oral healthcare is an integral component of the multidisciplinary care needed for individuals with EB because of their increased risk for dental caries (due to difficulty in maintaining adequate oral hygiene) and oral malignancies. The general dental management includes emphasis on preventive care (e.g., diet counseling, placement of fissure sealants, alcohol‐free fluoride rinses, fluoride varnish) and regular professional oral examinations. Special precautions are needed during dental visits to minimize injury to the oral mucosa. Copious lubrication of the oral tissues, gloves, radiographic films, and instruments as well as contact avoidance of suction tips on mucosal tissues should be routinely carried out. If blisters form during dental treatment, they may be drained with a sterile needle to limit blister growth.¹¹² The management of the oral ulcers is largely symptomatic (e.g., sucralfate, bland mouth rinses).^113,114 A recent pilot study evaluated the use of cord blood platelet gel with or without low‐level laser therapy and found them safe and effective for the treatment of oral lesions in individuals (mean age: 19 years, range: 9 to 34 years) with EB.¹¹⁵

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Type/ Inheritance	Gene	Defect and Level of Bullae/ Blister Formation	Common Subtypes	Key Findings	Oral Findings
					Blister/ Ulcer (Severity)	Scarring	Microstomia	Enamel Defects	Oral SCCA
EB Simplex/ mostly AD	Common KRT5 KRT14 Rare DSP DYS DST EXPH5 ITGA6 JUP KLHL24 PKP1 PLEC1 TGM5	Mostly caused by keratin defects, which result in a cleavage at the intraepidermal level	Localized Generalized intermediate Generalized severe	Onset at birth or early infancy for generalized types, may be later for localized type Bullae in areas of trauma (e.g., hands, elbows, and feet), which usually heal without scarring for milder types Generalized severe type may have nail and hair abnormalities Usually normal life span	Yes, severity depends on type (Localized: + Generalized: ++)	Localized: No Generalized severe: Yes	No	No	No
EB Junctional/ AR116	Common LAMA3 LAMB3 LAMC2 Others COL7A1 ITG6A ITGB4	Mostly caused by a lack of laminin‐332, which results in a structural defect of the anchoring filament, causing a cleavage at the intralamina lucida level	Localized Generalized intermediate Generalized severe	Onset at birth or early infancy for all types, though milder for localized type Localized type: mild with blistering localized to hands, feet, knees, and elbows that heal without scarring Generalized types: severe widespread mucocutaneous blistering that heals with scarring Generalized severe type is associated with mortality before 1 year of age	Yes, severity depends on type (Localized: ++ Generalized: +++)	Yes	Localized: No Generalized: Yes	Yes	No
EB Dystrophic/ AD or AR117	COL7A1	Mostly caused by collagen type VII defect (main constituent of anchoring fibrils), which results in a cleavage at the sublamina densa level	AD generalized AR generalized intermediate AR generalized severe